Oncology Research : Featuring Preclinical and Clinical Cancer Therapeutics

Co-Editors-in-Chief

American Continent:
Edward Chu
Albert Einstein College of Medicine, USA
Email: chueyale@yahoo.com

Asia and Pacific Rim:
Kazuo Umezawa
Aichi Medical University School of Medicine, Japan
Email: umezawa@aichi-med-u.ac.jp

European Continent:
Enrico Mini
University of Florence, Italy
Email: enrico.mini@unifi.it

Associate Editor:  Lois Malehorn

EDITORIAL ADVISORY BOARD

Alan C. Sartorelli,† Founding Editor

American Continent: Edward Chu, Co-Editor-in-Chief
L. J. Appleman, University of Pittsburgh, USA
N. Bahary, University of Pittsburgh, USA
J. R. Bertino, Rutgers Cancer Institute of New Jersey, USA
J. H. Beumer, Hillman Cancer Center, USA
M. Boyiadzis, University of Pittsburgh, USA
Y.-C. Cheng, Yale University School of Medicine, USA
M. S. Copur, University of Nebraska, USA
A. Krishnamurthy, University of Pittsburgh, USA
Y. Li, Sorrento Therapeutics, USA
G. D. Roodman, Indiana University, USA
M. Rudek, Johns Hopkins University, USA
J. C. Schmitz, University of Pittsburgh, USA
N. Wei, University of Pittsburgh, USA
L. Zhang, University of Pittsburgh, USA

European Continent: Enrico Mini, Co-Editor-in-Chief
A. H. Calvert, University of Newcastle upon Tyne, UK
A. Di Paolo, University of Pisa, Italy
D. Longley, Queen’s University, UK
S. Nobili, University of Florence, Italy
J. Robert, Université de Bordeaux, France
J. H. M. Schellens, Netherlands Cancer Institute, the Netherlands
P. Workman, CRC Center for Cancer Therapeutics, UK

Asia and Pacific Rim: Kazuo Umezawa, Co-Editor-in-Chief
A. Deguchi, Tokyo Women’s Medical University, Japan
X. Ding, Nanjing Medical University, China
S. Gantsev, Bashkirian State Medical University, Russia
R. Horie, Kitasato University, Japan
Y. Horiguchi, Tokyo Medical University, Japan
M. Imoto, Keio University, Japan
H. Kakeya, Kyoto University, Japan
M. Kawatani, RIKEN, Japan
E. Kikuchi, Keio University, Japan
K. P. Kim, University of Ulsan College of Medicine, Korea
T. W. Kim, University of Ulsan College of Medicine, Korea
Y. Lin, Aichi Medical University, Japan
J. Neuzil, Griffith University, Gold Coast Campus, Australia
O. Ohno, Kogakuin University, Japan
T. Ohsugi, Rakuno Gakuen University, Japan
H. Osada, RIKEN, Japan
M. Oya, Keio University, Japan
M. Ozaki, Hokkaido University, Japan
Y. Sasazawa, Juntendo University, Japan
W. Seubwai, Khon Kaen University, Thailand
K. Sidthipong, Mahidol University, Thailand
S. Simizu, Keio University, Japan
M. Takeiri, Ivy Cosmetics, Japan
E. Tashiro, Keio University, Japan
T. Ueno, Tsukuba University, Japan
M. Yamamoto, Waseda University, Japan

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INSTRUCTIONS TO CONTRIBUTORS

Open Access: Oncology Research is an open access journal and follows rules governed by open access publications. Accepted refereed articles published in the journal will be placed on the internet and will be publicly accessible, free of charge. In order to cover the costs of the journal, authors are expected to pay a publication fee. A $50.00 non refundable submission fee is required when your manuscript is sent out for review. You will also be asked to confirm that, if your manuscript is accepted for publication, you will pay the relatively inexpensive open access fee of $600.00 for less than 5 pages, or $1,000.00 for 5–12 pages and $50.00 for each additional page over 12 when billed at proof stage. The Open Access fee entitles the corresponding author to a free PDF file of the final version.

Color Options: Your article may contain figures that should be printed in color. There is a charge for figures appearing in color. The cost is $450.00 for figures appearing in color (this fee is for unlimited figures in one article).

Types of Contributions: The Journal publishes full-length papers and short communications, in English, describing the results of original experiments in basic and clinical cancer research. Commentaries, short research editorials of between 3,000 and 5,000 words in length (12–20 typewritten pages, double-spaced) are also published. These are editorial statements intended to stimulate thought on selected topics and should not be exhaustive reviews. They can be controversial and can focus on areas subject to much activity, or draw attention to relatively neglected fields in which there are both opportunities and the need for research. Authors may present personal views on the state of the subject on which they are reporting, and give their view as to where in the near or distant future the subject may be moving. Authors are encouraged to take issue with popular dogmas. Manuscripts are published in the shortest time possible commensurate with scientific quality.

Submission Requirements: Authors should submit the original manuscript electronically via email to orsubmit@gmail.com  Send the text portion of the manuscript, including tables and figure legends, as an email attachment in Microsoft Word (IBM compatible) format. Send the figures as separate files (Microsoft Word, or as tiff or jpeg). Note that large graphic files, especially color, may need to be compressed (zipped) to send via email.

Include a cover letter, and insert “Oncology Research Submission” in the subject line of the email. The cover letter should contain the name, address, telephone, and fax number and electronic mail address of the author responsible for correspondence. Follow the General Manuscript Form guidelines below to prepare the manuscript, figures, and tables.

Each submitted manuscript is required to include at least three suggested reviewers, with affiliations, and email addresses. Authors should consider carefully their suggested reviewers. Suggested reviewers should not have a conflict of interest for the submitted manuscript, nor have substantial ties to the authors of the manuscript. Email addresses must be from the suggested reviewer’s institutional affiliation, not a non-specific, generic email address. Suggested reviewers should have expertise in the subject matter of the submitted manuscript. Note that the Editors-in-Chief retain the sole right to decide whether or not the suggested reviewers are used.

Manuscripts are accepted for consideration with the understanding that they have not been published elsewhere except in abstract form and are not concurrently under review elsewhere. Material accepted for publication will not be released publicly prior to its appearance in the journal. Authors are notified by the appropriate editorial office if the manuscript is accepted for publication.

General Manuscript Form: Manuscripts should be typed in English, double spaced throughout with at least 3-cm margins. Please consult the most recent issue of the journal for style and format. Number all pages consecutively, beginning with the title page. Use metric units of measure; other units may be given in parentheses. Typically, only three levels of headings are recognized. The manuscript should be organized as follows.

Title Page: The title should be brief and specific. The title page should contain in the following order: title, name(s) and affiliation(s) of author(s) including department institution, city, state, and country, and a suggested short title for the running head of not more than 50 characters and spaces. Also indicate the author to whom correspondence should be addressed and provide complete mailing address, telephone and fax numbers (optional), and e-mail address.

Abstract/Key Words: An abstract of 300 words or less should begin on page 2. It should contain a concise summary of the results, conclusions, and other significant points. For the purpose of subject indexing, provide four to six key words immediately following the abstract.

Text: Arrange the text with main headings of Introduction, Materials and Methods, Results, Discussion, Acknowledgments (and source of funding), References, Tables, Figure legends (together, and separate from the figures), and Figures (or as separate files). Use generic names of drugs. Give name, city and state, and country of the manufacturer of any chemicals, equipment, or software mentioned in the text. Define all nonstandard abbreviations the first time they appear in the text.

