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

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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 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.

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Access Current Articles (Volume 28, Number 3)

Volume 28, Number 3

PRKAA1 Promotes Proliferation and Inhibits Apoptosis of Gastric Cancer Cells Through Activating JNK1 and Akt Pathways – 213
DOI: https://doi.org/10.3727/096504019X15668125347026

Yangmei Zhang,*1 Xichang Zhou,†1 Long Cheng,† Xiang Wang,* Qinglin Zhang,‡ Youwei Zhang,* and Sanyuan Sun*

*Department of Oncology, Xuzhou Central Hospital, Xuzhou Medical University, Xuzhou, P.R. China
†Department of Intervention, Xuzhou Central Hospital, Xuzhou Medical University, Xuzhou, P.R. China
‡Department of Central Laboratory, Xuzhou Central Hospital, Xuzhou Medical University, Xuzhou, P.R. China

PRKAA1 (protein kinase AMP-activated catalytic subunit a 1) is a catalytic subunit of AMP-activated protein kinase (AMPK), which plays a key role in regulating cellular energy metabolism through phosphorylation, and genetic variations in the PRKAA1 have been found to be associated with gastric cancer risk. However, the effect and underlying molecular mechanism of PRKAA1 on gastric cancer tumorigenesis, especially the proliferation and apoptosis, are not fully understood. Our data showed that PRKAA1 is highly expressed in BGC-823 and MKN45 cells and is expressed low in SGC-7901 and MGC-803 cells in comparison with the other gastric cancer cells. PRKAA1 downregulation by shRNA or treatment of AMPK inhibitor compound C significantly inhibited proliferation as well as promoted cell cycle arrest and apoptosis of BGC-823 and MKN45 cells. Moreover, the expression of PCNA and Bcl-2 and the activity of JNK1 and Akt signaling were also reduced in BGC-823 and MKN45 cells after PRKAA1 downregulation. In vivo experiments demonstrated that tumor growth in nude mice was significantly inhibited after PRKAA1 silencing. Importantly, inactivation of JNK1 or Akt signaling pathway significantly inhibited PRKAA1 overexpression-induced increased cell proliferation and decreased cell apoptosis in MGC-803 cells. In conclusion, our findings suggest that PRKAA1 increases proliferation and restrains apoptosis of gastric cancer cells through activating JNK1 and Akt pathways.

Key words: Gastric cancer; PRKAA1; Apoptosis; JNK1; Akt

MicroRNA-6884-5p Regulates the Proliferation, Invasion, and EMT of Gastric Cancer Cells by Directly Targeting S100A16 – 225
DOI: https://doi.org/10.3727/096504019X15753718797664

Huifang Lv, Honglin Hou, Huijun Lei, Caiyun Nie, Beibei Chen, Liangyu Bie, Lili Han, and Xiaobing Chen

Department of Oncology, The Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China

S100 binding protein A16 (S100A16) expression levels are closely associated with microRNA (miRNA) processing. Higher levels of S100A16 are reported during the progression of many cancers. Our study mainly explored the interaction between S100A16 and miR-6884-5p in gastric cancer (GC). Quantitative real-time polymerase chain reaction (qRT-PCR) was used to determine the level of S100A16 and miR-6884-5p in GC tissues and cell lines. The si-S100A16, pcDNA-S100A16, miR-6884-5p mimic or inhibitor was transfected into GC cells, and the effects of S100A16 and miR-6884-5p on the proliferation, invasion, and epithelial–mesenchymal transition (EMT) were explored by qRT-PCR and Western blot assays. Luciferase assays were performed to validate S100A16 as an miR-6884-5p target in GC cells. In our study, we found that the level of miR-6884-5p was significantly decreased and the expression of S100A16 was significantly increased in GC tissues and cell lines. There was a close association between these changes. Knockdown of S100A16 significantly inhibited the proliferation, invasion, and EMT of GC cells. The bioinformatics analysis predicted that S100A16 is a potential target gene of miR-6884-5p, and the luciferase reporter assay confirmed that miR-6884-5p could directly target S100A16. Introduction of miR-6884-5p to GC cells had similar effects to S100A16 silencing. Overexpression of S100A16 in GC cells partially reversed the inhibitory effects of the miR-6884-5p mimic. miR-6884-5p inhibited the proliferation, invasion, and EMT of GC cells by directly decreasing S100A16 expression.

