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.

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.

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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.

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Oncology Research (OR) Peer Review Policy

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

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

The peer review process for OR is laid out below:

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

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

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

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

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

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

Ethics Statement

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

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

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

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

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

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

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

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

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

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

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

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

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Access Current Articles (Volume 28, Number 6)

Volume 28, Number 6

Original Contributions

Microenvironment Analysis of Prognosis and Molecular Signature of Immune-Related Genes in Lung Adenocarcinoma – 561
DOI: https://doi.org/10.3727/096504020X15907428281601

Bo Ling, Zuliang Huang, Suoyi Huang, Li Qian, Genliang Li, and Qianli Tang

Youjiang Medical University for Nationalities, Baise, Guangxi, P.R. China

There is growing evidence on the clinical significance of tumor microenvironment (TME) cells in predicting prognosis and therapeutic effects. However, cell interactions in tumor microenvironments have not been thoroughly studied or systematically analyzed so far. In this study, 22 immune cell components in the lung adenocarcinoma (LUAD) TME were analyzed using gene expression profile from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO). The TME-based molecular subtypes of LUAD were defined to evaluate further the relationship between molecular subtypes, prognosis, and clinical characteristics. A TME risk score model was constructed by using the differentially expressed genes (DEGs) of molecular subtypes. The relationship between the TME score and clinical characteristics and genomic mutations was compared to identify the genes that have significant associations with the TME. The comprehensive analysis of the TME characteristics may be helpful in revealing the response of LUAD patients to immunotherapy, providing a new strategy for immunotherapy.

Key words: Tumor microenvironment; Lung adenocarcinoma; The Cancer Genome Atlas (TCGA); Gene Expression Omnibus (GEO); Immunotherapy

IL-24-Armed Oncolytic Vaccinia Virus Exerts Potent Antitumor Effects via Multiple Pathways in Colorectal Cancer – 579
DOI: https://doi.org/10.3727/096504020X15942028641011

Lili Deng,* Xue Yang,† Jun Fan,* Yuedi Ding,* Ying Peng,* Dong Xu,* Biao Huang,*‡ and Zhigang Hu†

*NHC Key Laboratory of Nuclear Medicine, Jiangsu Key Laboratory of Molecular Nuclear Medicine, Jiangsu Institute of Nuclear Medicine, Wuxi, P.R. China
†Wuxi Children’s Hospital, Wuxi People’s Hospital Affiliated to Nanjing Medical University, Wuxi, P.R. China
‡School of Life Science, Zhejiang Sci-Tech University, Hangzhou, P.R. China

Colorectal cancer is an aggressive malignancy for which there are limited treatment options. Oncolytic vaccinia virus is being developed as a novel strategy for cancer therapy. Arming vaccinia virus with immunostimulatory cytokines can enhance the tumor cell-specific replication and antitumor efficacy. Interleukin-24 (IL-24) is an important immune mediator, as well as a broad-spectrum tumor suppressor. We constructed a targeted vaccinia virus of Guang9 strain harboring IL-24 (VG9-IL-24) to evaluate its antitumor effects. In vitro, VG9-IL-24 induced an increased number of apoptotic cells and blocked colorectal cancer cells in the G₂/M phase of the cell cycle. VG9-IL-24 induced apoptosis in colorectal cancer cells via multiple apoptotic signaling pathways. In vivo, VG9-IL-24 significantly inhibited the tumor growth and prolonged the survival both in human and murine colorectal cancer models. In addition, VG9-IL-24 stimulated multiple antitumor immune responses and direct bystander antitumor activity. Our results indicate that VG9-IL-24 can inhibit the growth of colorectal cancer tumor by inducing oncolysis and apoptosis as well as stimulating the antitumor immune effects. These findings indicate that VG9-IL-24 may exert a potential therapeutic strategy for combating colorectal cancer.