References: Literature cited should be prepared according to the Council of Science Editors format (citation-sequence system). This format is conveniently in Endnote and the output style is available at the following site: http://endnote.com/downloads/style/cse-style-manual-7th-ed-citation-sequence. Some examples are provided below. References in the text should be cited by superscript number separated by a comma and listed in numerical order as they appear in the text (double spaced) on a separate page at the end of the manuscript. Journal citations in the reference list should contain the following: (a) reference number (note NOT superscript); (b) surnames and initials of all authors (surnames precede initials); (c) title of article; (d) journal title abbreviated as listed in ISSN.org; (e) year; volume, inclusive pages. See the examples shown and refer to Council of Science Editors format for more examples.

Journal Article:
1. Roth CG, Gillespie-Twardy A, Marks S. Agha M, Raptis A, Hou JZ, Farah R, Lin Y, Qian Y, Pantanowitz L, Boyiadzis M. Flow cytometric evaluation of double/triple hit lymphoma. Oncol Res. 2016;23(3):137-46.
Book:
1. Weinberg RA. The biology of cancer, 2nd ed. New York (NY): Garland Science; 2014.
Book Article/Chapter:
1. Hasskarl J. Sorafenib: Targeting multiple tyrosine kinases in cancer. In: Martens UM, editor. Small molecules in oncology, 2nd ed. Berlin, Germany: Springer-Verlag; 2014. p. 145-164.
Internet Source:
1. Cancer of the Colon and Rectum – SEER Stat Fact Sheets.  Surveillance, Epidemiology, and End Results (SEER) Program Research Data (1973-2011). Rockville (MD): National Cancer Institute; 2014 [accessed 2014 June 30]. http://seer.cancer.gov/statfacts/html/colorect.html

An example of an in-text citation is shown below.

Ovarian cancer is the third most common gynecological malignancy worldwide^1,2.

To cite multiple sources, all numbers associated with the reference being cited should be superscript, separated by a comma, with no spaces between them.

Supplementary Material: Please note that the journal does not host supplementary material. If you wish to include supplementary material, then you will need to provide a link to a permanent hosting site of this material within the manuscript.

Tables: Tables should be numbered and cited sequentially in the text. Prepare each table as a separate page at the end of the manuscript text, after the references. Avoid very wide or long tables that would not fit a printed page. Each table should have a title, and each column in the table should have a brief heading. Define all abbreviations in the table footnote at the bottom of the table.

Figures: Figures should be numbered and cited sequentially in the text. Prepare figures to provide high quality suitable for reproduction. Avoid light lettering and shading that will not reproduce well. Figure dimensions and scaling should be suitable for reduction (if necessary) to fit column or page size. Care must be taken that letters and other symbols do not become so small that they are illegible when the figure is reduced. Complex formulas should be prepared as illustrations. After acceptance final figures should be provided in high resolution. Simple black and white figures (e.g., line graphs, bar graphs, etc.) should be 1200 dpi. Halftone and color figures (or combo figures) should be 600 dpi. Final figure files should be submitted as tiff, jpg, or eps format. Do not include the figure number as part of the figure file (e.g., do not label Figure 1, etc., as part of the figure). Do not provide color in a figure file unless the figure will be printed in color (note there is a cost for printing figures in color).  (Do not embed figures within the manuscript text. Prepare as separate files or at the end of the manuscript, after tables and figure legends.) There is a cost to reproduce figures in color. The author is required to bear the costs for the publication of color figures (costs and color authorization form will be provided at proof stage).

Figure Legends: List all figure legends sequentially on one or more pages at the end of the manuscript text, after the references, and identify all symbols used in the figures. The figure legend should be as clear as possible and should fully describe the contents of the figure. (Do not include the figure legend as part of the figure.) If the figure is from a previously published article, indicate that permission has been obtained from the original publisher.

Use of Animal- and Human-derived tissue: Please confirm within the text that the appropriate ethical and/or regulatory body approved the use of animal- or human-derived tissue (as well as informed consent for humans). With human-derived data, articles are published on the understanding that appropriate measures to protect the privacy of the individuals were undertaken.

Permissions: If data from any other source is used in tables or figures it is the responsibility of the author(s) to obtain permission to reproduce such material. Provide proof that permission has been granted from the original publisher and indicate the source.

Page Proofs/Offprints: All material accepted for publication is subject to copyediting. Authors will receive page proofs of articles before publication, along with a Contributor’s Publishing Agreement, Open Access authorization form (with the final cost based on number of printed pages) and Color Figure authorization form (if there are potential color figures), which will need to be completed and returned before the article can be processed for publication. Only minor corrections are allowed at proof stage. Author can also request an offprint order form for ordering offprints or additional journal copies.

Copyright: Publications are copyrighted for the protection of authors and the publisher. A Transfer of Copyright Agreement will be sent to the corresponding author whose manuscript is accepted for publication. The form must be completed and returned with the final manuscript files(s).

Online Fast Track Publication: Accepted manuscripts will be loaded to Fast Track with DOI links online. Fast Track is an early e-pub system whereby subscribers to the journal can start reading and citing the articles prior to their inclusion in a journal issue. Please note that articles published in Fast Track are not the final print publication with proofs. Once the accepted manuscript is ready to publish in an issue of the journal, the corresponding author will receive a proof from our Production Department for approval. Once approved and published, the Fast Track version of the manuscript is deleted and replaced with the final published article. Online Fast Track publication ensures that the accepted manuscripts can be read and cited as quickly as possible.

Oncology Research (OR) Peer Review Policy

Peer review is the evaluation of scientific, academic, or professional work by others working in the same field to ensure that only good scientific research is published.

In order to maintain these standards, Oncology Research Featuring Preclinical and Clinical Cancer Therapeutics (OR) utilizes a single blind review process whereby the identity of the reviewers is not known to the authors but the authors are shown on the article being reviewed.

The peer review process for OR is laid out below:

A submitted article is forwarded to one of the Co-Editors (CE) based on the article’s country of origin. The CE determines if the article is within the scope of OR and whether it meets the basic standards of research.

If it is determined that the article should be forwarded to reviewers, the CE provides the Associate Editor (AE) with the names and contact information of at least two suggested reviewers for detailed peer review. The reviewers are always experts in their field and could be part of the OR editorial board. All reviewers would lack any conflict with the authors and are reviewers in good standing based on previous track record and history. Authors may not suggest reviewers; however, they are allowed to suggest reviewers to be avoided due to a potential conflict of interest.

Comments from the reviewers (minimum 2 reviewers) are expected in 2 weeks or less and are delivered to the AE. After the minimum is met, reviews are forwarded to the CE assigned to the submission. The CE then assesses the merit of the manuscript based on these comments as well as on their own assessment of the article. Special attention is given to declaration of conflict of interest if any.

If relevant, statements on use of appropriate animal protocol approved by institutional regulatory boards and inclusion of appropriate IRB approvals in cases of human studies are verified. Likewise, appropriate comments on use of appropriate statistical tests are ensured.

The CE provides the AE with their determination and authors receive detailed comments along with the final decision of:  accept, accept with minor revision, accept with major revision, or rejection. The comments to authors are blinded.

As a reviewer for OR you would have the benefit of reading and evaluating current research in your area of expertise at its early stage, thereby contributing to the integrity of scientific exploration. If you are interested in becoming a reviewer for OR, please contact the Editor-in-Chief Edward Chu, University of Pittsburgh, USA at chueyale@yahoo.com

Ethics Statement

The publishers and editorial board of Oncology Research have adopted the publication ethics and malpractice statements of the Committee on Publication Ethics (COPE) https://publicationethics.org/core-practices. These guidelines highlight what is expected of authors and what they can expect from the reviewers and editorial board in return. They also provide details of how problems will be handled. Briefly:

Author Responsibilities: Authors listed on a manuscript must have made a significant contribution to the study and/or writing of the manuscript. During revisions, authors cannot be removed without their permission and that of the other authors. All authors must also agree to the addition of new authors.  It is the responsibility of the corresponding author to ensure that this occurs.