Key words: Gastric cancer (GC); MicroRNA-6884-5p; S100 binding protein A16; Proliferation; Invasion; Epithelial–mesenchymal transition (EMT)

Vinorelbine in Non-Small Cell Lung Cancer: Real-World Data From a Single-Institution Experience – 237
DOI: https://doi.org/10.3727/096504019X15755437099308

Stefania Nobili,* Daniele Lavacchi,† Gabriele Perrone,* Giulio Vicini,† Renato Tassi,‡ Ida Landini,* AnnaMaria Grosso,§ Giandomenico Roviello,*¶ Roberto Mazzanti,‡ Carmine Santomaggio,¶ and Enrico Mini*¶

*Section of Clinical Pharmacology and Oncology, Department of Health Science, University of Florence, Florence, Italy
†School of Human Health, University of Florence, Florence, Italy
‡Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
§Unit of Pneumology and Thoracic-Pulmonary Physiopathology, Careggi University Hospital, Florence, Italy
¶Unit of Translational Oncology, Careggi University Hospital, Florence, Italy

The use of vinorelbine as a single agent or in combination regimens in non-small cell lung cancer (NSCLC) is associated with satisfactory clinical activity. However, the role of vinorelbine-based chemotherapy in chemonaive locally advanced unresectable or metastatic NSCLC patients, according to real-world treatment patterns, has still not been widely explored. Eighty-one patients treated at a single institution were retrospectively analyzed. Thirty-seven received standard first-line single-agent vinorelbine, and 44 received vinorelbine plus platinum drugs, based on physician’s choice; 61.7% were older than 70 years, and 60.5% were affected by ≥2 comorbidities. Sixty-three patients were evaluable for objective response: 22% achieved partial response and 41% stable disease. Median progression-free survival (PFS) was 5.4 months. A benefit in PFS was observed in patients treated with combinations vs. single-agent vinorelbine (6.7 vs. 3.5 months, p = 0.043). Median overall survival (OS) was 10.4 months without a statistically significant difference between treatments (12.4 vs. 7.5 months). In 55 stage IV patients, OS was positively correlated with combination regimens, M1a stage, or ≤2 metastatic lesions. Grade 3–4 toxicity occurred in 33% of patients, and dose reduction in 11%. A statistically significant higher incidence of toxicity was observed in patients receiving combinations, in women, in patients younger than 75 years, or patients with metastases. In this real-word analysis, we confirmed the efficacy and tolerability of vinorelbine as a single agent or combined with platinums in patients usually underrepresented in controlled clinical trials. Single-agent vinorelbine may represent a suitable option in elderly or unfit NSCLC patients and warrants investigation as a potential drug candidate for immunochemotherapy combination regimens.

Key words: Vinorelbine; Non-small cell lung cancer (NSCLC); Elderly; Unfit

The Comprehensive Analysis of Efficacy and Safety of CalliSpheres® Drug-Eluting Beads Transarterial Chemoembolization in 367 Liver Cancer Patients: A Multiple-Center, Cohort Study – 249
DOI: https://doi.org/10.3727/096504019X15766663541105

