Oncology Research : Featuring Preclinical and Clinical Cancer Therapeutics

Co-Editors-in-Chief

American Continent:
Edward Chu
University of Pittsburgh Cancer Institute, 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, ISA
J. J. Lee, 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
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
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
Y. Lin, Aichi Medical University, Japan
J. Neuzil, Griffith University, Gold Coast Campus, Australia
O. Ohno, Keio University, Japan
T. Ohsugi, Rakuno Gakuen University, Japan
H. Osada, RIKEN, Japan
M. Oya, Keio University, Japan
M. Ozaki, Hokkaido University, Japan
Y. Sasazawa, Keio University, Japan
W. Seubwai, Khon Kaen University, Thailand
K. Sidthipong, Mahidol University, Thailand
S. Simizu, Keio University, Japan
M. Takeiri, Kyoto University, Japan
E. Tashiro, Keio University, Japan
T. Ueno, Kyoto University Hospital, Japan
M. Yamamoto, Waseda University, Japan

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 nonrefundable 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 wordsin 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 muchactivity, 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 nearor 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 (IBMcompatible) 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. Followthe 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 priorto 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 ofnot 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 followingthe 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 separatefiles). 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, andeach 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 forreduction (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 figureswithin 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 colorauthorization 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.

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 thesource.

Page Proofs/Offprints: All material accepted for publication is subject to copyediting. Authors will receive page proofs of articles before publication, along with an 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 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 does not upload manuscripts on the authors’ behalf to PubMedCentral. The authors of NIH-funded manuscripts are granted permission to upload the final version of the manuscript themselves to PubMedCentral so that they remain in compliance with the NIH Public Access Policy. A PDF of the article is provided to the Corresponding Author for this purpose.

Authors have the opportunity to download their articles from open access files at: http://www.ingentaconnect.com/content/cog/or

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

View All Abstracts

Access Current Articles (Volume 28, Number 2)

Volume 28, Number 2

Original Contributions

Pathway Mutations in Breast Cancer Using Whole-Exome Sequencing – 107
DOI: https://doi.org/10.3727/096504019X15698362825407

Ya-Sian Chang,*†‡§ Chieh-Min Chang,†‡ Chien-Yu Lin,¶# Dy-San Chao,† Hsi-Yuan Huang,† and Jan-Gowth Chang*†‡**††

*Epigenome Research Center, China Medical University Hospital, Taichung, Taiwan
†Department of Laboratory Medicine, China Medical University Hospital, Taichung, Taiwan
‡Center for Precision Medicine, China Medical University Hospital, Taichung, Taiwan
§Department of Medical Laboratory Science and Biotechnology, China Medical University, Taichung, Taiwan
¶Graduate Institute of Clinical Medical Science and School of Medicine, China Medical University, Taichung, Taiwan
#Department of Laboratory Medicine, Taichung Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Taichung, Taiwan
**Graduate Institute of Biomedical Sciences, School of Medicine, China Medical University, Taichung, Taiwan
††Department of Bioinformatics and Medical Engineering, Asia University, Taichung, Taiwan

The genomic landscape of breast cancer (BC) is complex. The purpose of this study was to decipher the mutational profiles of Taiwanese patients with BC using next-generation sequencing. We performed whole-exome sequencing on DNA from 24 tumor tissue specimens from BC patients. Sanger sequencing was used to validate the identified variants. Sanger sequencing was also performed on paired adjacent nontumor tissues. After genotype calling and algorithmic annotations, we identified 49 deleterious variants in canonical cancer-related genes in our BC cohort. The most frequently mutated genes were PIK3CA (16.67%), FKBP9 (12.5%), TP53 (12.5%), ATM (8.33%), CHEK2 (8.33%), FOXO3 (8.33%), NTRK1 (8.33%), and NUTM2B (8.33%). Seven mutated variants (ATR p.V1581fs, CSF1R p.R579Q, GATA3 p.T356delinsTMKS, LRP5 p.W389*, MAP3K1 p.T918fs, MET p.K1161fs, and MTR p.P1178S) were novel variants that are not present in any gene mutation database. After grouping the samples according to molecular subtype, we found that the cell cycle, MAPK, and chemokine signaling pathways in the luminal A subtype of BC; the focal adhesion, axon guidance, and endocytosis pathways in the luminal B subtype; and amyotrophic lateral sclerosis in the basal-like subtype were exclusively altered. Survival curve analysis showed that the presence of the MAPK signaling pathway and endocytosis mutations were correlated with a poor prognosis. These survival data were consistent with cBioPortal analyses of 2,051 BC cases. We discovered novel mutations in patients with BC. These results have implications for developing strategic, adjuvant, and gene-targeted therapies.