Key words: Oncolytic vaccinia virus; Interleukin-24 (IL-24); Colorectal cancer (CRC); Immunotherapy; Apoptosis

Long Noncoding RNA WEE2-AS1 Plays an Oncogenic Role in Glioblastoma by Functioning as a Molecular Sponge for MicroRNA-520f-3p – 591
DOI: https://doi.org/10.3727/096504020X15982623243955

Hengzhou Lin, Dahui Zuo, Jiabin He, Tao Ji, Jianzhong Wang, and Taipeng Jiang

Department of Neurosurgery, Shenzhen Second People’s Hospital, the First Affiliated Hospital of Shenzhen University, Health Science Center, Shenzhen, P.R. China

The long noncoding RNA WEE2 antisense RNA 1 (WEE2-AS1) plays an oncogenic role in hepatocellular carcinoma and triple negative breast cancer progression. In this study, we investigated the expression and roles of WEE2-AS1 in glioblastoma (GBM). Furthermore, the molecular mechanisms behind the oncogenic actions of WEE2-AS1 in GBM cells were explored in detail. WEE2-AS1 expression was detected using quantitative real-time polymerase chain reaction. The roles of WEE2-AS1 in GBM cells were evaluated by the cell counting kit-8 assay, flow cytometric analysis, Transwell cell migration and invasion assays, and tumor xenograft experiments. WEE2-AS1 expression was evidently enhanced in GBM tissues and cell lines compared with their normal counterparts. An increased level of WEE2-AS1 was correlated with the average tumor diameter, Karnofsky Performance Scale score, and shorter overall survival among GBM patients. Functionally, depleted WEE2-AS1 attenuated GBM cell proliferation, migration, and invasion in vitro, promoted cell apoptosis, and impaired tumor growth in vivo. Mechanistically, WEE2-AS1 functioned as a molecular sponge for microRNA- 520f-3p (miR-520f-3p) and consequently increased specificity protein 1 (SP1) expression in GBM cells. A series of recovery experiments revealed that the inhibition of miR-520f-3p and upregulation of SP1 could partially abrogate the influences of WEE2-AS1 downregulation on GBM cells. In conclusion, WEE2-AS1 can adsorb miR-520f-3p to increase endogenous SP1 expression, thereby facilitating the malignancy of GBM. Therefore, targeting the WEE2-AS1–miR-520f-3p–SP1 pathway might be a promising therapy for the management of GBM in the future.

Key words: Glioblastoma (GBM); Competing endogenous RNAs (ceRNAs); Long noncoding RNAs (lncRNAs); MicroRNAs (miRNAs)

The Usefulness of Pretreatment MR-Based Radiomics on Early Response of Neoadjuvant Chemotherapy in Patients With Locally Advanced Nasopharyngeal Carcinoma – 605
DOI: https://doi.org/10.3727/096504020X16022401878096

Piao Yongfeng,*†‡§1 Jiang Chuner,*¶#1 Wang Lei,*†‡§ Yan Fengqin,*†‡§ Ye Zhimin,*†‡§ Fu Zhenfu,*†‡§ Jiang Haitao,*,**†† Jiang Yangming,‡‡ and Wang Fangzheng*†‡§

*Department of Radiation Oncology, Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Zhejiang, P.R. China
†Institute of Cancer and Basic Medicine (ICBM), Chinese Academy of Sciences, Zhejiang, P.R. China
‡Key Laboratory of Head Neck Cancer of Zhejiang Province, Zhejiang Cancer Hospital, Zhejiang, P.R. China
§Key Laboratory of Radiation Oncology of Zhejiang Province, Zhejiang, P.R. China
¶Department of Breast Tumor Surgery, Cancer Hospital of the University of Chinese Academy of Sciences, Zhejiang, P.R. China
#Department of Breast Tumor Surgery, Zhejiang Cancer Hospital, Zhejiang, P.R. China
**Department of Radiology, Cancer Hospital of the University of Chinese Academy of Sciences, Zhejiang, P.R. China
††Department of Radiology, Zhejiang Cancer Hospital, Zhejiang, P.R. China
‡‡Department of Digital Earth, Institute of Remote Sensing and Digital Earth, CAS, Beijing, P.R. China