Zhiyi Peng,* Guohong Cao,† Qinming Hou,‡ Ling Li,§ Shihong Ying,* Junhui Sun,¶ Guanhui Zhou,¶ Jian Zhou,# Xin Zhang,* Wenbin Ji,** Zhihai Yu,†† Tiefeng Li,‡‡ Dedong Zhu,§ Wenhao Hu,§§ Jiansong Ji,¶¶ Haijun Du,## Changsheng Shi,*** Xiaohua Guo,††† Jian Fang,‡‡‡ Jun Han,§§§ Wenjiang Gu,¶¶¶ Xiaoxi Xie,### Zhichao Sun,**** Huanhai Xu,†††† Xia Wu,‡‡‡‡ Tingyang Hu,§§§§ Jing Huang,¶¶¶¶ Hongjie Hu,‡‡‡‡ Jiaping Zheng,#### Jun Luo,#### Yutang Chen,#### Wenqiang Yu,§§§§ and Guoliang Shao####

*Department of Radiology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
†Department of Radiology, Shulan (Hangzhou) Hospital, Zhejiang University International Hospital, Hangzhou, China
‡Department of Radiology, Xixi Hospital of Hangzhou, Hangzhou 6th People’s Hospital, Hangzhou, China
§Department of Liver Oncology, Ningbo No. 2 Hospital, Ningbo, China
¶Hepatobiliary and Pancreatic Interventional Treatment Center, Division of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
#Department of Radiology, Hangzhou Cancer Hospital, Hangzhou, China
**Department of Radiology, Taizhou Hospital of Zhejiang Province, Linhai, China
††Department of Vascular and Interventional Radiology, The Affiliated Hospital of Medical College of Ningbo University, Ningbo, China
‡‡Department of Radiology, Beilun District People’s Hospital of Ningbo, Ningbo, China
§§Department of Intervention, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
¶¶Department of Radiology, Lishui Central Hospital, Lishui Hospital of Zhejiang University, The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui, China
##Department of Intervention, Dongyang People’s Hospital, Dongyang, China
***Department of Intervention, The Third Affiliated Hospital of Wenzhou Medical University, Ruian, China
†††Department of Intervention, Jinhua Central Hospital, Jinhua, China
‡‡‡Department of Hepatobiliary Surgery, Quzhou People’s Hospital, Quzhou, China
§§§Department of Intervention, Jiaxing First Hospital, Jiaxing, China
¶¶¶Department of Intervention, Jiaxing Second Hospital, Jiaxing, China
###Interventional Center, Xinchang People’s Hospital, Shaoxing, China
****Department of Radiology, The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, China
††††Division of Digestive Endoscopy, Yueqing City People’s Hospital, Yueqing, China
‡‡‡‡Department of Radiology, Sir Run Run Shaw Hospital, Zhejiang University College of Medicine, Hangzhou, China
§§§§Department of Intervention, Zhejiang Provincial People’s Hospital, Hangzhou, China
¶¶¶¶Department of Hepatobiliary Surgery, Ningbo Medical Center, Lihuili Eastern Hospital, Ningbo, China
####Department of Intervention, Zhejiang Cancer Hospital, Hangzhou, China

This study aimed to investigate the efficacy, safety, and prognostic factors of drug-eluting beads transarterial chemoembolization (DEB-TACE) in treating Chinese patients with liver cancer. A total of 367 liver cancer patients from 24 medical centers were consecutively enrolled in this multiple-center, prospective cohort study, including 275 hepatocellular carcinoma (HCC) cases, 37 intrahepatic cholangiocarcinoma (ICC) cases, and 55 secondary liver cancer cases. All the patients received CalliSpheres® DEB-TACE treatment. Treatment response, overall survival (OS), change of liver function, and adverse events (AEs) were assessed. DEB-TACE treatment achieved 19.9% complete response (CR) and 79.6% objective response rate (ORR), with mean OS of 384 days [95% confidence interval (CI): 375–393 days]. CR and ORR were both higher in HCC patients compared with primary ICC patients and secondary liver cancer patients, while no difference was discovered in OS. Portal vein invasion was an independent risk factor for CR, while portal vein invasion, previous conventional TACE (cTACE) treatment, and abnormal blood creatinine (BCr) were independent risk factors for ORR. In addition, largest nodule size ≥5.0 cm, abnormal albumin (ALB), and abnormal total bilirubin (TBIL) independently correlated with unfavorable OS. Most liver function indexes were recovered to baseline levels at 1–3 months after DEB-TACE. Common AEs were pain, fever, vomiting, and nausea; most of them were at mild grade. CalliSpheres® DEB-TACE is efficient and well tolerated in Chinese liver cancer patients. Portal vein invasion, previous cTACE treatment, largest nodule size, abnormal BCr, ALB, and TBIL correlate with worse prognosis independently.