Key words: Breast cancer (BC); Whole-exome sequencing; Gene mutation; Pathway mutation

Cost–Utility Analysis of Pembrolizumab Versus Chemotherapy as First-Line Treatment for Metastatic Non-Small Cell Lung Cancer With Different PD-L1 Expression Levels – 117
DOI: https://doi.org/10.3727/096504019X15707883083132

Xiuhua Weng,* Shaohong Luo,* Shen Lin,* Lixian Zhong,† Meiyue Li,* Rao Xin,* Pinfang Huang,* and Xiongwei Xu*

*Department of Pharmacy, First Affiliated Hospital of Fujian Medical University, Taijiang, Fuzhou, P.R. China
†College of Pharmacy, Texas A&M University, College Station, TX, USA

To evaluate the cost–utility of pembrolizumab versus chemotherapy as the first-line setting for metastatic non-small cell lung cancer (NSCLC) from the US health care system perspective, a Markov model was developed to compare the lifetime cost and effectiveness of pembrolizumab versus chemotherapy for untreated metastatic NSCLC, based on the clinical data derived from phase III randomized controlled trial (KEYNOTE-042; ClinicalTrials.gov; NCT02220894). Weibull distribution was fitted to simulate the parametric survival functions. Drug costs were collected from official websites, and utility values were obtained from published literature. Total costs, quality-adjusted life years (QALYs), and incremental cost-effectiveness ratios (ICERs) were computed as primary output indicators. The impact of different PD-L1 expression levels on ICER was also evaluated. One-way and probabilistic sensitivity analyses were performed to assess the model uncertainty. Compared with chemotherapy, patients treated with pembrolizumab provided an additional 1.13, 1.01, and 0.59 QALYs in patients with PD-L1 expression levels of ≥50%, ≥20%, and ≥1%, with corresponding incremental cost of $53,784, $47,479, and $39,827, respectively. The resultant ICERs of pembrolizumab versus chemotherapy were $47,596, $47,184, and $68,061/QALY, in three expression levels of PD-L1, respectively, all of which did not exceed the WTP threshold of 180,000/QALY. Probability sensitivity analysis outcome supported that pembrolizumab exhibited evident advantage over chemotherapy to be cost-effective. One-way sensitivity analysis found that ICERs were most sensitive to utility value of pembrolizumab in progression survival state. All the adjustment of parameters did not qualitatively change the result. For treatment-naive, metastatic NSCLC patients with PD-L1⁺, pembrolizumab was estimated to be cost-effective compared with chemotherapy for all PD-L1 expression levels at a WTP threshold of $180,000/QALY in the context of the US health care system.

Key words: Programmed cell death ligand 1 (PD-L1); Pembrolizumab; Non-small cell lung cancer (NSCLC); Cost–utility; Chemotherapy

Apatinib Monotherapy or Combination Therapy for Non-Small Cell Lung Cancer Patients With Brain Metastases – 127
DOI: https://doi.org/10.3727/096504019X15707896762251

Jianping Xu, Xiaoyan Liu, Sheng Yang, and Yuankai Shi

Department of Medical Oncology, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, P.R. China

