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
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 in addition to a hard copy of the journal issue.

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.

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.

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 chue2@upmc.edu

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.

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.

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Access Current Articles (Volume 28, Number 5)

Volume 28, Number 5

Original Contributions

Pivarubicin Is More Effective Than Doxorubicin Against Triple-Negative Breast Cancer In Vivo – 451
DOI: https://doi.org/10.3727/096504020X15898794315356

Leonard Lothstein,* Judith Soberman,† Deanna Parke,* Jatin Gandhi,* Trevor Sweatman,‡ and Tiffany Seagroves*

*Department of Pathology and Laboratory Medicine, The University of Tennessee Health Science Center, Memphis, TN, USA
†Department of Medicine, The University of Tennessee Health Science Center, Memphis, TN, USA
‡Department of Pharmacology, The University of Tennessee Health Science Center, Memphis, TN, USA

Triple-negative breast cancer (TNBC) is unresponsive to antiestrogen and anti-HER2 therapies, requiring the use of cytotoxic drug combinations of anthracyclines, taxanes, cyclophosphamide, and platinum compounds. Multidrug therapies achieve pathological cure rates of only 20–40%, a consequence of drug resistance and cumulative dose limitations necessitated by the reversible cardiotoxic effects of drug therapy. Safer and more effective treatments for TNBC are required to achieve durable therapeutic responses. This study describes the mechanistic analyses of the novel anthracycline, pivarubicin, and its in vivo efficacy against human primary TNBC. Pivarubicin directly activates PKCd, triggers rapid mitochondrial-dependent apoptosis, and circumvents resistance conferred by overexpression of P-glycoprotein, Bcl-2, Bcl-X_L, and Bcr-Abl. As a consequence, pivarubicin is more cytotoxic than doxorubicin against MDA-MB-231, and SUM159 TNBC cell lines grown in both monolayer culture and tumorspheres. Comparative in vivo efficacy of pivarubicin and doxorubicin was performed in an orthotopic NSG mouse model implanted with MDA-MB-231 human TNBC cells and treated with the maximum tolerated doses (MTDs) of pivarubicin and doxorubicin. Tumor growth was monitored by digital caliper measurements and determination of endpoint tumor weight and volume. Endpoint cardiotoxicity was assessed histologically by identifying microvacuolization in ventricular cardiomyocytes. Primary tumors treated with multiple rounds of doxorubicin at MTD failed to inhibit tumor growth compared with vehicle-treated tumors. However, administration of a single MTD of pivarubicin produced significant inhibition of tumor growth and tumor regression relative to tumor volume prior to initiation of treatment. Histological analysis of hearts excised from drug- and vehicle-treated mice revealed that pivarubicin produced no evidence of myocardial damage at a therapeutic dose. These results support the development of pivarubicin as a safer and more effective replacement for doxorubicin against TNBC as well as other malignancies for which doxorubicin therapy is indicated.

Key words: Pivarubicin; Doxorubicin; Apoptosis; Triple-negative breast cancer (TNBC); Chemotherapy; Cardiotoxicity

Curcumol Inhibits Lung Adenocarcinoma Growth and Metastasis via Inactivation of PI3K/AKT and Wnt/β-Catenin Pathway – 467
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, GSK3β and p-β-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

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 – 483
DOI: https://doi.org/10.3727/096504020X15925659763817

Dong Li,*1 Fei-fan Sun,*1 Dan Wang,*1 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-L1; Hepatoma cells; MicroRNA-1 (miR-1); Nuclear factor E2-related factor 2 (NRF-2)

Proteasome Inhibitors Diminish c-Met Expression and Induce Cell Death in Non-Small Cell Lung Cancer Cells – 497
DOI: https://doi.org/10.3727/096504020X15929939001042

Yanhui Li,*† Su Dong,*† Arya Tamaskar,† Heather Wang,† Jing Zhao,† Haichun Ma,* and Yutong Zhao†

*Department of Anesthesia, the First Hospital of Jilin University, Changchun, Jilin, P.R. China
†Department of Physiology and Cell Biology, Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University, Columbus, OH, USA