Key words: Drug-eluting beads transarterial chemoembolization (DEB-TACE); Liver cancer; Efficacy; Safety; Prognosis

Fzd2 Contributes to Breast Cancer Cell Mesenchymal-Like Stemness and Drug Resistance – 273
DOI: https://doi.org/10.3727/096504020X15783052025051

Ping Yin,* Wei Wang,* Jian Gao,† Yu Bai,* Zhuo Wang,* Lei Na,* Yu Sun,* and Chenghai Zhao*

*Department of Pathophysiology, College of Basic Medical Science, China Medical University, Shenyang, China
†Center of Laboratory Technology and Experimental Medicine, China Medical University, Shengyang, China

Cancer cell stemness is responsible for cancer relapse, distal metastasis, and drug resistance. Here we identified that Frizzled 2 (Fzd2), one member of Wnt receptor Frizzled family, induced human breast cancer (BC) cell stemness via noncanonical Wnt pathways. Fzd2 was overexpressed in human BC tissues, and Fzd2 overexpression was associated with an unfavorable outcome. Fzd2 knockdown (KD) disturbed the mesenchymal-like phenotype, migration, and invasion of BC cells. Moreover, Fzd2 KD impaired BC cell mammosphere formation, reduced Lgr5⁺ BC cell subpopulation, and enhanced sensitivity of BC cells to chemical agents. Mechanistically, Fzd2 modulated and bound with Wnt5a/b and Wnt3 to activate several oncogenic pathways such as interleukin-6 (IL-6)/Stat3, Yes-associated protein 1 (Yap1), and transforming growth factor-β1 (TGF-β1)/Smad3. These data indicate that Fzd2 contributes to BC cell mesenchymal-like stemness; targeting Fzd2 may inhibit BC recurrence, metastasis, and chemoresistance.

Key words: Frizzled 2 (Fzd2); Mesenchymal-like stemness; Lgr5; Drug resistance; Wnt

Correlating Transcriptional Networks to Papillary Renal Cell Carcinoma Survival: A Large-Scale Coexpression Analysis and Clinical Validation – 285
DOI: https://doi.org/10.3727/096504020X15791676105394

Xingliang Feng,*1 Meng Zhang,*†1 Jialin Meng,* Yongqiang Wang,† Yi Liu,* Chaozhao Liang,* and Song Fan*

*Department of Urology, The First Affiliated Hospital of Anhui Medical University, Institute of Urology, Anhui Province Key Laboratory of Genitourinary Diseases, Anhui Medical University, Hefei, China
†Urology Institute of Shenzhen University, The Third Affiliated Hospital of Shenzhen University, Shenzhen University, Shenzhen, China

We aimed to investigate the potential mechanisms of progression and identify novel prognosis-related biomarkers for papillary renal cell carcinoma (PRCC) patients. The related data were derived from The Cancer Genome Atlas (TCGA) and then analyzed by weighted gene coexpression network analysis (WGCNA). The correlation between each module and the clinical traits were analyzed by Pearson’s correlation analysis. Pathway analysis was conducted to reveal potential mechanisms. Hub genes within each module were screened by intramodule analysis, and visualized by Cytoscape software. Furthermore, important hub genes were validated in an external dataset and clinical samples. A total of 5,839 differentially expressed genes were identified. By using WGCNA, we identified 21 coregulatory gene clusters based on 289 PRCC samples. We found many modules were significantly associated with clinicopathological characteristics. The gray, pink, light yellow, and salmon modules served as prognosis indicators for PRCC patients. Pathway enrichment analyses found that the hub genes were significantly enriched in the cancer-related pathways. With the external Gene Expression Omnibus (GEO) validation dataset, we found that PCDH12, GPR4, and KIF18A in the pink and yellow modules were continually associated with the survival status of PRCC, and their expressions were positively correlated with pathological grade. Notably, we randomly chose PCDH12 for validation, and the results suggested that the PRCC patients with higher pathological grades (II + III) mostly had higher PCDH12 protein expression levels compared with those patients in grade I. These validated hub genes play critical roles in the prognosis prediction of PRCC and serve as potential biomarkers for future personalized treatment.