Apatinib, an oral small molecular receptor tyrosine kinase inhibitor (TKI) developed first in China, exerts antiangiogenic and antineoplastic function through selectively binding and inhibiting vascular endothelial growth factor receptor 2 (VEGFR-2). In this study, we aimed to explore the efficacy and safety profile of apatinib monotherapy, or combined with chemotherapy or endothelial growth factor receptor (EGFR)-TKI in heavily pretreated non-small cell lung cancer (NSCLC) patients with brain metastases. We performed a retrospective analysis for relapsed NSCLC patients with brain metastases from our institute, who received apatinib (250 mg or 500 mg p.o. qd) monotherapy, or combination with EGFR-TKI or chemotherapy as second or more line systemic therapy until disease progression or unacceptable toxicity occurred. The objective response rate (ORR), disease control rate (DCR), median progression-free survival (mPFS), median overall survival (mOS), and safety were analyzed. A total of 26 eligible patients were included: 24 patients diagnosed with adenocarcinoma, 2 with squamous carcinoma, and 14 patients harboring EGFR sensitizing mutations. The mPFS and mOS were 4.93 (range, 0.27−32.91; 95% CI 3.64−6.22) and 14.70 (range, 0.27−32.91; 95% CI 0.27−43.60) months for the whole group. The ORR and DCR were 7.7% (2/26) and 69.2% (18/26) for the entire lesions, and 7.7% (2/26) and 79.6% (20/26) for brain metastases, respectively. Compared with patients who received apatinib monotherapy, patients who received apatinib combination treatment had more favorable mPFS (11.77 vs. 2.27 months, p < 0.05) and mOS (24.03 vs. 6.07 months, p < 0.05). Treatment-related toxicities were tolerable including grade 1/2 hypertension, hand-and-foot syndrome, fatigue, nausea, liver dysfunction, myelosuppression, skin rash, and palpitation. In conclusion, apatinib exhibited high activity and good tolerance for NSCLC patients with brain metastasis, and it might become a potential choice for metastatic brain tumors in NSCLC patients. Key words: Apatinib; Non-small cell lung cancer (NSCLC); Brain metastases; VEGFR-2

Long Noncoding RNA KCNQ1OT1 Accelerates the Progression of Ovarian Cancer via MicroRNA-212-3/LCN2 Axis – 135
DOI: https://doi.org/10.3727/096504019X15719983040135

Xiaoqin Lu,*1 Fuying Wang,* Meizhou Fu,† Yuankun Li,* and Lijun Wang*

*Department of Obstetrics and Gynecology, the Second Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, P.R. China
†Education and Training Department, People’s Hospital of Zhengzhou University, Zhengzhou, Henan, P.R. China

Long noncoding RNA KCNQ1OT1 (KCNQ1OT1) has been identified to be deregulated in several kinds of cancers. However, its expression pattern and functions in ovarian cancer remain unknown. Bioinformatics analysis showed that miR-212-3p, an identified suppressor in ovarian cancer, was a direct target of KCNQ1OT1, suggesting that KCNQ1OT1 may play a role in ovarian cancer progression via targeting miR-212-3p. Here we aimed to explore the effect of KCNQ1OT1 on the carcinogenesis of ovarian cancer, as well as to investigate miR-212-3p roles in this process. The expression of KCNQ1OT1 and miR-212-3p in ovarian cancer tissues and cells was detected by qPCR. MTT, flow cytometry, wound healing, Transwell chambers, and in vivo tumor formation assays were carried out to assess cell proliferation, apoptosis, migration, invasion, and tumorigenesis, respectively. RNA pulldown and luciferase gene reporter assays were used to evaluate the RNA–RNA interaction. The results showed that KCNQ1OT1 was overexpressed in ovarian cancer tissues and cells, which closely associated with the advanced clinic process and poor prognosis in ovarian cancer patients. Upregulation of KCNQ1OT1 significantly enhanced cell growth, migration, and invasion and inhibited cell apoptosis via miR-212-3p. In addition, we identified that lipocalin2 (LCN2) was a direct target of miR-212-3p and functioned as an oncogene to promote cell growth and to inhibit cell apoptosis. Furthermore, we observed that KCNQ1OT1 overexpression significantly enhanced the tumorigenesis of SKOV3 cells, whereas this effect was significantly impaired when LCN2 expression was downregulated. Overall, the present study reveals that KCNQ1OT1 functions as an oncogene in ovarian cancer via targeting miR-212-3p/LCN2 axis, which might provide new markers and targets for ovarian cancer diagnosis and treatment.