Financial support and conflicts of interest for all authors must be declared.  Further information on this can be obtained from the International Committee for Medical Journal Editors (http://www.icmje.org/).

The reported research must be novel and authentic and the authors should confirm that the same data has not been and is not going to be submitted to another journal (unless already rejected).  Statements made in the introduction and discussion should be supported by appropriate references and sufficient experimental detail should be provided to allow for repetition of the study by another group. Plagiarism of the text/data will not be tolerated and could result in retraction of an accepted article. Any text or figures reproduced for another source require the permission of the original copyright holders (normally the publishers).

Any manipulation of figures should be equally applied and described in the text including pseudo-coloring and must not change the meaning of the figure.

When humans, animals or tissue derived from them have been used, then mention of the appropriate ethical approval must be included in the manuscript.

Author must sign a Transfer of Copyright form giving rights to the Publisher, at proof stage.

Reviewer Responsibilities: Reviewers are expected to not possess any conflicts of interest with the authors and research. They should review the science objectively and provide recommendations for improvements where necessary. When aware of relevant published work not being cited, the reviewers should recommend inclusion of these references.  If the reviewer feels that they would be unable to repeat the study as described, then additional methodological details should be requested. Any unpublished information read by a reviewer should be treated as confidential.

Editorial Responsibilities: The section editors are expected to select an appropriate number of reviewers for the manuscript so that they can make an informed decision about whether to reject/accept a manuscript. Their decision must be based only on the paper’s importance, originality and clarity and whether it is suitable for the journal. They must not have a conflict of interest with the authors or work described. The anonymity of the reviewers must be maintained.

Should problems come to light after acceptance then the editors agree to promote the publication of corrections and/or retractions as deemed necessary.

NIH Public Access Policy: Cognizant Communication Corporation uploads published manuscripts on the authors’ behalf to PubMed Central so authors may remain in compliance with the NIH Public Access Policy.

Publishing Responsibilities: The publishers agree to ensure that to the best of their abilities, the information that they publish is genuine and ethically sound. If publishing ethics issues come to light, not limited to accusations of fraudulent data or plagiarism, during or after the publication process, they will be investigated by the editorial board including contact with the authors’ institutions if necessary, so that a decision on the appropriate corrections, clarifications or retractions can be made. The publishers agree to publish this as necessary so as to maintain the integrity of the academic record.

View All Abstracts

Access Current Articles (Volume 28, Numbers 7-8)

Curcumol Inhibits Lung Adenocarcinoma Growth and Metastasis via Inactivation of PI3K/AKT and Wnt/β-Catenin Pathway – 685
DOI: https://doi.org/10.3727/096504020X15917007265498

Sheng Li,* Guoren Zhou,* Wei Liu,† Jinjun Ye,† Fangliang Yuan,‡ and Zhi Zhang‡

*Department of Chemotherapy, Jiangsu Cancer Hospital and Jiangsu Institute of Cancer Research and Nanjing Medical University Affiliated Cancer Hospital, Nanjing, P.R. China
†Department of Radiotherapy, Jiangsu Cancer Hospital and Jiangsu Institute of Cancer Research and Nanjing Medical University Affiliated Cancer Hospital, Nanjing, P.R. China
‡Department of Thoracic Surgery, Jiangsu Cancer Hospital and Jiangsu Institute of Cancer Research and Nanjing Medical University Affiliated Cancer Hospital, Nanjing, P.R. China

Curcumol (Cur), isolated from the Traditional Chinese Medical plant Rhizoma Curcumae, is the bioactive component of sesquiterpene reported to possess antitumor activity. However, its bioactivity and mechanisms against lung adenocarcinoma are still unclear. We investigated its effect on lung adenocarcinoma and elucidated its underlying molecular mechanisms. In vitro, Cur effectively suppressed proliferation, migration, and invasion of lung adenocarcinoma cells A549 and H460, which were associated with the altered expressions of signaling molecules, including p-AKT, p-PI3K, p-LRP5/6, AXIN, APC, GSK3b and p-b-catenin, matrix metalloproteinase (MMP)-2, and MMP-9. Furthermore, Cur significantly induced cell apoptosis of A549 and H460 by promoting the expression of Bax, caspase 3, and caspase 9 and suppressing the expression of Bcl-2, and arrested the cell cycle at the G₀/G₁ phase by lowering the levels of cyclin D1, CDK1, and CDK4. In vivo experiment revealed that Cur could inhibit lung tumor growth and lung metastasis, which were consistent with these in vitro results. In xenograft model mice, Cur strongly decreased tumor weight and tumor volume, which may be related to the downregulation of p-AKT and p-PI3K by immunofluorescence analysis. In addition, a lung metastasis model experiment suggested that Cur dramatically decreased the ratio of lung/total weight, tumor metastatic nodules, and the expressions of MMP-2 and MMP-9 in lung tissues compared with the control. Overall, these data suggested that the inhibitory activity of Cur on lung adenocarcinoma via the inactivation of PI3K/Akt and Wnt/β-catenin pathways, at least in part, indicates that curcumol may be a potential antitumor agent for lung adenocarcinoma therapy.

Key words: Curcumol; Lung adenocarcinoma; Proliferation; Metastasis; PI3K/AKT; Wnt/β-catenin

Prognostic Value of EGFR Expression for Patients With Stage III Colorectal Cancer Receiving Fluoropyrimidine Metronomic Maintenance Therapy After Radical Resection and Adjuvant Oxaliplatin-Based Chemotherapy – 701
DOI: https://doi.org/10.3727/096504020X15986099915822

Ching-Wen Huang,* Cheng-Jen Ma,*† Wei-Chih Su,* Yi-Ting Chen,‡§ Hsiang-Lin Tsai,*¶ Yung-Sung Yeh,*# Tsung-Kun Chang,* Wen-Hung Hsu,**†† Fang-Jung Yu,**†† and Jaw-Yuan Wang*¶‡‡§§¶¶##

*Division of Colorectal Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
†Division of General and Digestive Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
‡Department of Pathology, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
§Department of Pathology, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
¶Department of Surgery, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
#Division of Trauma and Surgical Critical Care, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
**Division of Gastroenterology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
††Department of Internal Medicine, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
‡‡Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
§§Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
¶¶Clinical Pharmacogenomics and Pharmacoproteinomics, College of Pharmacy, Taipei Medical University, Taipei, Taiwan
##Center for Cancer Research, Kaohsiung Medical University, Kaohsiung, Taiwan

This study evaluated the survival effects of metronomic maintenance therapy with oral fluoropyrimidine in patients with stage III colorectal cancer (CRC) according to epidermal growth factor receptor (EGFR) expression. We enrolled 197 patients with stage III CRC who had undergone radical resection and FOLFOX regimen adjuvant chemotherapy. The clinicopathological features and effects of metronomic maintenance therapy with oral capecitabine (daily dose of 850 mg/m², twice daily, on days 1–14 every 3 weeks for 6 months) on survival according to treatment group and EGFR expression were analyzed. By conducting an in vitro cell line study and in vivo study through knockout of the EGFR gene, we analyzed the capacities of cell proliferation and migration. Relapse and survival were significantly more common in the FOLFOX group. Metronomic maintenance therapy was a significantly independent associated factor of relapse and survival as well as a prognostic factor of disease-free survival and overall survival. Significant intergroup differences in survival were only observed in patients with positive EGFR expression. Thus, our findings suggest EGFR expression is a prognostic factor in patients with stage III CRC receiving metronomic maintenance therapy. Analysis of EGFR expression in these patients helps identify potential candidates who may receive the optimal survival benefit from metronomic maintenance therapy.

