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 4)

Volume 28, Number 4

A Novel BCL-2 Inhibitor APG-2575 Exerts Synthetic Lethality With BTK or MDM2-p53 Inhibitor in Diffuse Large B-Cell Lymphoma – 331
DOI: https://doi.org/10.3727/096504020X15825405463920

Qiuyun Luo,*† Wentao Pan,*†‡ Suna Zhou,*†¹ Guangfeng Wang,‡ Hanjie Yi,*§ Lin Zhang,*¶ Xianglei Yan,*† Luping Yuan,*† Zhenyi Liu,# Jing Wang,** Haibo Chen,# MiaoZhen Qiu,*†† DaJun Yang,*†‡ and Jian Sun*‡‡

*State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, P.R. China
†Department of Experimental Research, Sun Yat-Sen University Cancer Center, Guangzhou, P.R. China ‡Suzhou Ascentage Pharma Inc., Jiangsu, P.R. China
§The Second Affiliated Hospital of Nanchang University, Nanchang, P.R. China
¶University Department of Clinical Laboratory, Sun Yat-Sen University Cancer Center, Guangzhou, P.R. China
#Peking University Shenzhen Hospital, Shenzhen, P.R. China
**Guangzhou Red Cross Hospital, Guangzhou, P.R. China
††Department of Medical Oncology, Sun Yat-Sen University Cancer Center, Guangzhou, P.R. China
‡‡Department of Clinical Research, Sun Yat-Sen University Cancer Center, Guangzhou, P.R. China

Despite therapeutic advances, the effective treatment for relapsed or refractory diffuse large B-cell lymphoma (DLBCL) remains a major clinical challenge. Evasion of apoptosis through upregulating antiapoptotic B-cell lymphoma-2 (BCL-2) family members and p53 inactivation, and abnormal activation of B-cell receptor signaling pathway are two important pathogenic factors for DLBCL. In this study, our aim is to explore a rational combination of BCL-2 inhibitor plus Bruton’s tyrosine kinase (BTK) blockade or p53 activation for treating DLBCL with the above characteristics. We demonstrated that a novel BCL-2 selective inhibitor APG-2575 effectively suppressed DLBCL with BCL-2 high expression via activating the mitochondrial apoptosis pathway. BTK inhibitor ibrutinib combined with BCL-2 inhibitors showed synergistic antitumor effect in DLBCL with mean expression of BCL-2 and myeloid cell leukemia-1 (MCL-1) through upregulating the expression level of BIM and modulating MCL-1 and p-Akt expression. For p53 wild-type DLBCL with high expression of BCL-2, APG-2575 showed strong synergic effect with mouse double minute 2 (MDM2)–p53 inhibitor APG- 115 that can achieve potent antitumor effect and markedly prolong survival in animal models. Collectively, our data provide an effective and precise therapeutic strategy through rational combination of BCL-2 and BTK or MDM2–p53 inhibitors for DLBCL, which deserves further clinical investigation.

Key words: B-cell lymphoma-2 (BCL-2); Apoptosis; Small molecule inhibitor; Diffuse large B-cell lymphoma (DLBCL); Combination therapy

EIF5A2 Is Highly Expressed in Anaplastic Thyroid Carcinoma and Is Associated With Tumor Growth by Modulating TGF-β Signals – 345
DOI: https://doi.org/10.3727/096504020X15834065061807

Fengyun Hao,* Qingli Zhu,† Lingwei Lu,† Shukai Sun,‡ Yichuan Huang,§ Jinna Zhang,¶ Zhaohui Liu,†# Yuanqing Miao,** Xuelong Jiao,†† and Dong Chen††

*Department of Pathology, the Affiliated Hospital of Qingdao University, Qingdao, P.R. China
†Department of Thyroid Surgery, the Affiliated Hospital of Qingdao University, Qingdao, P.R. China
‡Department of Clinical Lab, the Affiliated Hospital of Qingdao University, Qingdao, P.R. China
§Department of Otolaryngology, the Affiliated Hospital of Qingdao University, Qingdao, P.R. China
¶Department of Medical Experiment Center, the Affiliated Hospital of Qingdao University, Qingdao, P.R. China
#Department of Molecular Biochemistry and Genetic Engineering, Shenzhen University, Shenzhen, P.R. China
**Department of Medical Network Information Center, the Affiliated Hospital of Qingdao University, Qingdao, P.R. China
††Department of General Surgery, the Affiliated Hospital of Qingdao University, Qingdao, P.R. China