The aim of this study was to explore the predictive role of pretreatment MRI-based radiomics on early response of neoadjuvant chemotherapy (NAC) in locoregionally advanced nasopharyngeal carcinoma (NPC) patients. Between January 2016 and December 2016, a total of 108 newly diagnosed NPC patients who were hospitalized in the Cancer Hospital of the University of Chinese Academy of Sciences were reviewed. All patients had complete data of enhanced MR of nasopharynx before treatment, and then received two to three cycles of TP-based NAC. After 2 cycles of NAC, enhanced MR of nasopharynx was conducted again. Compared with the enhanced MR images before treatment, the response after NAC was evaluated. According to the evaluation criteria of RECIST1.1, 108 cases were divided into two groups: 52 cases for the NAC-sensitive group and 56 cases for the NAC-resistance group. ITK-SNAP software was used to manually sketch and segment the region of interest (ROI) of nasopharyngeal tumor on the MR enhanced T1WI sequence image. The parameters were analyzed and extracted by using AI Kit software. ANOVA/MW test, correlation analysis, and LASSO were used to select texture features. We used multivariate logistic regressions to select texture features and establish a predictive model. The ROC curve was used to evaluate the efficiency of the predictive model. A total of 396 texture features were obtained by using feature calculation. After all features were screened, we selected two features including ClusterShade_angle135_offset4 and Correlation_AllDirection_offshe1_SD. Based on these two features, we established a predictive model by using multivariate logistic regression. The AUC of the two features used alone (0.804, 95% CI = 0.602–0.932; 0.762, 95% CI = 0.556–0.905) was smaller than the combination of these two features (0.905, 95% CI = 0.724–0.984, p = 0.0005). Moreover, the sensitivity values of the two features used alone and the combined use were 92.9%, 51.7%, and 85.7%, respectively, while the specificity values were 66.7%, 91.7%, and 83.3%, respectively, in the early response of NAC for NPC. The predictive model based on MRI-enhanced sequence imaging could distinguish the sensitivity and resistance to NAC and provide new biomarkers for the early prediction of the curative effect in NPC patients.

Key words: Nasopharyngeal carcinoma (NPC); Neoadjuvant chemotherapy (NAC); Response prediction; Magnetic resonance imaging (MRI); Radiomics; Texture analysis

MicroRNA-548m Suppresses Cell Migration and Invasion by Targeting Aryl Hydrocarbon Receptor in Breast Cancer Cells – 615
DOI: https://doi.org/10.3727/096504020X16037933185170

WM Farhan Syafiq B. WM Nor,*† Ivy Chung,‡§ and Nur Akmarina B. M. Said†

*Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
†Department of Pharmaceutical Life Sciences, Faculty of Pharmacy, University of Malaya, Kuala Lumpur, Malaysia
‡Department of Pharmacology, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
§University of Malaya Cancer Research Institute, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia

Breast cancer is the most commonly diagnosed cancer among women and one of the leading causes of cancer mortality worldwide, in which the most severe form happens when it metastasizes to other regions of the body. Metastasis is responsible for most treatment failures in advanced breast cancer. Epithelial–mesenchymal transition (EMT) plays a significant role in promoting metastatic processes in breast cancer. MicroRNAs (miRNAs) are highly conserved endogenous short noncoding RNAs that play a role in regulating a broad range of biological processes, including cancer initiation and development, by functioning as tumor promoters or tumor suppressors. Expression of miR-548m has been found in various types of cancers, but the biological function and molecular mechanisms of miR-548m in cancers have not been fully studied. Here we demonstrated the role of miR-548m in modulating EMT in the breast cancer cell lines MDA-MB-231 and MCF-7. Expression data for primary breast cancer obtained from NCBI GEO data sets showed that miR-548m expression was downregulated in breast cancer patients compared with healthy group. We hypothesize that miR-548m acts as a tumor suppressor in breast cancer. Overexpression of miR-548m in both cell lines increased E-cadherin expression and decreased the EMT-associated transcription factors SNAI1, SNAI2, ZEB1, and ZEB2, as well as MMP9 expression. Consequently, migration and invasion capabilities of both MDA-MB-231 and MCF-7 cells were significantly inhibited in miR-548m-overexpressing cells. Analysis of 1,059 putative target genes of miR-548m revealed common pathways involving both tight junction and the mTOR signaling pathway, which has potential impacts on cell migration and invasion. Furthermore, this study identified aryl hydrocarbon receptor (AHR) as a direct target of miR-548m in breast cancer cells. Taken together, our findings suggest a novel function of miR-548m in reversing the EMT of breast cancer by reducing their migratory and invasive potentials, at least in part via targeting AHR expression.