Non-small cell lung cancer (NSCLC) is the most common type of lung cancer and accounts for 85% of all lung carcinomas. The hepatocyte growth factor receptor (c-Met) has been considered as a potential therapeutic target for NSCLC. Proteasome inhibition induces cell apoptosis and has been used as a novel therapeutic approach for treating diseases including NSCLC; however, the effects of different proteasome inhibitors on NSCLC have not been fully investigated. The aim of this study is to determine a precise strategy for treating NSCLC by targeting c-Met using different proteasome inhibitors. Three proteasome inhibitors, bortezomib, MG132, and ONX 0914, were used in this study. Bortezomib (50 nM) significantly reduced c-Met levels and cell viability in H1299 and H441 cells, while similar effects were observed in H460 and A549 cells when a higher concentration (~100 nM) was used. Bortezomib decreased c-Met gene expression in H1299 and H441 cells, but it had no effect in A549 and H460 cells. MG-132 at a low concentration (0.5 μM) diminished c-Met levels in H441 cells, while neither a low nor a high concentration (~20 μM) altered c-Met levels in A549 and H460 cells. A higher concentration of MG-132 (5 μM) was required for decreasing c-Met levels in H1299 cells. Furthermore, MG-132 induced cell death in all four cell types. Among all the four cell lines, H441 cells expressed higher levels of c-Met and appeared to be the most susceptible to MG-132. MG-132 decreased c-Met mRNA levels in both H1299 and H441 cells. ONX 0914 reduced c-Met levels in H460, H1299, and H441 cells but not in A549 cells. c-Met levels were decreased the most in H441 cells treated with ONX 0914. ONX 0914 did not alter cell viability in H441; however, it did induce cell death among H460, A549, and H1299 cells. This study reveals that different proteasome inhibitors produce varied inhibitory effects in NSCLS cell lines.

Key words: Non-small cell lung cancer (NSCLC); Proteasome inhibitor; c-Met; Cell viability

miR-186 Represses Proliferation, Migration, Invasion, and EMT of Hepatocellular Carcinoma via Directly Targeting CDK6 – 509
DOI: https://doi.org/10.3727/096504020X15954139263808

Junfeng Lu,* Zhongsong Zhao,† and Yanhong Ma‡

*Department of Vascular Surgery, Shandong Provincial Third Hospital, Cheeloo College of Medicine, Shandong University, Jinan, P.R. China
†Department of Gastroenterology, Shandong Provincial Third Hospital, Cheeloo College of Medicine, Shandong University, Jinan, P.R. China
‡Department of Ultrasound, Shandong Provincial Third Hospital, Cheeloo College of Medicine, Shandong University, Jinan, P.R. China

The present study aimed to investigate the effect of miR-186 on proliferation, migration, invasion, and epithelial–mesenchymal transition (EMT) of hepatocellular carcinoma (HCC). In this work, miR-186 was downregulated in HCC tissues and cells, and low miR-186 level helped predict the occurrence of vascular invasion and poor prognosis in patients with HCC. miR-186 overexpression inhibited cell proliferation and tumor growth in nude mice, repressed migration and invasion abilities, and enhanced apoptosis in HCC cells. miR-186 also retarded progression of EMT. miR-186 directly bound to the 3′-untranslated regions of cyclin-dependent kinase 6 (CDK6) to inhibit its expression. Overexpression of CDK6 markedly reversed inhibitory effects of miR-186 on proliferation, apoptosis, migration, and invasion of HCC cells. Conversely, inhibition of CDK6 exerted synergic effect on the biological functions of miR-186. In conclusion, miR-186 represses proliferation, migration, invasion, and EMT, and induces apoptosis through targeting CDK6 in HCC, which may provide a new therapeutic target for HCC.

Key words: miR-186; Cyclin-dependent kinase 6 (CDK6); Epithelial–mesenchymal transition (EMT); Hepatocellular carcinoma (HCC)

Pyrotinib Sensitizes 5-Fluorouracil-Resistant HER2+ Breast Cancer Cells to 5-Fluorouracil – 519
DOI: https://doi.org/10.3727/096504020X15960154585410

Jianing Yi,* Shuai Chen,* Pingyong Yi,† Jinlin Luo,* Meng Fang,* Yang Du,* Lianhong Zou,* and Peizhi Fan*

*Surgical Department of Breast and Thyroid Gland, The First Affiliated Hospital of Hunan Normal University/Hunan Provincial People’s Hospital, Changsha, P. R. China
†Department of Oncology, Changsha Kexin Cancer Hospital, Changsha, P. R. China