Key words: Ovarian cancer; KCNQ1OT1; LCN2; Proliferation; Apoptosis; Tumorigenesis

MicroRNA-561 Affects Proliferation and Cell Cycle Transition Through PTEN/AKT Signaling Pathway by Targeting P-REX2a in NSCLC – 147
DOI: https://doi.org/10.3727/096504019X15732109856009

ZiJun Liao,*† Qi Zheng,† Ting Wei,‡ YanBing Zhang,† JieQun Ma,† Zheng Zhao,§ HaiFeng Sun,§ and KeJun Nan*

*Department of Medical Oncology, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi Province, P.R. China
†First Department of Medical Oncology, Affiliated Shaanxi Provincial Cancer Hospital, College of Medicine, Xi’an Jiaotong University, Shaanxi Province, P.R. China
‡Department of Ophthalmology, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi Province, P.R. China
§Third Department of Medical Oncology, Affiliated Shaanxi Provincial Cancer Hospital, College of Medicine, Xi’an Jiaotong University, Shaanxi Province, P.R. China

MicroRNAs (miRNAs) play crucial roles in tumorigenesis and tumor progression. miR-561 has been reported to be downregulated in gastric cancer and affects cancer cell proliferation and metastasis. However, the role and underlying molecular mechanism of miR-561 in human non-small cell lung cancer (NSCLC) remain unknown and need to be further elucidated. In this study, we discovered that miR-561 expression was downregulated in human NSCLC tissues and cell lines. The overexpression of miR-561 inhibited NSCLC cell proliferation and cell cycle G₁/S transition and induced apoptosis. The inhibition of miR-561 facilitated cell proliferation and G₁/S transition and suppressed apoptosis. miR-561 expression was inversely correlated with P-REX2a expression in NSCLC tissues. P-REX2a was confirmed to be a direct target of miR-561 using a luciferase reporter assay. The overexpression of miR-561 decreased P-REX2a expression, and the suppression of miR-561 increased P-REX2a expression. Particularly, P-REX2a silencing recapitulated the cellular and molecular effects observed upon miR-561 overexpression, and P-REX2a overexpression counteracted the effects of miR-561 overexpression on NSCLC cells. Moreover, both exogenous expression of miR-561 and silencing of P-REX2a resulted in suppression of the PTEN/AKT signaling pathway. Our study demonstrates that miR-561 inhibits NSCLC cell proliferation and G₁/S transition and induces apoptosis through suppression of the PTEN/AKT signaling pathway by targeting P-REX2a. These findings indicate that miR-561 plays a significant role in NSCLC progression and serves as a potential therapeutic target for NSCLC.

Key words: miR-561; P-REX2a; Non-small cell lung cancer (NSCLC), Proliferation; Cell cycle; Apoptosis

Enhancement of Radiosensitivity by Eurycomalactone in Human NSCLC Cells Through G₂/M Cell Cycle Arrest and Delayed DNA Double-Strand Break Repair – 161
DOI: https://doi.org/10.3727/096504019X15736439848765

Nahathai Dukaew,*† Teruaki Konishi,‡§ Kongthawat Chairatvit,¶ Narongchai Autsavapromporn,# Noppamas Soonthornchareonnon,** and Ariyaphong Wongnoppavich†

*Graduate/PhD’s Degree Program in Biochemistry, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand
†Department of Biochemistry, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand
‡Single Cell Radiation Biology Group, Institute for Quantum Life Science, National Institutes for Quantum and Radiological Science and Technology (QST), Chiba, Japan
§Department of Basic Medical Sciences for Radiation Damages, National Institute of Radiological Sciences (NIRS), Chiba, Japan
¶Department of Oral Biology, Faculty of Dentistry, Mahidol University, Bangkok, Thailand
#Division of Radiation Oncology, Department of Radiology, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand
**Department of Pharmacognosy, Faculty of Pharmacy, Mahidol University, Bangkok, Thailand