Key words: Breast cancer; MicroRNA-548m; Aryl hydrocarbon receptor; Epithelial–mesenchymal transition (EMT); Invasion; Migration

PNN and KCNQ1OT1 Can Predict the Efficacy of Adjuvant Fluoropyrimidine-Based Chemotherapy in Colorectal Cancer Patients – 631
DOI: https://doi.org/10.3727/096504020X16056983169118

Andrea Lapucci,*† Gabriele Perrone,*† Antonello Di Paolo,‡§ Cristina Napoli,*† Ida Landini,*† Giandomenico Roviello,*† Laura Calosi,¶ Antonio Giuseppe Naccarato,# Alfredo Falcone,# Daniele Bani,¶ Enrico Mini,*†§ and Stefania Nobili*†§

*Department of Health Sciences, University of Florence, Florence, Italy
†DENOTHE Excellence Center, University of Florence, Florence, Italy
‡Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
§Cancer Pharmacology Working Group of the Italian Society of Pharmacology, Milan, Italy
¶Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
#Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy

The benefit of adjuvant chemotherapy in the early stages of colorectal cancer (CRC) is still disappointing and the prediction of treatment outcome quite difficult. Recently, through a transcriptomic approach, we evidenced a role of PNN and KCNQ1OT1 gene expression in predicting response to fluoropyrimidine-based adjuvant chemotherapy in stage III CRC patients. Thus, the aim of this study was to validate in an independent cohort of stages II–III CRC patients our previous findings. PNN and KCNQ1OT1 mRNA expression levels were evaluated in 74 formalin-fixed paraffin-embedded tumor and matched normal mucosa samples obtained by stages II–III CRC patients treated with fluoropyrimidine-based adjuvant chemotherapy. PININ, the protein encoded by PNN, was immunohistochemically evaluated in 15 tumor and corresponding normal mucosa samples, selected on the basis of a low, medium, or high mRNA expression tumor/mucosa ratio. PNN and KCNQ1OT1 mRNA mean expression levels were significantly higher in tumor compared with normal tissues. Patients with high PNN or KCNQ1OT1 tumor mRNA levels according to ROC-based cutoffs showed a shorter disease-free survival (DFS) compared with patients with low tumor mRNA gene expression. Also, patients with tumor mRNA expression values of both genes below the identified cutoffs had a significantly longer DFS compared with patients with the expression of one or both genes above the cutoffs. In a representative large cohort of stages II–III CRC untreated patients retrieved from GEO datasets, no difference in DFS was observed between patients with high and low PNN or KCNQ1OT1 gene expression levels. These data confirm our previous findings and underscore the relevance of PNN and KCNQ1OT1 expression in predicting DFS in early stages of CRC treated with fluoropyrimidine-based adjuvant chemotherapy. If further validated in a prospective case series, both biomarkers could be used to identify patients who benefit from this treatment and to offer alternative chemotherapy regimens to potential unresponsive patients. In relation to the suggested biological role of PNN and KCNQ1OT1 in CRC, they might also be exploited as potential therapeutic targets.