5-Fluorouracil (5-FU) is a widely used chemotherapeutic agent for breast cancer. However, acquired chemoresistance leads to a loss of its efficacy; methods to reverse are urgently needed. Some studies have shown that pyrotinib, an ErbB receptor tyrosine kinase inhibitor, is effective against HER2+ breast cancer. However, whether pyrotinib sensitizes 5-FU-resistant breast cancer cells to 5-FU is unknown. We hypothesized that the combination of pyrotinib and 5-FU would show synergistic antitumor activity, and pyrotinib could reverse 5-FU resistance in HER2⁺ breast cancer cells in vitro and in vivo. Our data showed that pyrotinib inhibited the growth of 5-FU-resistant SKBR-3/FU and MDA-MB-453/FU cell lines and the parental cell lines. 5-FU remarkably suppressed the growth of SKBR-3 and MAD-MB-453 cells. However, SKBR-3/FU and MADMB-453/FU cells showed resistance to 5-FU. A combination of pyrotinib and 5-FU resulted in the synergistic inhibition of the growth of the 5-FU-resistant SKBR-3/FU and MDA-MB-453/FU cell lines and the parental cell lines. Pyrotinib decreased significantly the IC₅₀ values of 5-FU and the thymidylate synthase (TS) mRNA expression levels in the 5-FU-resistant SKBR-3/FU and MDA-MB-453/FU cell lines and the parental cell lines and increased significantly the intracellular concentration of 5-FU in SKBR-3/FU and MDA-MB-453/FU cells. In addition, pyrotinib reduced the ABCG2 mRNA and protein expression levels in SKBR-3/FU and MDA-MB-453/FU cells and downregulated the protein expression levels of pAKT, pHER2, and pHER4 in all four cell lines. After TS or ABCG2 in 5-FU-resistant breast cancer cells was knocked down, the sensitivity of SKBR-3/FU and MDA-MB-453/FU cells to 5-FU was restored. Moreover, in vivo experiments demonstrated that pyrotinib in combination with 5-FU more effectively inhibited SKBR-3/FU tumor growth than either pyrotinib or 5-FU alone. In conclusion, our findings suggest that pyrotinib could restore sensitivity of 5-FU-resistant HER2+ breast cancer cells to 5-FU through downregulating the expression levels of TS and ABCG2.

Key words: Pyrotinib; 5-Fluorouracil (5-FU); HER2; Breast cancer; Chemoresistance

Reviews

CD13: A Key Player in Multidrug Resistance in Cancer Chemotherapy – 533
DOI: https://doi.org/10.3727/096504020X15919605976853

Qie Guo,* Xiao Li,* Meng-Na Cui,* Jia-Lin Sun,* Hong-Yan Ji,* Bei-Bei Ni,* and Mei-Xing Yan†

*Department of Clinical Pharmacy, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, P.R. China
†Department of Pharmacy, Qingdao Women and Children’s Hospital, Qingdao, Shandong, P.R. China

Cancer is one of the most serious diseases that are harmful to human health. Systemic chemotherapy is an optimal therapeutic strategy for the treatment of cancer, but great difficulty has been encountered in its administration in the form of multidrug resistance (MDR). As an enzyme on the outer cell surface, CD13 is documented to be involved in the MDR development of tumor cells. In this review, we will focus on the role of CD13 in MDR generation based on the current evidence.

Key words: CD13; Multidrug resistance (MDR); Drug efflux; Chemotherapy; Reactive oxygen species; Immune suppression

Anticancer Activity of Novel NF-kB Inhibitor DHMEQ by Intraperitoneal Administration – 541
DOI: https://doi.org/10.3727/096504020X15929100013698

Kazuo Umezawa,* Andrzej Breborowicz,† and Shamil Gantsev‡

*Department of Molecular Target Medicine, Aichi Medical University, Nagakute, Japan
†Department of Pathophysiology, Poznan University of Medical Sciences, Poznan, Poland
‡Scientific Research Institute of Oncology, Bashkortostan State Medical University, Ufa, Russia

There have been great advances in the therapy of cancer and leukemia. However, there are still many neoplastic diseases that are difficult to treat. For example, it is often difficult to find effective therapies for aggressive cancer and leukemia. An NF-κB inhibitor named dehydroxymethylepoxyquinomicin (DHMEQ) was discovered in 2000. This compound was designed based on the structure of epoxyquinomicin isolated from a microorganism. It was shown to be a specific inhibitor that directly binds to and inactivates NF-κB components. Until now, DHMEQ has been used by many scientists in the world to suppress animal models of cancer and inflammation. Especially, it was shown to suppress difficult cancer models, such as hormone-insensitive breast cancer and prostate cancer, cholangiocarcinoma, and multiple myeloma. No toxicity has been reported so far. DHMEQ was administered via the intraperitoneal (IP) route in most of the animal experiments because of its simplicity. In the course of developmental studies, it was found that IP administration never increased the blood concentration of DHMEQ because of the instability of DHMEQ in the blood. It is suggested that inflammatory cells in the peritoneal cavity would be important for cancer progression, and that IP administration, itself, is important for the effectiveness and safety of DHMEQ. In the present review, we describe mechanism of action, its in vivo anticancer activity, and future clinical use of DHMEQ IP therapy.