Radiotherapy (RT) is an important treatment for non-small cell lung cancer (NSCLC). However, the major obstacles to successful RT include the low radiosensitivity of cancer cells and the restricted radiation dose, which is given without damaging normal tissues. Therefore, the sensitizer that increases RT efficacy without dose escalation will be beneficial for NSCLC treatment. Eurycomalactone (ECL), an active quassinoid isolated from Eurycoma longifolia Jack, has been demonstrated to possess anticancer activity. In this study, we aimed to investigate the effect of ECL on sensitizing NSCLC cells to X-radiation (X-ray) as well as the underlying mechanisms. The results showed that ECL exhibited selective cytotoxicity against the NSCLC cells A549 and COR-L23 compared to the normal lung fibroblast. Clonogenic survival results indicated that ECL treatment prior to irradiation synergistically decreased the A549 and COR-L23 colony number. ECL treatment reduced the expression of cyclin B1 and CDK1/2 leading to induce cell cycle arrest at the radiosensitive G₂/M phase. Moreover, ECL markedly delayed the repair of radiation-induced DNA double-strand breaks (DSBs). In A549 cells, pretreatment with ECL not only delayed the resolving of radiation-induced g-H2AX foci but also blocked the formation of 53BP1 foci at the DSB sites. In addition, ECL pretreatment attenuated the expression of DNA repair proteins Ku-80 and KDM4D in both NSCLC cells. Consequently, these effects led to an increase in apoptosis in irradiated cells. Thus, ECL radiosensitized the NSCLC cells to X-ray via G₂/M arrest induction and delayed the repair of X-ray-induced DSBs. This study offers a great potential for ECL as an alternative safer radiosensitizer for increasing the RT efficiency against NSCLC.

Key words: Eurycomalactone; Radiosensitization; Non-small cell lung cancer (NSCLC); G₂/M arrest; DNA double strand break (DSB) repair

IOX-101 Reverses Drug Resistance Through Suppression of Akt/mTOR/NF-κB Signaling in Cancer Stem Cell-Like, Sphere-Forming NSCLC Cell – 177
DOI: https://doi.org/10.3727/096504019X15746768080428

Majed Al Fayi,*† Ahmad Alamri,* and Prasanna Rajagopalan*†

*Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, King Khalid University, Abha, Saudi Arabia
†Central Research Laboratory, College of Applied Medical Sciences, King Khalid University, Abha, Saudi Arabia

Drug discovery research to fight lung cancer is incessantly challenged by drug resistance. In this study, we used drug-resistant lung cancer stem like cells (A549-CS) to compare the efficacy of standard drugs like cisplatin (DDP) and gemcitabine (GEM) with a novel arylidene derivative IOX-101. A549-CS was derived from regular A549 cells by growing in special media. Resistance proteins were detected using Western blotting. Cell proliferations were assessed by MTT assay. Cytokine release was enumerated using enzyme-linked immunosorbent assay. The effect of drugs on apoptosis and cell cycle was studied with flow cytometry protocols. Apoptosis-related proteins, caspases, and other signaling protein expressions like Akt and mammalian target of rapamycin (mTOR) were assessed by Western blotting. Expression of CD133 and nuclear factor κB (NF-κB) phosphorylation was assessed using flow cytometry. A549-CS showed significant increase in CD133 expression in comparison with A549 cells. Expression of resistance markers like MDR-1, lung resistance protein (LRP), and GST-II were detected in A549-CS. While DDP and GEM had relatively lower efficacy in A549-CS, IOX-101 inhibited the proliferation of both A549 and A549-CS with GI₅₀ values of 268 and 296.5 nM, respectively. IOX-101 increased the sub-G₀ phase in the cell cycle of A549-CS and increased the percentage of apoptotic cells. Western blot analysis revealed activation of caspases, Bax, and reduction in Bcl-2 levels. Further mechanistic investigation revealed IOX-101 to deactivate Akt, mTOR, and NF-κB signaling in A549-CS cells. Additionally, IOX-101 treatment to A549-CS also reversed MDR-1 and LRP expressions. Collectively, our results demonstrate efficacy of IOX-101 in A549-CS, which was resistant against the tested standard drugs. The activity was mediated by suppressing Akt/mTOR/NF-κB signaling.