Anaplastic thyroid carcinoma (ATC) is resistant to standard therapies and has no effective treatment. Eukaryotic translation initiation factor 5A2 (EIF5A2) has shown to be upregulated in many malignant tumors and proposed to be a critical gene involved in tumor metastasis. In this study, we aimed to investigate the expression status of EIF5A2 in human ATC tissues and to study the role and mechanisms of EIF5A2 in ATC tumorigenesis in vitro and in vivo. Expression of EIF5A2 protein was analyzed in paraffin-embedded human ATC tissues and adjacent nontumorous tissues (ANCT) (n = 24) by immunochemistry. Expressions of EIF5A2 mRNA and protein were analyzed in fresh-matched ATC and ANCT (n = 23) and ATC cell lines by real-time polymerase chain reaction (PCR) and Western blotting. The effect of targeting EIF5A2 with short hairpin RNA (shRNA) or EIF5A2 overexpression on the ATC tumorigenesis and TGF-ß/Smad2/3 signals in vitro and in vivo was investigated. Expression of EIF5A2 was significantly upregulated in ATC tissues and cell lines compared with ANCT and normal follicular epithelial cell line. Functional studies found that targeting EIF5A2 induced SW1736 cell death in vitro and in vivo, followed by significantly downregulated phosphorylation of Smad2/3 (p-Smad2/3) in SW1736 cells at the protein level. Ectopic expression of EIF5A2 could promote 8505C cell growth in vitro and in vivo, followed by significantly upregulated p-Smad3 at the protein level. Recombinant human TGF-ß1 (hTGF-ß1) treatment decreased the antiproliferative activity of the EIF5A2 downexpressing 8505C cells through reversing pSmad2/3. Using the specific inhibitor SB431542 to block TGF-ß pathway or Smad3 siRNA to knock down Smad3 increased the antiproliferative activity of the EIF5A2-overexpressing 8505C cells through inhibiting pSmad2/3. Our findings indicated that EIF5A2 controled cell growth in ATC cells, and EIF5A/TGF-ß/Smad2/3 signal may be a potential therapeutic target for ATC treatment.

Key words: Anaplastic thyroid carcinoma (ATC); Eukaryotic translation initiation factor 5A2 (EIF5A2); Transforming growth factor-β (TGF-β)

miR-4792 Inhibits Acute Myeloid Leukemia Cell Proliferation and Invasion and Promotes Cell Apoptosis by Targeting Kindlin-3 – 357
DOI: https://doi.org/10.3727/096504020X15844389264424

Yun Qin,* Yu Wang,†‡§ and Dongbo Liu¶

*Second Clinical College, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, P. R. China
†Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, P. R. China
‡Hubei Province for the Clinical Medicine Research Center of Hepatic Surgery, Wuhan, P. R. China
§Key Laboratory of Organ Transplantation, Ministry of Education and Ministry of Public Health, Wuhan, P. R. China
¶Cancer Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, P. R. China

It has been reported that kindlin-3 expression is closely associated with progression of many cancers and microRNA (miRNA) processing. However, the effects and precise mechanisms of kindlin-3 in acute myeloid leukemia (AML) have not been well clarified. Our study aimed to explore the interaction between kindlin-3 and miR-4792 in AML. In our study, we found that the expression of kindlin-3 was dramatically increased in AML samples and cell lines, and the miR-4792 level was significantly downregulated. Interestingly, the low miR-4792 level was closely associated with upregulated kindlin-3 expression in AML samples. Moreover, introduction of miR-4792 dramatically suppressed proliferation and invasion and induced apoptosis of AML cells. We demonstrated that miR-4792 could directly target kindlin-3 by using both bioinformatics analysis and luciferase reporter assay. In addition, kindlin-3 silencing had similar effects with miR-4792 overexpression on AML cells. Overexpression of kindlin-3 in AML cells partially reversed the inhibitory effects of miR-4792 mimic. miR-4792 inhibited cell proliferation and invasion and induced apoptosis of AML cells by directly downregulating kindlin-3 expression, and miR-4792 targeting kindlin-3 was responsible for the regulation of the proliferation, invasion, and apoptosis of AML cells.