Key words: Papillary renal cell carcinoma (PRCC); Weighted gene coexpression network analysis (WGCNA); Hub gene; Prognosis

MafF Is Regulated via the circ-ITCH/miR-224-5p Axis and Acts as a Tumor Suppressor in Hepatocellular Carcinoma – 299
DOI: https://doi.org/10.3727/096504020X15796890809840

Minhua Wu,* Xubin Deng,† Yu Zhong,‡ Li Hu,* Xiujuan Zhang,§ Yanqin Liang,* Xiaofang Li,¶ and Xiaoxia Ye*

*Department of Histology and Embryology, Guangdong Medical University, Zhanjiang, P.R. China
†Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou, P.R. China
‡Analysis Center, Guangdong Medical University, Zhanjiang, P.R. China
§Department of Physiology, Guangdong Medical University, Zhanjiang, P.R. China
¶Pathological Diagnosis and Research Center, Affiliated Hospital of Guangdong Medical University, Zhanjiang, P.R. China

MafF is a member of the basic leucine zipper (bZIP) transcription factor Maf family and is commonly downregulated in multiple cancers. But the expression and function of MafF in hepatocellular carcinoma (HCC) remain unclear. In this study, we investigated the relationship between endogenous MafF expression and HCC progression and explored the regulatory mechanism of MafF expression in HCC. We found that MafF decreased in HCC tissues and cells. Lentivirus-mediated MafF overexpression inhibited HCC cell proliferation and induced cell apoptosis. Bioinformatics analysis and luciferase assay identified MafF as a direct target of miR-224-5p. RNA pull-down assay demonstrated that circular RNA circ-ITCH could sponge miR-224-5p specifically in HCC. The rescue experiments further elucidated that the expression and antitumor effects of MafF could be regulated via the circ-ITCH/miR-224-5p axis. This study verified that MafF acted as a tumor suppressor in HCC and revealed the upstream regulation mechanism of MafF, which provided a new perspective for potential therapeutic targets of HCC.

Key words: MafF; miR-224-5p; circ-ITCH; Hepatocellular carcinoma (HCC)

lncRNA HOXA11-AS Promotes Proliferation and Migration via Sponging miR-155 in Hypopharyngeal Squamous Cell Carcinoma – 311
DOI: https://doi.org/10.3727/096504020X15801233454611

Jianing Xu,*† Qiyu Bo,‡ Xiang Zhang,§ Dapeng Lei,† Jue Wang,* and Xinliang Pan†

*Central Lab, Institute of Medical Science, The Second Hospital of Shandong University, Jinan, China
†Department of Otorhinolaryngology, Qilu Hospital of Shandong University, NHC Key Laboratory of Otorhinolaryngology (Shandong University), Jinan, China
‡Department of First Operating Room, Qilu Hospital of Shandong University, Jinan, China
§Department of Urology, Qilu Hospital of Shandong University, Jinan, China