Key words: A549; A549-CS; Akt; CD133; Drug resistance; GST-II; Lung resistance protein (LRP); Lung cancer; Multidrug resistance gene (MDR-1); mTOR; NF-κB; Stem-like cells

RPSAP52 lncRNA Inhibits p21Waf1/CIP Expression by Interacting With the RNA Binding Protein HuR – 191
DOI: https://doi.org/10.3727/096504019X15761465603129

Daniela D’Angelo,* Claudio Arra,† and Alfredo Fusco*

*Istituto per l’Endocrinologia e l’Oncologia Sperimentale (IEOS) “G. Salvatore,” Consiglio Nazionale delle Ricerche (CNR) c/o Dipartimento di Medicina Molecolare e Biotecnologie Mediche (DMMBM), Universita degli Studi di Napoli “Federico II,” Naples, Italy
†Animal Facility Unit, Istituto Nazionale dei Tumori, Fondazione Pascale, Naples, Italy

Long noncoding RNAs have been recently demonstrated to have an important role in fundamental biological processes, and their deregulated expression has been found in several human neoplasias. Our group has recently reported a drastic overexpression of the long noncoding RNA (lncRNA) RPSAP52 (ribosomal protein SA pseudogene 52) in pituitary adenomas. We have shown that this lncRNA increased cell proliferation by upregulating the expression of the chromatinic proteins HMGA1 and HMGA2, functioning as a competing endogenous RNA (ceRNA) through competitively binding to microRNA-15a (miR-15a), miR-15b, and miR-16. The aim of this work was to identify further mechanisms by which RPSAP52 overexpression could contribute to the development of pituitary adenomas. We investigated the involvement of RPSAP52 in the modulation of the expression of cell cycle-related genes, such as p21Waf1/CIP, whose deregulation plays a critical role in pituitary cell transformation. We report that RPSAP52, interacting with the RNA binding protein HuR (human antigen R), favors the delocalization of miR-15a, miR-15b, and miR-16 on the cyclin-dependent kinase inhibitor p21Waf1/CIP1 that, accordingly, results in downregulation in pituitary adenomas. A RNA immunoprecipitation sequencing (RIPseq) analysis performed on cells overexpressing RPSAP52 identified 40 messenger RNAs (mRNAs) enriched in Argonaute 2 (AGO2) immunoprecipitated samples. Among them, we focused on GAS8 (growth arrest-specific protein 8) gene. Consistently, GAS8 expression was downregulated in all the analyzed pituitary adenomas with respect to normal pituitary and in RPSAP52-overepressing cells, supporting the role of RPSAP52 in addressing genes involved in growth inhibition and cell cycle arrest to miRNA-induced degradation. This study unveils another RPSAP52-mediated molecular mechanism in pituitary tumorigenesis.

Key words: Pituitary adenomas; HMGA; p21Waf1/CIP; GAS8

miRNA-101 Targets TGF-βR1 to Retard the Progression of Oral Squamous Cell Carcinoma – 203
DOI: https://doi.org/10.3727/096504019X15761480623959

Yong Wang,* Rui-Zhi Jia,* Shu Diao,* Jun He,† and Li Jia†

*Department of Pediatric Dentistry, Beijing Stomatological Hospital & School of Stomatology, Capital Medical University, Beijing, China
†Evaluation and Research Center for Toxicology, Institute of Disease Control and Prevention of PLA, Beijing, China

Despite the considerable knowledge on the involvement of microRNA-101 (miR-101) in the evolution of oral squamous cell carcinoma (OSCC), the underlying mechanisms remain obscure. In this study, miR-101 expression was markedly downregulated in the OSCC cell lines and tissues. Cell counting kit-8 (CCK-8), ethynyl deoxyuridine (EdU), and colony formation assays showed that miR-101 inhibited the proliferation of OSCC cells. Flow cytometry and caspase 3 activity assays indicated that miR-101 induced OSCC cell apoptosis. Transwell assays demonstrated that this miRNA also repressed OSCC cell migration and invasion. Moreover, tube formation assay showed that miR-101 abated the proangiogenesis of OSCC cells. Dual-luciferase reporter assay confirmed that miR-101 directly targeted transforming growth factor-b receptor 1 (TGF-βR1) in OSCC. Ectopic expression of TGF-βR1 counteracted the effects of miR-101 on the OSCC cell characteristics. Thus, miR-101 significantly abolished the proliferation, motility, and proangiogenesis of OSCC cells and induced their apoptosis by targeting TGF-βR1. These results imply the potential application of miR-101 in OSCC treatment.

Key words: miR-101; Transforming growth factor-β receptor 1 (TGF-βR1); Oral squamous cell carcinoma (OSCC); Growth; Metastasis

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