Key words: Acute myeloid leukemia (AML); MicroRNA-4792; Kindlin-3; Proliferation; Invasion; Apoptosis

Corosolic Acid Inhibits Cancer Progress Through Inactivating YAP in Hepatocellular Carcinoma – 371
DOI: https://doi.org/10.3727/096504020X15853075736554

Ming Jia,* Yulin Xiong,† Maoshi Li,* and Qing Mao*

*Institute of Infectious Diseases of Chinese PLA, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, P.R. China
†Department of Laboratory, The Fourth Medical Center of PLA General Hospital, Beijing, P.R. China

Chemotherapy is critical for the treatment of hepatocellular carcinoma (HCC). Despite the proapoptotic effects of corosolic acid (CA) treatment, its underlying mechanism is not completely clear. The aim of this study was to determine the molecular mechanism of CA in HCC treatment. MTT assay was used to determine the IC₅₀ of CA. Immunoprecipitation and immunofluorescence were used to detect the interaction and subcellular localization of Yes-associated protein (YAP) and mouse double minute 2 (MDM2). In addition, in vivo xenotransplantation was performed to assess the effects of CA, YAP, and MDM2 on tumorigenesis. The IC₅₀ of CA was about 40 μM in different HCC cell lines, and CA decreased YAP expression by reducing its stability and increasing its ubiquitination. CA treatment and MDM2 overexpression significantly decreased the cross-talk between YAP and cAMP-responsive element-binding protein (CREB), TEA domain transcription factor (TEAD), and Runt-related transcription factor 2 (Runx2). CA stimulation promoted the translocation of YAP and MDM2 from the nucleus to the cytoplasm and increased their binding. In addition, CA treatment obviously reduced tumorigenesis, whereas this effect was abolished when cells were transfected with sh-MDM2 or Vector-YAP. The present study uncovered that CA induced cancer progress repression through translocating YAP from the nucleus in HCC, which might provide a new therapeutic target for HCC.

Key words: Hepatocellular carcinoma (HCC); Corosolic acid (CA); Yes-associated protein (YAP); Mouse double minute 2 (MDM2)

Cylindromatosis Is Required for Survival of a Subset of Melanoma Cells – 385
DOI: https://doi.org/10.3727/096504020X15861709922491

Ting La,*† Lei Jin,*‡ Xiao Ying Liu,* Ze Hua Song,* Margaret Farrelly,† Yu Chen Feng,† Xu Guang Yan,† Yuan Yuan Zhang,† Rick F. Thorne,*§ Xu Dong Zhang,*† and Liu Teng*

*Translational Research Institute, Henan Provincial People’s Hospital, Academy of Medical Science, Zhengzhou University, Zhengzhou, P.R. China
†School of Biomedical Sciences and Pharmacy, The University of Newcastle, Callaghan, NSW, Australia
‡School of Medicine and Public Health, The University of Newcastle, Callaghan, NSW, Australia
§School of Environmental and Life Sciences, The University of Newcastle, Callaghan, NSW, Australia

The deubiquitinase cylindromatosis (CYLD) functions as a tumor suppressor inhibiting cell proliferation in many cancer types including melanoma. Here we present evidence that a proportion of melanoma cells are nonetheless addicted to CYLD for survival. The expression levels of CYLD varied widely in melanoma cell lines and melanomas in vivo, with a subset of melanoma cell lines and melanomas displaying even higher levels of CYLD than melanocyte lines and nevi, respectively. Strikingly, although short hairpin RNA (shRNA) knockdown of CYLD promoted, as anticipated, cell proliferation in some melanoma cell lines, it reduced cell viability in a fraction of melanoma cell lines with relatively high levels of CYLD expression and did not impinge on survival and proliferation in a third type of melanoma cell lines. The decrease in cell viability caused by CYLD knockdown was due to induction of apoptosis, as it was associated with activation of the caspase cascade and was abolished by treatment with a general caspase inhibitor. Mechanistic investigations demonstrated that induction of apoptosis by CYLD knockdown was caused by upregulation of receptorinteracting protein kinase 1 (RIPK1) that was associated with elevated K63-linked polyubiquitination of the protein, indicating that CYLD is critical for controlling RIPK1 expression in these cells. Of note, microRNA (miR) profiling showed that miR-99b-3p that was predicted to target the 3′-untranslated region (3′-UTR) of the CYLD mRNA was reduced in melanoma cell lines with high levels of CYLD compared with melanocyte lines. Further functional studies confirmed that the reduction in miR-99b-3p expression was responsible for the increased expression of CYLD in a highly cell line-specific manner. Taken together, these results reveal an unexpected role of CYLD in promoting survival of a subset of melanoma cells and uncover the heterogeneity of CYLD expression and its biological significance in melanoma.