Hypopharyngeal squamous cell carcinoma (HSCC) remains one of the most lethal malignancies in the head and neck. Long noncoding RNA (lncRNA) HOXA11-AS is proven to function as an oncogene and a therapeutic target in various tumors. Our previous study and others have demonstrated that HOXA11-AS is one of the most upregulated lncRNAs in HSCC. However, the role of HOXA11-AS in HSCC has not yet been identified. The current study demonstrated that the expression of HOXA11-AS was significantly upregulated in HSCC tumors and was positively associated with lymph node metastasis. Moreover, functional experiments revealed that HOXA11-AS knockdown suppressed the proliferation and migration potential in FaDu cells. Furthermore, luciferase reporter gene assay combined with cellular functional experiments demonstrated that HOXA11-AS functioned as a molecular sponge for miR-155, and inhibition of miR-155 attenuated the suppressive effect of HOXA11-AS knockdown on the aggressive phenotype in HSCC. This study identifies a tumor-promoting role of HOXA11-AS in HSCC and suggests HOXA11-AS might be a potential diagnostic and therapeutic target for HSCC.

Key words: Hypopharyngeal squamous cell carcinoma (HSCC); Long noncoding RNAs (lncRNAs); HOXA11-AS; miR-155; Proliferation; Migration

miRNA–mRNA Profiling Reveals Prognostic Impact of SMC1A Expression in Acute Myeloid Leukemia – 321
DOI: https://doi.org/10.3727/096504020X15816752427321

Nikhil Gadewal,* Rohit Kumar,† Swapnil Aher,† Anagha Gardane,† Tarang Gaur,† Ashok K. Varma,*‡§ Navin Khattry,¶ and Syed K. Hasan†§¶

*Bioinformatics Centre, Advanced Centre for Treatment, Research and Education in Cancer (ACTREC), Navi Mumbai, India
†Cell and Tumor Biology Group, Advanced Centre for Treatment, Research and Education in Cancer, Navi Mumbai, India
‡Varma Laboratory, Advanced Centre for Treatment, Research and Education in Cancer, Navi Mumbai, India
§Homi Bhabha National Institute (HBNI), Anushaktinagar, Mumbai, India
¶Adult Hemato-lymphoid Disease Management Group, Tata Memorial Hospital, Mumbai, India

Acute myeloid leukemia (AML) with NPM1 mutation is a disease driving genetic alteration with good prognosis. Although it has been suggested that NPM1 mutation induces chemosensitivity in leukemic cells, the underlying cause for the better survival of NPM1 mutated patients is still not clear. Mutant NPM1 AML has a unique microRNA and their target gene (mRNA) signature compared to wild-type NPM1. Dynamic regulation of miRNA–mRNA has been reported to influence the prognostic outcome. In the present study, in silico expression data of miRNA and mRNA in AML patients was retrieved from genome data commons, and differentially expressed miRNA and mRNA among NPM1 mutated (n = 21) and NPM1 wild-type (n = 162) cases were identified to establish a dynamic association at the molecular level. In vitro experiments using highthroughput RNA sequencing were performed on human AML cells carrying NPM1 mutated and wild-type allele. The comparison of in vitro transcriptomics data with in silico miRNA–mRNA expression network data revealed downregulation of SMC1A. On establishing miRNA–mRNA interactive pairs, it has been observed that hsa-mir-215-5p (logFC: 0.957; p = 0.0189) is involved in the downregulation of SMC1A (logFC: –0.481; p = 0.0464) in NPM1 mutated AML. We demonstrated that transient expression of NPM1 mutation upregulates miR-215-5p, which results in downregulation of SMC1A. We have also shown using a rescue experiment that neutralizing miR-215-5p reverses the effect of NPM1 mutation on SMC1A. Using the leukemic blasts from AML patients, we observed higher expression of miR-215-5p and lower expression of SMC1A in NPM1 mutated patients compared to wild-type cases. The overall survival of AML patients was significantly inferior in SMC1A high expressers compared to low expressers (20.3% vs. 58.5%, p = 0.018). The data suggest that dynamic miR-215-SMC1A regulation is potentially modulated by NPM1 mutation, which might serve as an explanation for the better outcome in NPM1 mutated AML.

Key words: miRNA–mRNA; NPM1 mutation; Acute myeloid leukemia (AML); SMC1A

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