Key words: NF-κB; Dehydroxymethylepoxyquinomicin (DHMEQ); Intraperitoneal administration; Cancer; Lymphoma

Erratum – 551
DOI: https://doi.org/10.3727/096504020X16032056440085

The following was originally published in Volume 25, No. 6, pages 913–921, 2017 (doi: https://doi.org/10.3727/09650 4016X14792098307036). There was an error in Figure 2C for the si-NC of U87 and U251 images. A corrected version of the figure is shown here, and the figure has been replaced with the corrected version in the original published article in the online site (https://www.ingentaconnect.com/contentone/cog/or/2017/00000025/00000006/art00007). The original version of the figure did not affect the results or the conclusion of the article.

Knockdown of Long Noncoding RNA CCAT2 Inhibits Cellular Proliferation, Invasion, and Epithelial–Mesenchymal Transition in Glioma Cell

Jing Zeng,* Tianping Du,† Yafeng Song,‡ Yan Gao,‡ Fuyan Li,‡ Ruimin Wu,‡ Yijia Chen,‡ Wei Li,‡ Hong Zhou,‡ Yi Yang,‡ and Zhijun Pei‡

*Department of Infection Control, Taihe Hospital, Hubei University of Medicine, Shiyan, Hubei Province, P.R. China
†Department of Neurosurgery, Renmin Hospital, Hubei University of Medicine, Shiyan, Hubei Province, P.R. China
‡Department of PET Center and Institute of Anesthesiology and Pain, Taihe Hospital, Hubei University of Medicine, Shiyan, Hubei Province, P.R. China

Long noncoding RNA (lncRNA) colon cancer-associated transcript 2 (CCAT2) has been demonstrated to play an important role in diverse tumorigenesis. However, the biological function of lncRNAs in glioma is still unknown. In this study, we found that lncRNA CCAT2 was overexpressed in glioma tissues and cell lines and associated with tumor grade and size. Furthermore, patients with high levels of lncRNA CCAT2 had poorer survival than those with lower levels of lncRNA CCAT2. Knocking down lncRNA CCAT2 expression significantly suppressed the glioma cell growth, migration, and invasion, as well as induced early apoptosis of glioma cells in vitro. Moreover, lncRNA CCAT2 regulated epithelial–mesenchymal transition (EMT)-associated gene expression. In conclusion, lncRNA CCAT2 plays an important role in glioma tumorigenesis and progression and may act as a potential biomarker for therapeutic strategy and prognostic prediction.

Key words: Long noncoding RNAs (lncRNAs); Colon cancer-associated transcript 2 (CCAT2); Glioma; Proliferation; Invasion; Epithelial–mesenchymal transition (EMT)

Erratum – 553
DOI: https://doi.org/10.3727/096504020X16032056440094

The following was originally published in Volume 25, No. 6, pages 967–974, 2017 (doi: https://doi.org/10.3727/096504016X14803476672380). Because it was recently revealed that the testing reagent supplier used had some inferior products, we wanted to repeat the testing and check the reliability of the data. As a result, some of the expression levels were revealed to be different from the experimental results, which affected some of the display in the figures. Therefore, corrected versions of Figures 1, 2, 3, and 4 are provided here. The figures have also been replaced with the corrected versions in the original published version in the online site (https://www.ingentaconnect.com/contentone/cog/or/2017/00000025/00000006/art00013). These corrections do not affect the conclusion of the original article.

miR-107 Promotes Proliferation and Inhibits Apoptosis of Colon Cancer Cells by Targeting Prostate Apoptosis Response-4 (Par4)

Fen Liu,*† Shaojun Liu,* Feiyan Ai,*† Decai Zhang,*† Zhiming Xiao,* Xinmin Nie,‡ and Yunfeng Fu§

*Department of Gastroenterology, The Third Xiangya Hospital of Central South University, Changsha, Hunan, P.R. China
†Hunan Key Laboratory of Nonresolving Inflammation and Cancer, Changsha, Hunan, P.R. China
‡ Clinical Laboratory of The Third Xiangya Hospital of Central South University, Changsha, Hunan, P.R. China
§The Third Xiangya Hospital of Central South University, Changsha, Hunan, P.R. China