Key words: Metronomic maintenance therapy; Capecitabine; Epidermal growth factor receptor (EGFR); Oxaliplatin-based regimen; Stage III colorectal cancer (CRC)

Identification of a Novel Cancer Stemness-Associated ceRNA Axis in Lung Adenocarcinoma via Stemness Indices Analysis – 715
DOI: https://doi.org/10.3727/096504020X16037124605559

Pihua Han,*† Haiming Yang,‡ Xiang Li,* Jie Wu,* Peili Wang,§ Dapeng Liu,* Guodong Xiao,¶ Xin Sun,* and Hong Ren*

*The Second Department of Thoracic Surgery, Cancer Center, the First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, P.R. China
†Department of Breast Surgery, Shaanxi Provincial Cancer Hospital, Xi’an, P.R. China
‡Department of Breast Surgery, Wei Nan Central Hospital, Wei Nan, P.R. China
§Breast Cancer Center, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, P.R. China
¶Department of Oncology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, P.R. China

The aim of this study was to identify a novel cancer stemness-related ceRNA regulatory axis in lung adenocarcinoma (LUAD) via weighted gene coexpression network analysis of a stemness index. The RNA sequencing expression profiles of 513 cancer samples and 60 normal samples were obtained from the TCGA database. Differentially expressed mRNAs (DEmRNAs), lncRNAs (DElncRNAs), and miRNAs (DEmiRNAs) were identified with R software. Functional enrichment analysis was conducted using DAVID 6.8. The ceRNA network was constructed via multiple bioinformatics analyses, and the correlations between possible ceRNAs and prognosis were analyzed using Kaplan–Meier plots. WGCNA was then applied to distinguish key genes related to the mRNA expression-based stemness index (mRNAsi) in LUAD. After combining the weighted gene coexpression and ceRNA networks, a novel ceRNA regulatory axis was identified, and its biological functions were explored in vitro and vivo. In total, 1,825 DElncRNAs, 291 DEmiRNAs, and 3,742 DEmRNAs were identified. Functional enrichment analysis revealed that the DEmRNAs might be associated with LUAD onset and progression. The ceRNA network was constructed with 14 lncRNAs, 10 miRNAs, and 52 mRNAs. Kaplan–Meier analysis identified 2 DEmiRNAs, 5 DElncRNAs, and 41 DEmRNAs with remarkable prognostic power. One gene (MFAP4) in the ceRNA network was found to be closely related to mRNAsi by using WGCNA. Functional investigation further confirmed that the C8orf34-as1/miR-671-5p/MFAP4 regulatory axis has important functions in LUAD cell migration and stemness. This study provides a deeper understanding of the lncRNA–miRNA–mRNA ceRNA network and, more importantly, reveals a novel ceRNA regulatory axis, which may provide new insights into novel molecular therapeutic targets for inhibiting LUAD stem characteristics.

Key words: ceRNA network; Weighted gene correlation network analysis (WGCNA); Stemness index; Lung adenocarcinoma (LUAD)

miR-325-3p Promotes the Proliferation, Invasion, and EMT of Breast Cancer Cells by Directly Targeting S100A2 – 731
DOI: https://doi.org/10.3727/096504020X16100888208039

Huiling Wang,*1 Xin Hu,† Feng Yang,‡ and Hui Xiao*

*Department of Surgery, Hunan Provincial People’s Hospital (The First Affiliated Hospital of Hunan Normal University), Changsha, P.R. China
†Department of Surgery, Hunan Children’s Hospital, Changsha, P.R. China
‡Department of Pharmacy, Hunan Provincial People’s Hospital (The First Affiliated Hospital of Hunan Normal University), Changsha, P.R. China

This study was designed to investigate the precise mechanisms of miR-325-3p/S100A2 axis in breast cancer (BC). In this study, we found that the level of miR-325-3p was dramatically increased in BC tissues and cell lines, and the expression of S100A2 was significantly decreased. Also, the high level of miR-325-3p was closely associated with low expression of S100A2 in BC tissues. Moreover, introduction of miR-325-3p significantly promoted proliferation, invasion, and EMT of BC cells. Bioinformatics analysis predicted that the S100A2 was a potential target gene of miR-325-3p. Luciferase reporter assay demonstrated that miR-325-3p could directly target S100A2. In addition, miR-325-3p overexpression had similar effects with knockdown of S100A2 on BC cells. Overexpression of S100A2 in BC cells partially reversed the promoted effects of miR-325-3p mimic. Overexpression of miR-325-3p promoted cell proliferation, invasion, and EMT of BC cells by directly downregulating S100A2 expression.

Key words: Breast cancer (BC); MicroRNA-325-3p; S100A2; Proliferation; Epithelial–mesenchymal transition (EMT)

Therapeutic Targeting PLK1 by ON-01910.Na Is Effective in Local Treatment of Retinoblastoma – 745
DOI: https://doi.org/10.3727/096504021X16130322409507

Huan Ma,1 Cong Nie,1 Ying Chen, Jinmiao Li, Yanjie Xie, Zhixin Tang, Yang Gao, Siming Ai, Yuxiang Mao, Qian Sun, and Rong Lu

State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-Sen University, Guangzhou, P.R. China

Cell cycle deregulation is involved in the pathogenesis of many cancers and is often associated with protein kinase aberrations, including the polo-like kinase 1 (PLK1). We used retinoblastoma, an intraocular malignancy that lacks targeted therapy, as a disease model and set out to reveal targetability of PLK1 with a small molecular inhibitor ON-01910.Na. First, transcriptomic analysis on patient retinoblastoma tissues suggested that cell cycle progression was deregulated and confirmed that PLK1 pathway was upregulated. Next, antitumor activity of ON-01910.Na was investigated in both cellular and animal levels. Cytotoxicity induced by ON-01910.Na was tumor specific and dose dependent in retinoblastoma cells, while nontumor cells were minimally affected. In three-dimensional culture, ON-01910.Na demonstrated efficient drug penetrability with multilayer cell death. Posttreatment transcriptomic findings revealed that cell cycle arrest and MAPK cascade activation were induced following PLK1 inhibition and eventually resulted in apoptotic cell death. In Balb/c nude mice, a safe threshold of 0.8 nmol intravitreal dosage of ON-01910.Na was established for intraocular safety, which was demonstrated by structural integrity and functional preservation. Furthermore, intraocular and subcutaneous xenograft were significantly reduced with ON-01910.Na treatments. For the first time, we demonstrated targetability of PLK1 in retinoblastoma by efficiently causing cell cycle arrest and apoptosis. Our study is supportive that local treatment of ON-01910.Na may be a novel, effective modality benefiting patients with PLK1-aberrant tumors.