Key words: Colorectal cancer; Adjuvant chemotherapy; Predictive biomarkers; Gene expression; PNN; KCNQ1OT1

Targeted Therapeutic Approaches in Vulvar Squamous Cell Cancer (VSCC): Case Series and Review of the Literature – 645
DOI: https://doi.org/10.3727/096504020X16076861118243

Linn Woelber,*1 Sabrina Mathey,*1 Katharina Prieske,*† Sascha Kuerti,* Christoph Hillen,* Eike Burandt,‡ Anja Coym,§ Volkmar Mueller,* Barbara Schmalfeldt,* and Anna Jaeger*

*Department of Gynecology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
†Mildred Scheel Cancer Career Center HaTriCS4, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
‡Department of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
§Center for Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

Therapeutic options in recurrent or metastasized vulvar squamous cell cancer (VSCC) not amenable to radiotherapy or radical surgery are limited. Evidence for the use of targeted therapies is sparse. All patients with VSCC treated at the Gynecological Cancer Center Hamburg-Eppendorf 2013–2019 were retrospectively evaluated for targeted therapeutic approaches. Furthermore, a MEDLINE, EMBASE, Web of Science, Scopus, and OVID database search was performed using the terms: “vulvar cancer” AND “targeted therapy,” “erlotinib,” “EGFR,” “bevacizumab,” “VEGF,” “pembrolizumab,” or “immunotherapy.” Twelve of 291 patients (4.1%) with VSCC received at least one targeted therapy at our institution. Previously, one or more platinum-based chemotherapy was applied to all patients [median 3.5 previous lines (range 2–5)]. In the erlotinib subgroup, two of five patients (40%) achieved stable disease (SD), while two patients (2/5, 40%) experienced partial response (PR). Treatment was given as monotherapy in second/third line for a median of 3.4 months (range 2–6 months). Bevacizumab (n = 9) was given as maintenance therapy after platinum-based first-line chemotherapy (9/9); best response was complete response (CR) (n = 2/9 22.2%). Median duration of treatment was 7 months (range 4–13 months) with two patients still under ongoing treatment. Best response in the pembrolizumab (n = 3) subset was SD (n = 1/3 33%). Treatment was given as monotherapy in second/third line for a median of 3.3 months (range 3–4 months). Nine of 12 patients (75%) experienced treatment-related adverse events (TRAEs), most commonly grade 1/2. Rapidly evolving antibody treatments have proven clinical benefit especially in HPV-driven tumor entities; however, clinical investigations in VSCC are still limited. These reported cases provide evidence for the clinical utility and feasibility while ensuring an acceptable safety profile.

Key words: Vulvar cancer (VC); Targeted therapy; EGFR targeting; VEGF signaling pathway; Immuno-oncology

Review

Frizzled Receptors in Tumors, Focusing on Signaling, Roles, Modulation Mechanisms, and Targeted Therapies – 661
DOI: https://doi/org/10.3727/096504020X16014648664459

Yu Sun, Wei Wang, and Chenghai Zhao

Department of Pathophysiology, College of Basic Medical Science, China Medical University, Shenyang, P.R. China

Wnt molecules play crucial roles in development and adult homeostasis through their receptors Frizzled proteins (Fzds). Fzds mediate canonical b-catenin pathway and various noncanonical b-catenin-independent pathways. Aberrant Fzd signaling is involved in many diseases including cancer. Wnt/b-catenin is a well-established oncogenic pathway involved in almost every aspect of tumor development. However, Fzd-mediated noncanonical Wnt pathways function as both tumor promoters and tumor suppressors depending on cellular context. Fzd-targeted therapies have proven to be effective on cultured tumor cells, tumor cell xenografts, mouse tumor models, and patient-derived xenografts (PDX). Moreover, Fzd-targeted therapies synergize with chemotherapy in preclinical models. However, the occurrence of fragility fractures in patients treated with Fzd-targeted agents such as OMP-54F28 and OMP-18R5 limits the development of this combination. Along with new insights on signaling, roles, and modulation mechanisms of Fzds in human tumors, more Fzd-related therapeutic targets will be developed.