Key words: Cylindromatosis (CYLD); Melanoma; miR-99b-3p; Receptor-interacting protein kinase 1 (RIPK1)

miR-202 Suppresses Hepatocellular Carcinoma Progression via Downregulating BCL2 Expression – 399
DOI: https://doi.org/10.3727/096504020X15864296270581

Donghai Zhuang, Li Liang, Hongzhan Zhang, and Xianguang Feng

Department of Hepatobiliary Surgery, Shandong Provincial Third Hospital, Cheeloo College of Medicine, Shandong University, Jinan, P.R. China

miRNAs play an important role in progression of hepatocellular carcinoma (HCC). In this work, we assessed the function of miR-202 in human HCC and identified BCL2 as its target. We found miR-202 expression was found significantly downregulated, while BCL2 expression was markedly upregulated in HCC tissues and cell lines (HepG2, Hep3B, and HCCLM3). Both miR-202 and BCL2 were closely correlated with major vascular invasion and advanced TNM stage as well as overall survival of HCC patients. Overexpression of miR-202 significantly inhibited cell proliferation, induced apoptosis and cell cycle arrest at the G₀/G₁ phase, and prevented tumor formation in a xenograft nude mouse model. Further, miR-202 dramatically inhibited migration, invasion, and epithelial–mesenchymal transition. miR-202 bound to the 3′-untranslated region (3′-UTR) of BCL2 mRNA and downregulated the expression level of BCL2 protein. Exogenous BCL2 overexpression weakened the inhibitory effects of miR-202, while inhibition of BCL2 enhanced the inhibitory effects of miR-202. In conclusion, miR-202 serves as a tumor suppressor in HCC progression by downregulating BCL2 expression, indicating miR-202 might be a potential target for HCC.

Key words: miR-202; BCL2; Hepatocellular carcinoma (HCC); Progression

Tripartite Motif-Containing 46 Promotes Viability and Inhibits Apoptosis of Osteosarcoma Cells by Activating NF-κB Signaling Through Ubiquitination of PPARα – 409
DOI: https://doi.org/10.3727/096504020X15868639303417

Wenwei Jiang,* Xinyu Cai,* Tianyang Xu,* Kaiyuan Liu,* Dong Yang,* Lin Fan,* Guodong Li,* and Xiao Yu†

*Department of Orthopedics, Shanghai Tenth People’s Hospital, Tong Ji University School of Medicine, Shanghai, P.R. China
†Department of Orthopedics, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Suzhou, P.R. China

Osteosarcoma (OS), the most common bone cancer, causes high morbidity in children and young adults. TRIM46 is a member of the family of tripartite motif (TRIM)-containing proteins that serve as important regulators of tumorigenesis. Here we investigate the possible role of TRIM46 in OS and the underlying molecular mechanism. We report an increase in the expression of TRIM46 in OS and its association with tumor size, Enneking’s stage, and patient prognosis. TRIM46 knockdown inhibits OS cell viability and cell cycle progression and induces apoptosis, while TRIM46 overexpression exerts inverse effects, which are inhibited by peroxisome proliferator-activated receptor alpha (PPARα) overexpression and the nuclear factor kappa B (NF-κB) inhibitor, pyrrolidine dithiocarbamate (PDTC). Furthermore, TRIM46 negatively regulates PPARα expression via ubiquitination-mediated protein degradation and modification. PPARα overexpression also inactivates NF-κB signaling and NF-κB promoter activity in OS cells overexpressing TRIM46. Moreover, TRIM46 knockdown inhibits tumor growth and induces apoptosis of OS cells in vivo. TRIM46 acts as an oncogene in OS by interacting with and ubiquitinating PPARα, resulting in the activation of NF-κB signaling pathway. Thus, TRIM46 may be a potential biomarker of carcinogenesis.

Key words: Osteosarcoma (OS); TRIM46; Ubiquitination; NF-κB; PPARα

The AKT/GSK3β-Mediated Slug Expression Contributes to Oxaliplatin Resistance in Colorectal Cancer via Upregulation of ERCC1 – 423
DOI: https://doi.org/10.3727/096504020X15877284857868

Wei Wei,* Xiao-Dong Ma,† Guan-Min Jiang,‡ Bin Shi,§ Wen Zhong,¶ Chun-Lei Sun,§ Liang Zhao,* Yan-Jiao Hou,* and Hao Wang*

*Department of Laboratory Medicine, The Affiliated Anhui Provincial Hospital of Anhui Medical University, Hefei, P.R. China
†Department of Medicinal Chemistry, School of Pharmacy, Anhui University of Chinese Medicine, Hefei, P.R. China
‡Department of Clinical Laboratory, The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, P.R. China
§Department of General Surgery, The Affiliated Anhui Provincial Hospital of Anhui Medical University, Hefei, P.R. China
¶Department of Pathology, The Affiliated Anhui Provincial Hospital of Anhui Medical University, Hefei, P.R. China