Key words: Retinoblastoma; PLK1 signaling pathway; MAPK signaling pathway; ON-01910.Na; Targeted therapy; Retina safety

(−)-Epigallocatechin-3-Gallate Inhibits EBV Lytic Replication via Targeting LMP1-Mediated MAPK Signal Axes – 763
DOI: https://doi.org/10.3727/096504021X16135618512563

Hongde Li,*†‡ Yueshuo Li,*†‡ Jianmin Hu,*†‡ Sufang Liu,§ Xiangjian Luo,*†‡¶ Min Tang,*†‡ Ann M. Bode,# Zigang Dong,#** Xinqi Liu,†† Weihua Liao,‡‡ and Ya Cao*†‡¶ §§¶¶

*Key Laboratory of Carcinogenesis and Invasion, Chinese Ministry of Education, Department of Radiology, Xiangya Hospital, Central South University, Changsha, P.R. China
†Cancer Research Institute and School of Basic Medical Science, Xiangya School of Medicine, Central South University, Changsha, P.R. China
‡Key Laboratory of Carcinogenesis, Chinese Ministry of Health, Changsha, P.R. China
§Division of Hematology, Institute of Molecular Hematology, the Second Xiangya Hospital, Central South University at Changsha, Changsha, P.R. China
¶Molecular Imaging Research Center of Central South University, Changsha, P.R. China
#The Hormel Institute, University of Minnesota, Austin, MN, USA
**College of Medicine, Zhengzhou University, Zhengzhou, P.R. China
††State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences, Nankai University at Tianjin, Tianjin, P.R. China
‡‡Department of Radiology, Xiangya Hospital, Central South University at Changsha, Changsha, P.R. China
§§Research Center for Technologies of Nucleic Acid Based Diagnostics and Therapeutics Hunan Province, Changsha, P.R. China
¶¶National Joint Engineering Research Center for Genetic Diagnostics of Infectious Diseases and Cancer, Changsha, P.R. China

Epstein–Barr virus (EBV)-encoded latent membrane protein 1 (LMP1) plays an important oncogenic role in the viral latent infection. Recently, increasing evidence indicates that the high expression of LMP1 during EBV lytic cycle is related to the viral lytic replication. However, the mechanism by which LMP1 regulates EBV lytic replication remains unclear. (−)-Epigallocatechin-3-gallate (EGCG) prevents carcinogenesis by directly targeting numerous membrane proteins and effectively inhibits EBV lytic cascade. Here, we demonstrated that LMP1 promotes EBV lytic replication through the downstream signal molecules MAPKs, including ERKs, p38, and JNKs. LMP1 induces the phosphorylation of p53 through MAPKs to enhance the ability of wild-type p53 (wt-p53) to activate expression of BZLF1 gene, while the JNKs/c-Jun signal axis appears to be involved in EBV lytic replication induced by LMP1 in p53 mutant manner. We provided the first evidence that EGCG directly targets the viral membrane LMP1 (K_d = 0.36 μM, n = 1) using fluorescence quenching, isothermal titration calorimetry (ITC) assay, and CNBR-activated Sepharose 4B pull-down affinity chromatography. Furthermore, we revealed that EGCG inhibits EBV lytic replication via suppressing LMP1 and thus blocking the downstream MAPKs/wt-p53 signal axis in AGS-EBV cells and JNKs/c-Jun signal axis in p53 mutant B95.8 cells. Our study, for the first time, reports the binding and inhibitory efficacy of EGCG to the LMP1, which is a key oncoprotein encoded by EBV. These findings suggest the novel function of LMP1 in the regulation of EBV lytic cycle and reveal the new role of EGCG in EBV-associated malignancies through suppressing viral reactivation.

Key words: Latent membrane protein 1 (LMP1); Epstein–Barr virus (EBV) lytic replication; MAPKs; p53; (−)-Epigallocatechin-3-gallate (EGCG)

TBK1 Inhibitor Exerts Antiproliferative Effect on Glioblastoma Multiforme Cells – 779
DOI: https://doi.org/10.3727/096504021X16161478258040

Sarah A. Scuderi,* Marika Lanza,* Giovanna Casili,* Francesca Esposito,† Cristina Colarossi,‡ Dario Giuffrida,‡ Paterniti Irene,* Salvatore Cuzzocrea,* Emanuela Esposito,* and Michela Campolo*

*Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Messina, Italy
†IOM Ricerca Srl, Viagrande, Italy
‡Istituto Oncologico del Mediterraneo Spa, Viagrande, Italy

Glioma are common malignant brain tumors, among which glioblastoma multiforme (GBM) has the worst prognosis. Different studies of GBM revealed that targeting nuclear factor kB (NF-kB) induced an attenuation tumor proliferation and prolonged cell survival. TBK1 {TANK [TRAF (TNF (tumor-necrosis-factor) receptor-associated factor)-associated NF-kB activator]-binding kinase 1} is a serine/threonine protein kinase, and it is a member of the IkB kinase (IKK) family involved in NF-kB pathway activation. The aim of this study was to investigate the potential effect of BX795, an inhibitor of TBK1, in an in vitro and ex vivo model of GBM. GBM cell lines (U87 and U138) and primary GBM cells were treated with different concentrations of BX795 at different time points (24, 48, and 72h) to evaluate cell viability, autophagy, inflammation, and apoptosis. Our results demonstrated that BX795 10 μM was able to reduce cell viability, showing antiproliferative effect in U87, U138, and primary GBM cells. Moreover, treatment with BX795 10 μM increased the proapoptotic proteins Bax, p53, caspase 3, and caspase 9, whereas the antiapoptotic Bcl-2 expression was reduced. Additionally, our results showed a marked decrease in autophagy following BX795 treatment, reducing Atg 7, Atg 5/12, and AKT expression. The anti-inflammatory effect of BX795 was demonstrated by a significantly reduction in NIK, IKKa, and TNF-a expression, accompanied by a downregulation of angiogenesis. Furthermore, in primary GBM cell, BX795 10 μM was able to reduce TBK1 pathway activation and SOX3 expression. In conclusion, these findings showed that TBK1 is involved in GBM proliferation, demonstrating that the inhibitor BX795, thanks to its abilities, could improve therapeutic strategies for GBM treatment.

Key words: Glioblastoma multiforme (GBM); TBK1 (TANK-binding kinase); Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB); IkB kinase subunit epsilon (IKKε)

Excellent Early Outcomes of Combined Chemotherapy With Arsenic Trioxide for Stage 4/M Neuroblastoma in Children: A Multicenter Nonrandomized Controlled Trial – 791
DOI: https://doi.org/10.3727/096504021X16184815905096

Chunmou Li,* Xiaomin Peng,* Chuchu Feng,* Xilin Xiong,* Jianxin Li,† Ning Liao,‡ Zhen Yang,§ Aiguo Liu,¶ Pingping Wu,* Xuehong Liang,† Yunyan He,‡ Xin Tian,§ Yunbi Lin,§ Songmi Wang,¶ and Yang Li*

*Pediatric Hematology/Oncology, Sun Yet-Sen Memorial Hospital, Sun Yet-Sen University, Guangzhou, P.R. China
†Department of Hematology and Oncology, Wuhan Children’s Hospital, Tongji Medical College, Huazhong University of Science & Technology, Wuhan, P.R. China
‡Department of Pediatrics, The First Affiliated Hospital of GuangXi Medical University, Nanning, P.R. China
§Department of Hematology, Kunming Children’s Hospital, Kunming, P.R. China
¶Department of Pediatric Hematology & Oncology, Tongji Medical College, Huazhong University of Science & Technology, Wuhan, P.R. China

This nonrandomized, multicenter cohort, open-label clinical trial evaluated the efficacy and safety of combined chemotherapy with arsenic trioxide (ATO) in children with stage 4/M neuroblastoma (NB). We enrolled patients who were newly diagnosed with NB and assessed as stage 4/M and received either traditional chemotherapy or ATO combined with chemotherapy according to their own wishes. Twenty-two patients were enrolled in the trial group (ATO combined with chemotherapy), and 13 patients were enrolled in the control group (traditional chemotherapy). Objective response rate (ORR) at 4 weeks after completing induction chemotherapy was defined as the main outcome, and adverse events were monitored and graded in the meantime. Data cutoff date was December 31, 2019. Finally, we found that patients who received ATO combined with chemotherapy had a significantly higher response rate than those who were treated with traditional chemotherapy (ORR: 86.36% vs. 46.16%, p = 0.020). Reversible cardiotoxicity was just observed in three patients who were treated with ATO, and no other differential adverse events were observed between the two groups. ATO combined with chemotherapy can significantly improve end-induction response in high-risk NB, and our novel regimen is well tolerated in pediatric patients. These results highlight the superiority of chemotherapy with ATO, which creates new opportunity for prolonging survival. In addition, this treatment protocol minimizes therapeutic costs compared with anti-GD2 therapy, MIBG, and proton therapy and can decrease the burden to families and society. However, we also need to evaluate more cases to consolidate our conclusion.