Key words: Wnt; Frizzled; β-Catenin; Tumor

Erratums

Erratum – 675
DOI: https://doi.org/10.3727/096504021X16137463165406

The following was originally published in Volume 26, No. 2, pages 209–217, 2018 (doi: https://doi.org/10.3727/096504017X14944585873622). In the original article there were inadvertent mistakes for images of Western blot in Figures 2, 3, 4, 5, and 6. The figures have been reorganized using images from repeated experiments to rectify the errors. Corrected versions of the figures are shown here and the figures have been replaced with the corrected versions in the original published article in the online site (https://www.ingentaconnect.com/contentone/cog/or/2018/00000026/00000002/art00005). The corrections do not change any conclusion of the article. The authors apologize for any inconvenience caused.

Procaine Inhibits the Proliferation and Migration of Colon Cancer Cells Through Inactivation of the ERK/MAPK/FAK Pathways by Regulation of RhoA
Chang Li,* Shuohui Gao,* Xiaoping Li,† Chang Li,‡ and Lianjun Ma§

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

Colon cancer is one of the most lethal varieties of cancer. Chemotherapy remains as one of the principal treatment approaches for colon cancer. The anticancer activity of procaine (PCA), which is a local anesthetic drug, has been explored in different studies. In our study, we aimed to explore the anticancer effect of PCA on colon cancer and its underlying mechanism. The results showed that PCA significantly inhibited cell viability, increased the percentage of apoptotic cells, and decreased the expression level of RhoA in HCT116 cells in a dose-dependent manner (p < 0.05 or p < 0.01). Moreover, PCA increased the proportion of HCT116 cells in the G₁ phase as well as downregulated cyclin D1 and cyclin E expressions (p < 0.05). In addition, we found that PCA remarkably inhibited cell migration in HCT116 cells (p < 0.01). However, all these effects of PCA on cell proliferation, apoptosis, and migration were significantly reversed by PCA + pc-RhoA (p < 0.05 or p < 0.01). PCA also significantly decreased the levels of p-ERK, p-p38MAPK, and p-FAK, but PCA + pc-RhoA rescued these effects. Furthermore, the ERK inhibitor (PD098059), p38MAPK inhibitor (SB203580), and FAK inhibitor (Y15) reversed these results. These data indicate that PCA inhibited cell proliferation and migration but promoted apoptosis as well as inactivated the ERK/MAPK/FAK pathways by regulation of RhoA in HCT116 cells. Key words: Colon cancer; HCT116; Procaine (PCA); RhoA; ERK/MAPK/FAK

Erratum – 681
DOI: https://doi.org/10.3727/096504021X16137463165424

The following was originally published in Volume 27, No. 2, pages 193–202, 2019 (doi: https://doi.org/10.3727/096504018X15150662230295). There was an error in the Matrigel Transwell assay in Figure 2A. A corrected version of the figure is shown here and the figure has been replaced with the corrected version in the original published article in the online site (https://www.ingentaconnect.com/contentone/cog/or/2019/00000027/00000002/art00007). All authors sincerely apologize for the error and all inconveniences caused.

Emodin Inhibits Colon Cancer Cell Invasion and Migration by Suppressing Epithelial–Mesenchymal Transition via the Wnt/β-Catenin Pathway

Juan Gu,* Chang-fu Cui,† Li Yang,‡ Ling Wang,* and Xue-hua Jiang*

*Department of Clinical Pharmacy, West China School of Pharmacy, Sichuan University, Sichuan, P.R. China
†Department of Neurology, Research Institute of China Weapons Industry, 521 Hospital, Shanxi, P.R. China
‡Microbiological Laboratory, Xinyang Vocational and Technical College, Henan, P.R. China