Colorectal cancer (CRC) is one of the most common malignancies in the world, with a high incidence and a high mortality. However, the pathogenesis of CRC carcinogenesis is still unexplored. In this study, we investigated the role of miR-107 in the regulation of CRC cell proliferation and apoptosis. First, the expression of miR-107 was observed to be aberrantly increased in human CRC tumor tissues and cell lines when compared to the colonic control tissues and colon epithelial cells. Further study showed that the proliferative and apoptotic capacities of human CRC SW480 and LoVo cells were aberrantly regulated by miR-107. The proliferation of SW480 and LoVo cells was remarkably enhanced by the miR-107 mimic but suppressed by the miR-107 inhibitor when compared to the negative control. On the contrary, the apoptotic rate of both SW480 and LoVo cells was significantly inhibited by miR-107 overexpression but increased by miR-107 inhibition. In addition, we identified prostate apoptosis response-4 (Par4) as a direct target of miR-107 with a potential binding site on the 3¢-UTR of mRNA, as evaluated by bioinformatics prediction and luciferase reporter assay. Par4 expression levels were significantly inhibited by the miR-107 mimic but upregulated by the miR-107 inhibitor in both SW480 and LoVo cells. Compared to the control, the increase in Par4 expression significantly inhibited the induction role of miR-107 in the proliferation of SW480 and LoVo cells, and the apoptotic rate of cells repressed by the miR-107 mimic was also reversed by Par4 overexpression. In summary, our results demonstrated that miR-107 exerts a positive role in the survival of CRC cells by directly targeting Par4. This might reveal a novel understanding about human CRC pathogenesis.

Key words: miR-107; Prostate apoptosis response-4 (Par4); Colorectal cancer (CRC); Proliferation; Apoptosis

Erratum – 559
DOI: https://doi.org/10.3727/096504020X16032056440102

The following was originally published in Volume 25, No. 8, pages 1329–1340, 2017 (doi: https://doi.org/10.3727/096504017X14876227286564). Recently, it was discovered that Figure 5 displayed overlapping images, which unfortunately caused the images to be incorrect. To correct the problem, the experiment was repeated so the errors in the images could be corrected. The figure has also been replaced with the corrected version in the original published article in the online site (https://www.ingentaconnect.com/contentone/cog/or/2017/00000025/00000008/art00012). The results of the repeated experiments were in adherence to our original conclusion.

TRAF4 Regulates Migration, Invasion, and Epithelial–Mesenchymal Transition via PI3K/AKT Signaling in Hepatocellular Carcinoma

Kairui Liu,* Xiaolin Wu,* Xian Zang,† Zejian Huang,* Zeyu Lin,‡ Wenliang Tan,* Xiang Wu,* Wenrou Hu,* Baoqi Li,* and Lei Zhang*

*Department of Hepatobiliary Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong Province, P.R. China
†Physical Examination Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong Province, P.R. China
‡Department of Hepatobiliary Surgery, The Six Affiliated Hospital, Sun Yat-Sen University, Guangzhou, Guangdong Province, P.R. China

Overexpression of the tumor necrosis factor receptor-associated factor 4 (TRAF4) has been detected in many cancer types and is considered to foster tumor progression. However, the role of TRAF4 in hepatocellular carcinoma (HCC) remains elusive. In this study, we found that TRAF4 was highly expressed in HCC cell lines and HCC tissues compared with normal liver cell lines and adjacent noncancerous tissues. TRAF4 overexpression in HCC tissues was correlated with tumor quantity and vascular invasion. In vitro studies showed that TRAF4 was associated with HCC cell migration and invasion. An in vivo study verified that TRAF4 overexpression facilitated metastasis in nude mice. In addition, overexpressed TRAF4 promoted the phosphorylation of Akt and induced Slug overexpression, leading to downregulated E-cadherin and upregulated vimentin, while silencing TRAF4 moderated the phosphorylation of Akt and repressed the expression of Slug, which resulted in upregulated E-cadherin and downregulated vimentin. These effects were inversed after pretreatment of the PI3K/Akt inhibitor LY294002 or overexpression of constitutively active Akt1. Our study demonstrated that TRAF4 was involved in promoting HCC cell migration and invasion. The process was induced by the EMT through activation of the PI3K/Akt signaling pathway.

Key words: Tumor necrosis factor receptor-associated factor 4 (TRAF4); Hepatocellular carcinoma (HCC); Epithelial–mesenchymal transition (EMT); PI3K/Akt signaling pathway

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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