Key words: Chemotherapy; Arsenic trioxide (ATO); Neuroblastoma (NB); Children; Clinical Trial

A Pilot Study of Silymarin as Supplementation to Reduce Toxicities in Metastatic Colorectal Cancer Patients Treated With First-Line FOLFIRI Plus Bevacizumab – 801
DOI: https://doi.org/10.3727/096504021X16218531628569

Tsung-Kun Chang,*† Tzu-Chieh Yin,‡§ Wei-Chih Su,*† Hsiang-Lin Tsai,*¶ Ching-Wen Huang,*¶ Yen-Cheng Chen,* Ching-Chun Li,* Po-Jung Chen,* Cheng-Jen Ma,*§ Kuo-Hsiang Chuang,# Tian-Lu Cheng,** and Jaw-Yuan Wang*†¶††‡‡§§

*Division of Colorectal Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
†Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
‡Department of Surgery, Kaohsiung Municipal Tatung Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
§Division of General and Digestive Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
¶Department of Surgery, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
#Graduate Institute of Pharmacognosy, Taipei Medical University, Taipei, Taiwan
**Center for Biomarkers and Biotech Drugs, Kaohsiung Medical University, Kaohsiung, Taiwan
††Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
‡‡Center for Cancer Research, Kaohsiung Medical University, Kaohsiung, Taiwan
§§Cohort Research Center, Kaohsiung Medical University, Kaohsiung, Taiwan

Irinotecan, a topoisomerase inhibitor, is a common cytotoxic agent prescribed for metastatic colorectal cancer (mCRC) patients. Diarrhea is the most common adverse event (AE). The underlying mechanism of irinotecan-induced diarrhea is intestinal mucosal damage caused by SN-38 (active metabolite of irinotecan) hydrolyzed from SN-38G (inactive metabolite) by bacterial β-glucuronidase (βG). According to an animal study, silymarin reduces the activity of bacterial βG without impairing antitumor efficacy. We conducted a prospective open-label pilot study to evaluate the effect of silymarin as supplementation in reducing toxicities of mCRC patients undergoing irinotecan-based chemotherapy. We enrolled and randomized 70 mCRC patients receiving first-line FOLFIRI (5-fluorouracil/leucovorin/irinotecan) plus bevacizumab. In each treatment cycle, the study group was administered silymarin capsules (150 mg) three times daily for 7 days. The study group experienced less AEs in diarrhea (5.7% vs. 14.6%, p = 0.002) and nausea (27.0% vs. 40.2%, p = 0.005) in comparison with the control group, but no significant differences in hepatic toxicities were observed. In conclusion, simultaneous administration of silymarin is a potential effective supplementation for reducing toxicities in mCRC patients undergoing first-line FOLFIRI plus bevacizumab, especially in diarrhea and nausea.

Key words: Silymarin; FOLFIRI plus bevacizumab; Metastatic colorectal cancer; Toxicity

Brief Communication

Outcomes of Patients With Acute Myeloid Leukemia Who Relapse After 5 Years of Complete Remission – 811
DOI: https://doi.org/10.3727/096504020X15965357399750

Arisha Patel, Mounzer Agha, Anastasios Raptis, Jing-Zhou Hou, Rafic Farah, Robert L. Redner, Annie Im, Kathleen A. Dorritie, Alison Sehgal, James Rossetti, Melissa Saul, Daniel Normolle, Konstantinos Lontos, and Michael Boyiadzis

Division of Hematology-Oncology, University of Pittsburgh School of Medicine, UPMC Hillman Cancer Center, Pittsburgh, PA, USA

Leukemia relapse 5 years after achieving first complete remission (CR1) is uncommon in patients with acute myeloid leukemia (AML). In this study, we evaluated the outcomes of AML patients with late relapse at our institution and reviewed the literature for these patients. The study cohort consisted of nine AML patients with late relapse. The median interval between CR1 and AML relapse was 6.1 years (range: 5.1–16.2 years). At relapse, the karyotype was different from the initial AML diagnosis in 50% of patients. At the time of AML relapse, seven patients received induction chemotherapy and two patients received hypomethylating agents with an overall CR rate of 66%. The median time to relapse after achieving second CR (CR2) was 16.5 months [95% confidence interval (CI): 9.4, NA]. The median overall survival after first relapse was 28.6 months (95% CI: 7.3, 3.4–66.5 months). Despite initial CR after reinduction therapy, relapse rates are still high, suggesting that alternative strategies for postremission therapies are warranted in CR2. These approaches include the use of allogeneic hematogenic cell transplantation and the use of newly approved AML agents as maintenance therapy in nontransplant eligible patients.

Key words: Acute myeloid leukemia (AML); Late relapse; Prognostic factors; Survival

Erratums

Erratum – 815
DOI: https://doi.org/10.3727/096504021X16240202939988

The following was originally published in Volume 25, Number 1, pages 43–53 (doi: https://doi.org/10.3727/096504016X14719078133285). In the original article there were some inappropriately organized images of Western blots and some images did not show the best experimental results. We have revised the figures to correct these images (Figs. 2A, 4A, 6A, 7B and C, and 8C and D). The figures have been reorganized using images from repeated experiments to rectify the errors. Corrected versions of the figures are shown here and the figures have been replaced with the corrected versions in the original published article in the online site (https://www.ingentaconnect.com/contentone/cog/ or/2017/00000025/00000001/art00006). The corrections do not change any results or conclusion of the article. The authors apologize for any inconvenience caused.

Inhibition of Beclin-1-Mediated Autophagy by MicroRNA-17-5p Enhanced the Radiosensitivity of Glioma Cells

Weichen Hou,* Lei Song,† Yang Zhao,* Qun Liu,* and Shuyan Zhang‡

*Department of Neurology, The First Hospital of Jilin University, Changchun, Jilin Province, P.R. China
†Department of Respiratory Medicine, The First Hospital of Jilin University, Changchun, Jilin Province, P.R. China
‡Department of Neurotrauma, The First Hospital of Jilin University, Changchun, Jilin Province, P.R. China

The role of miRNAs in the radiosensitivity of glioma cells and the underlying mechanism is still far from clear. In the present study, we detected six downregulated and seven upregulated miRNAs in the serum after radiotherapy compared with paired serum samples before radiotherapy via miRNA panel PCR. Among these, miR-17-5p was highly reduced (fold change = −4.21). Further, we validated the levels of miR-17-5p in all serum samples with qRT-PCR. In addition, statistical analysis suggested that a reduced miR-17-5P level was positively associated with advanced clinical stage of glioma, incidence of relapse, and tumor differentiation. Moreover, we provided evidence that irradiation markedly activated autophagy and decreased miR-17-5p in the glioma cell line. Further, we demonstrated that irradiation-induced autophagy activation was mediated by beclin-1, and downregulation of beclin-1 via siRNA significantly abolished the irradiation-activated autophagy. Interestingly, we demonstrated that miR-17-5p could directly target beclin-1 via luciferase gene reporter assay. Exotic expression of miRNA-17-5p decreased autophagy activity in vitro. In nude mice, miRNA-17-5p upregulation sensitized the xenograft tumor to irradiation and suppressed irradiation-induced autophagy. Finally, pharmacal inhibition of autophagy markedly enhanced the cytotoxicity of irradiation in RR-U87 cells.