Colon cancer (CC) is the third most common cancer worldwide. Emodin is an anthraquinone-active substance that has the ability to affect tumor progression. Our study aims to explore the effects and the relevant mechanism of emodin on the invasion and migration of CC in vitro and in vivo. In our study, we found that emodin inhibited the invasion and migration abilities of RKO cells and decreased the expression of matrix metalloproteinase-7 (MMP-7), MMP-9, and vascular endothelial growth factor (VEGF) in a dose-dependent manner. Further research suggested that emodin inhibited EMT by increasing the mRNA level of E-cadherin and decreasing the expression of N-cadherin, Snail, and b-catenin. Emodin also significantly inhibited the activation of the Wnt/β-catenin signaling pathway by downregulating the expression of related downstream target genes, including TCF4, cyclin D1, and c-Myc. A Wnt/β-catenin signaling pathway agonist abolished the effect of emodin on EMT and cell mobility, suggesting that emodin exerted its regulating role through the Wnt/b-catenin pathway. The CC xenograft model was established to study the antitumor efficiency of emodin in vivo. The in vivo study further demonstrated that emodin (40 mg/kg) suppressed tumor growth by inhibiting EMT via the Wnt/β-catenin signaling pathway in vivo. Taken together, we suggest that emodin inhibits the invasion and migration of CC cells in vitro and in vivo by blocking EMT, which is related with the inhibition of the Wnt/β-catenin signaling pathway.

Key words: Emodin; Colon cancer (CC); Invasion; Migration; Epithelial–mesenchymal transition (EMT); Wnt/β-catenin

Erratum – 683
DOI: https://doi.org/10.3727/096504021X16137463165433

The following was originally published in Volume 26, No. 1, pages 103–110, 2018 (doi: https://doi.org/10.3727/0965040 17X14934860122864). There was an error in Figure 4E in the Transwell assay. A corrected version of the figure is shown here and the figure has been replaced with the corrected version in the original published article in the online site (https://www.ingentaconnect.com/contentone/cog/or/2018/00000026/00000001/art00011). The original version of the figure did not affect the results or conclusion of the article.

Long Noncoding RNA UCA1 Targets miR-122 to Promote Proliferation, Migration, and Invasion of Glioma Cells

Yang Sun,*1 Jun-Gong Jin,*1 Wei-Yang Mi,† Hao-Wu,* Shi-Rong Zhang,‡ Qiang Meng,* and Shi-Tao Zhang‡

*Department of Neurosurgery, Tangdu Hospital, Fourth Military Medical University, Xi’an, P.R. China
†Department of Neurosurgery, Xi’an Children’s Hospital, Xi’an, P.R. China
‡Department of Neurosurgery, Xi’an No. 3 Hospital, Xi’an, P.R. China

Glioma is the most common and lethal malignant intracranial tumor. Long noncoding RNAs (lncRNAs) have been identified as pivotal regulators in the tumorigenesis of glioma. However, the role of lncRNA urothelial carcinoma-associated 1 (UCA1) in glioma genesis is still unknown. The purpose of this study was to investigate the underlying function of UCA1 on glioma genesis. The results demonstrated that UCA1 was upregulated in glioma tissue and indicated a poor prognosis. UCA1 knockdown induced by si-UCA1 significantly suppressed the proliferative, migrative, and invasive activities of glioma cell lines (U87 and U251). Bioinformatics analysis and luciferase reporter assay verified the complementary binding within UCA1 and miR-122 at the 3′-UTR. Functional experiments revealed that UCA1 acted as an miR-122 “sponge” to modulate glioma cell proliferation, migration, and invasion via downregulation of miR-122. Overall, the present study demonstrated that lncRNA UCA1 acts as an endogenous sponge of miR-122 to promote glioma cell proliferation, migration, and invasion, which provides a novel insight and therapeutic target in the tumorigenesis of glioma.

Key words: Glioma; Long noncoding RNAs (lncRNAs); Urothelial carcinoma-associated 1 (UCA1); miR-122; Migration; Invasion

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

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

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

Respectfully,

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

Updated as of December 2020

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