Although oxaliplatin serves as one of the first-line drugs prescribed for treating colorectal cancer (CRC), the therapeutic effect is disappointing due to drug resistance. So far, the molecular mechanisms mediating oxaliplatin resistance remain unclear. In this study, we found the chemoresistance in oxaliplatin-resistant HCT116 cells (HCT116/OXA) was mediated by the upregulation of ERCC1 expression. In addition, the acquisition of resistance induced epithelial–mesenchymal transition (EMT) as well as the Slug overexpression. On the contrary, Slug silencing reversed the EMT phenotype, decreased ERCC1 expression, and ameliorated drug resistance. Further mechanistical studies revealed the enhanced Slug expression resulted from the activation of AKT/glycogen synthase kinase 3β (GSK3β) signaling. Moreover, in CRC patients, coexpression of Slug and ERCC1 was observed, and increased Slug expression was significantly correlated with clinicopathological factors and prognosis. Taken together, the simultaneous inhibition of the AKT/GSK3β/Slug axis may be of significance for surmounting metastasis and chemoresistance, thereby improving the therapeutic outcome of oxaliplatin.

Key words: Excision repair cross-complementation group 1 (ERCC1); Slug; Drug resistance; Epithelial–mesenchymal transition (EMT); AKT/GSK3β

Review

Sulforaphane: Expected to Become a Novel Antitumor Compound – 439
DOI: https://doi.org/10.3727/096504020X15828892654385

Geting Wu,* Yuanliang Yan,†‡ Yangying Zhou,§ Yumei Duan,* Shuangshuang Zeng,†‡ Xiang Wang,†‡ Wei Lin,* Chunlin Ou,* Jianhua Zhou,* and Zhijie Xu*‡

*Department of Pathology, Xiangya Hospital, Central South University, Changsha, P.R. China
†Department of Pharmacy, Xiangya Hospital, Central South University, Changsha, P.R. China
‡National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, P.R. China
§Department of Oncology, Xiangya Hospital, Central South University, Changsha, P.R. China

Natural products are becoming increasingly popular in a variety of traditional, complementary, and alternative systems due to their potency and slight side effects. Natural compounds have been shown to be effective against many human diseases, especially cancers. Sulforaphane (SFE) is a traditional Chinese herbal medicine. In recent years, an increasing number of studies have been conducted to evaluate the antitumor effect of SFE. The roles of SFE in cancers are mainly through the regulation of potential biomarkers to activate or inhibit related signaling pathways. SFE has exhibited promising inhibitory effects on breast cancer, lung cancer, liver cancer, and other malignant tumors. In this review, we summarized the reports on the activity and functional mechanisms of SFE in cancer treatment and explored the efficacy and toxicity of SFE.

Key words: Sulforaphane; Malignant tumor; Antitumor effects

ERRATUM – 447
DOI: https://doi.org/10.3727/096504020X15970683241756

The following was originally published in Volume 24, No. 2, pages 99–108, 2016 (doi: http://dx.doi.org/10.3727/09650 4016X14611963142173). The images of Figure 3E and Figure 4E were incorrect in the published article. The corrected version of both figures are provided here. The figures have also been replaced with the correct versions in the original published version in the online site (https://www.ingentaconnect.com/contentone/cog/or/2016/00000024/00000002/art00004). The original versions of the figures did not affect any results or conclusions in the article.

The Downregulation of MicroRNA-10b and its Role in Cervical Cancer

Dongling Zou,* Qi Zhou,† Dong Wang,† Lili Guan,* Li Yuan,*† and Shaolin Li*

*Department of Radiological Medicine, Chongqing Medical University, Chongqing, China
†Department of Gynecologic Oncology, Chongqing Cancer Institute, Chongqing, China

It has been demonstrated that microRNAs (miRNAs) act as oncogenes or tumor suppressors in a variety of cancers. Our previous work suggested that miR-10a/b functioned as a tumor suppressor in gastric cancer, and miR-10b was also reported to be significantly downregulated in advanced stage cervical cancer tissues. However, the aberrant expression of miR-10b in cervical cancer and its possible role in cervical carcinogenesis was largely unknown. In this study, we investigated the expression of miR-10b in cervical cancer tissues, carcinoma in situ tissues, mild dysplasia, moderate dysplasia, severe dysplasia tissues, and normal controls. We found that miR-10b was significantly downregulated during cervical cancer progression, and the lower level of miR-10b in cervical cancer was significantly associated with a more aggressive tumor phenotype. Moreover, overexpression of miR-10b in cervical cancer cells could inhibit the cell proliferation and invasion, and the further mechanism study suggested that its role was possibly through directly targeting HOXA1. These results suggested that the downregulation of miR-10b and the resulting elevated HOXA1 level in cervical cancer tissues might play critical roles in cervical cancer progression.

Key words: Cervical cancer; miR-10b; HOXA1; Tumor suppressor

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