Key words: Glioma; MicroRNA-17-5p; Beclin-1; Autophagy; Radiosensitivity

Erratum – 819
DOI: https://doi.org/10.3727/096504021X16240202940003

The following was originally published in Volume 25, Number 7, pages 1169–1176 (doi: https://doi.org/10.3727/096504017X14847395834985). In the original article there were some errors in images of flow cytometry analysis and Western blots in Figures 2, 3, 5 and 6. We have revised the figures to correct these images. Corrected versions of the figures are shown here and the figures have been replaced with the corrected versions in the original published article in the online site (https://www.ingentaconnect.com/contentone/cog/or/2017/00000025/00000007/art00014). The corrections do not change any results or conclusion of the article. The authors apologize for any inconvenience caused.

MicroRNA-133a Inhibits Proliferation of Gastric Cancer Cells by Downregulating ERBB2 Expression

Chang Li,* Xiaoping Li,† Shuohui Gao,* Chang Li,‡ and Lianjun Ma§

*Department of Gastrointestinal Internal Medicine, China–Japan Union Hospital of Jilin University, Changchun, P.R. China
†Department of Pediatrics, The First Hospital of Jilin University, Changchun, P.R. China
‡Department of Cadre’s Ward, China–Japan Union Hospital of Jilin University, Changchun, P.R. China
§Endoscopy Center, China–Japan Union Hospital of Jilin University, Changchun, P.R. China

Gastric cancer is the fourth most common type of cancer and the second highest leading cause of cancer-related deaths worldwide. It has already been established that miR-133a is involved in gastric cancer. In this study, we investigated the molecular mechanisms by which miR-133a inhibits the proliferation of gastric cancer cells. We analyzed the proliferative capacity of human gastric cancer cells SNU-1 using an MTT assay. Cell apoptosis was determined using flow cytometry. The expression levels of ERBB2, p-ERK1/2, and p-AKT in SNU-1 cells were determined using Western blot analysis. To confirm that ERBB2 is a direct target of miR-133a, a luciferase reporter assay was performed. Results showed that miR-133a overexpression inhibited SNU-1 cell proliferation and increased apoptosis. ERBB2 was a direct target of miR-133a, and it was negatively regulated by miR-133a. Interestingly, ERBB2 silencing has a similar impact to miR-133a overexpression, in that it significantly induced apoptosis and inhibited ERK and AKT activation. Our study showed that miR-133a inhibits the proliferation of gastric cancer cells by downregulating the expression of ERBB2 and its downstream signaling molecules p-ERK1/2 and p-AKT. Therefore, miR-133a might be used as a therapeutic target for treating gastric cancer.

Key words: MicroRNA-133a (miR-133a); Gastric cancer; ERBB2; p-ERK1/2; p-AKT

Erratum – 823
DOI: https://doi.org/10.3727/096504021X16240202940021

The following was originally published in Volume 26, Number 3, pages 411–420 (doi: https://doi.org/10.3727/096504017X14974343584989). In the original article there were some errors in the display of Figures 2C and 5C. We have revised the figures to correct these figures. Corrected versions of the figures are shown here and the figures have been replaced with the corrected versions in the original published article in the online site (https://www.ingentaconnect.com/content one/cog/or/2018/00000026/00000003/art00008). The errors did not have an impact of the results or conclusions reported in the study. The authors apologize for any inconvenience caused.

MicroRNA-139-5p Inhibits Cell Proliferation and Invasion by Targeting RHO-Associated Coiled-Coil-Containing Protein Kinase 2 in Ovarian Cancer

Yanli Wang,* Jia Li,† Chunling Xu,† and Xiaomeng Zhang†

*Department of Gynecology, The First Hospital of Jilin University, Changchun, P.R. China
†Department of Ophthalmology, The Second Hospital of Jilin University, Changchun, P.R. China

Increasing evidence indicates that the dysregulation of microRNAs is associated with the development and progression of various cancers. MicroRNA-139-5p (miR-139-5p) has been reported to have a tumor suppressive role in many types of cancers. The role of miR-139-5p in ovarian cancer (OC) is poorly understood. The purpose of the present study was to explore the expression of miR-139-5p and its function in OC. The results showed that miR-139-5p expression was markedly downregulated in OC tissues and cell lines. In addition, underexpression of miR-139-5p was significantly associated with FIGO stage, lymph mode metastasis, and poor overall survival of OC patients. Functional analyses indicated that overexpression of miR-139-5p significantly inhibited proliferation, colony formation, migration, and invasion of OC cells. Rho-associated coiled- coil-containing protein kinase 2 (ROCK2) was identified as a direct target of miR-139-5p using luciferase reporter assays, qualitative real-time reverse transcriptase PCR (qRT-PCR), and Western blot. In addition, ROCK2 expression was upregulated and was inversely correlated with miR-139-5p levels in OC tissues. Rescue experiments showed that overexpression of ROCK2 effectively reversed the inhibitory effect of OC cells induced by miR-139-5p. Most interestingly, in vivo studies indicated that miR-139-5p markedly suppressed the growth of tumors by repressing ROCK2 expression in nude mice. Taken together, these findings demonstrated that miR-139-5p plays an important tumor suppressor role in OC by directly binding to ROCK2, providing a novel target for the molecular treatment of OC.

Key words: MicroRNAs; miR-139-5p; Ovarian cancer (OC); ROCK2; Proliferation; Invasion

Erratum – 827
DOI: https://doi.org/10.3727/096504021X16280937554409

The following was originally published in Volume 28, Number 5, pages 467–481 (doi: https://doi.org/10.3727/096504020X15925659763817). In the original article there was misuse of Figure 3C. Because of this error the corrected figure is provided here and the figure has been replaced with the correct version in the original article in the online site (https://www.ingentaconnect.com/contentone/cog/or/2020/00000028/00000005/art00002). We apologize for our carelessness and inconvenience to readers.

Programmed Death Ligand-1 (PD-L1) Regulated by NRF-2/MicroRNA-1 Regulatory Axis Enhances Drug Resistance and Promotes Tumorigenic Properties in Sorafenib-Resistant Hepatoma Cells

Dong Li,* Fei-fan Sun,* Dan Wang,* Tao Wang,* Jing-jing Peng,* Jian-Qiong Feng,* Hua Li,* Chao Wang,† Dai-jun Zhou,* Hong Luo,* Zeng-qiang Fu,* and Tao Zhang*

*Department of Oncology, The General Hospital of Western Theater Command, Chengdu, P.R. China
†Department of Pathology, The General Hospital of Western Theater Command, Chengdu, P.R. China

Sorafenib, a multityrosine kinase inhibitor, is a standard treatment for advanced hepatocellular carcinoma (HCC), but the clinical response to sorafenib is seriously limited by drug resistance. Programmed death ligand-1 (PD-L1) is one of the most important inhibitory molecules involved in tumor immune evasion. Recently, it has been reported that PD-L1 could play crucial roles in drug resistance of many kinds of cancers. However, the expression, function, and regulation of PD-L1 in sorafenib-resistant hepatoma cells remain unclear. In this study, we reported that PD-L1 was overexpressed in sorafenib-resistant hepatoma cells, and shRNA-mediated PD-L1 depletion attenuated drug resistance and suppressed the migration, invasion, colony formation, and tumorigenesis in sorafenib-resistant hepatoma cells in vitro and in vivo. Mechanistic investigations indicated that loss of microRNA-1 (miR-1), a tumor-suppressive microRNA, contributed to the PD-L1 upregulation in sorafenib-resistant hepatoma cells, and PD-L1 was a direct regulatory target of miR-1. Further study revealed that an oncogenic transcriptional factor, nuclear factor E2-related factor 2 (NRF-2), was induced in sorafenib-resistant hepatoma cells and inhibited expression of miR-1 in vitro. From molecular mechanism insight back to the functional verification, we eventually demonstrated that miR-1 executed its tumor-suppressive effects on drug resistance and other malignant properties in sorafenib-resistant hepatoma cells partially by PD-L1 inhibition in vitro and in vivo. In conclusion, our data suggested that a NRF-2/miR-1/PD-L1 regulatory axis contributed to the development and maintenance of drug resistance and other tumorigenic properties in sorafenib-resistant hepatoma cells and provided a potential therapeutic target for overcoming sorafenib resistance in HCC.

Key words: Sorafenib; Drug resistance; PD

Retractions

Retraction – 829
DOI: https://doi.org/10.3727/096504021X16207253542097

Retraction notice to “MicroRNA-98 Plays a Suppressive Role in Non-Small Cell Lung Cancer Through Inhibition of SALL4 Protein Expression” [Oncology Research 25(6) (2017) 975-988]

Wenliang Liu,* Peng Xiao,† Han Wu,* Li Wang,* Demiao Kong,* and Fenglei Yu*

*Department of Thoracic Surgery, Second Xiangya Hospital of Central South University, Changsha, Hunan, P.R. China
†Department of Thoracic Surgery, Third Xiangya Hospital of Central South University, Changsha, Hunan, P.R. China

Retraction Statement: Our research group found several mistakes in the images in this article. We did these experiments in the public laboratory, in which many other research groups also conducted their studies. All images captured by the photograph system were stored in a public computer. One laboratory technician in our study group misused several images, which were found recently. In order to prevent greater impact, we apply for withdrawal of the article. All authors have agreed to retract this article. We deeply apologize for the adverse influence it has brought.

Retraction – 831
DOI: https://doi.org/10.3727/096504020X16231418632584

Retraction notice to “MicroRNA-539 Inhibits the Epithelial-Mesenchymal Transition of Esophageal Cancer Cells by Twist-Related Protein 1-Mediated Modulation of Melanoma-Associated Antigen A4” [Oncology Research 26(4) (2018) 529-536]

Zhili Cao,*1 Xiang Zheng,†1 Lei Cao,* and Naixin Liang*

*Department of Thoracic Surgery, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, P.R. China
†Department of Cardiothoracic Surserv. PeoDle’s Hospital of Beijing Daxing District, Beijing, P.R. China

Retraction Statement: Because of COVID-19, the lab we worked together with was no longer functioning and closed. When reviewing the data of the study completed in cooperation with the original laboratory, we found that some of the data in the above article were not scientific enough, some Western Blot images were not clear enough (as in Fig. 1, the band of a-SMA was blurred and do not seem darker than vimentin but lighter than E-adherin), and some of the research data contained excessive standard errors [as in Fig. 2B, standard error of vimentin and a-SMA of miR-539 mimic+Pb-TWIST1(IV) were too large, so the average of the expression may be not accurate], which may lead to the researchers’ wrong interpretation of the data and misjudgment of its scientific nature. For the sake of rigor, we took the initiative to contact the experimental operator of the original study. Unfortunately, the person who completed the primary operation of the original study has left China to study in the United States. Due to COVID-19 and other reasons, we could not contact this experimenter to confirm the original research data, so we cannot repeat and verify the data for the time being.

Retraction – 833
DOI: https://doi.org/10.3727/096504018X16233193839045

Retraction notice to “High Blood miR-802 Is Associated With Poor Prognosis in HCC Patients by Regulating DNA Damage Response 1 (REDD 1)-Mediated Function of T Cells” [Oncology Research 27(9) (2019) 1025-1034]

Chao Jiang,* Xueyan Liu,† Meng Wang,* Guoyue Lv,* and Guangyi Wang*

*Department of Hepatobiliary Pancreatic Surgery, First Hospital of Jilin University, Changchun, P.R. China
†Department of Cardiology, China-Japan Union Hospital of Jilin University, Changchun, P.R. China

Retraction Statement: When reviewing the data and article, we found that some of the data or writing in the above article were not scientific enough. First, the normal hepatocyte cell lines we used were L02, as shown in Figure 3A, but it was written as THLE-3 cells in the Method section by mistake. Second, the internal reference antibody in Western blot analysis was GAPDH instead of b-actin, which was listed in the article. Those mistakes may lead to the researchers’ wrong interpretation of the data and misjudgment of its scientific nature. For these reasons, the authors have decided to retract the article from the publication. All the named authors on the article agree to this retraction. The authors sincerely apologize for any inconvenience that might result from the retraction of this article.

Retraction – 835
DOI: https://doi.org/10.3727/096504021X16261699250204

MicroRNA-296 Targets Specificity Protein 1 to Suppress Cell Proliferation and Invasion in Cervical Cancer [Oncology Research 26(5) (2018) 775–783]

Lili Lv* and Xiaodong Wang†

*Department of Oncology and Hematology, The Second Hospital of Jilin University, Changchun, Jilin, P.R. China
†Department of Digestive Endoscopy, The Second Hospital of Jilin University, Changchun, Jilin, P.R. China

Retraction Statement: Recently, we found that HeLa and SiHa cell lines used in this study were contaminated by another type of cell line. Thus, we think that this weakened our confidence in this article. Accordingly, we believe it is most appropriate to retract the article at the moment. All authors agree to retract the article, and regret any inconvenience caused to the readership of the journal.

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On behalf of my co-editors, Drs. Mini and Umezawa, we would like to respond to the negative comments that have been recently voiced on social media regarding published material in Oncology Research. As co-editors we can assure the public that we are deeply committed to ensuring a fair and appropriate review process for the journal. When a manuscript is sent out for review, we work hard to identify appropriate reviewers with special expertise in the research area that is covered in the submitted manuscript, and admittedly, we rely heavily on the reviews that are submitted by our expert reviewers. As editors, we then go over the reviews submitted and then make a decision for the manuscript. In the event that a manuscript needs to be revised, we ensure that all of the major reviewers’ comments are addressed and incorporated in the revised manuscript and, in most cases, will return the revised manuscript to the original group of reviewers to make sure that they are in agreement with publication.  Given the recent issues surrounding the possibility of plagiarism, we have now instituted a similarity check process to ensure that the revised manuscript is high-quality, original research. However, the issue with proposing to have a similarity check process is “how does one actually search and find similar blots in all of PubMed?” Many of the identified plagiarized images are from different institutions with different authors. While there has been talk of developing software to find duplicate images, we do not believe that this is yet ready for prime time. We may also get some questions or pushback as to how our journal will actually institute such a process.

In all our collective years of reviewing manuscripts and editing this journal as well as others, we have never faced a situation where so many issues relating to published manuscripts have been identified. We firmly believe in a review process that is transparent, fair, and rigorous, and we believe in publishing high-quality scientific research. We also firmly believe that authors need to take ownership over this process and that they need to be honest and transparent when they submit a manuscript to Oncology Research or any other journal. Unfortunately, with modern technology, it has become even easier for manipulation of scientific data to occur. While we firmly believe in the integrity of the review process, it is clear that there are some authors willing to skirt the truth and present falsified data. As such, we need to be even more rigorous and vigilant in our efforts to review manuscripts. At this time, we will take whatever corrective actions are necessary to ensure the integrity of our journal and our good names as editors. We have already requested that several of the manuscripts under question be retracted and/or for the authors to provide additional information that addresses concerns relating to their published work. We plan to move forward with stricter review and acceptance policies, will remind our reviewers to take an even more rigorous approach to their review of submissions, and will have all potentially accepted manuscripts go through a similarity check to rule out the possibility of plagiarism.

Working together as a team to resolve these various issues, we are highly confident that we can restore the integrity of the journal.

Respectfully,

The Co-Editors of Oncology Research
Edward Chu, Enrico Mini, and Kazuo Umezawa

Updated as of December 2020

Number of submissions:  239
Number of reviews requested:  219
Number of reviews received:  92
Approval rate:  8%
Average time between submission and publication:  9 months