Downregulation of miR-374b-5p promotes chemotherapeutic resistance in pancreatic cancer by upregulating multiple anti-apoptotic proteins

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Abstract

Resistance to first-line chemotherapeutic drugs such as gemcitabine contributes to the poor prognosis of patients with pancreatic cancer. MicroRNAs (miRNA) regulate chemoresistance in pancreatic cancer. By analyzing the miRNA sequencing dataset of pancreatic cancer from The Cancer Genome Atlas, it was demonstrated that miR-374b-5p expression was dramatically reduced in pancreatic cancer tissues compared with adjacent normal tissues, as well as decreased in chemoresistant compared with chemosensitive pancreatic carcinoma tissues. The decreased expression of miR-374-5p was associated with poor overall and progression-free survival in patients with pancreatic cancer. Furthermore, increased expression of miR-374b-5p abrogated, while the silencing miR-374b-5p increased the chemoresistance of pancreatic cancer cells to gemcitabine in vitro. Importantly, the upregulation of miR-374b-5p ameliorated the chemoresistance of pancreatic cancer cells to gemcitabine in vivo. It was also demonstrated that miR-374b-5p targeted several anti-apoptotic proteins, including B-cell lymphoma 2, Baculoviral IAP Repeat Containing 3 and X-linked inhibitor of apoptosis in pancreatic cancer cells, which further attenuated chemo-resistance in pancreatic cancer. Therefore, the results of the current study indicate that miR-374b-5p serves as a potential diagnostic marker. It also suggests that miR-374b-5p sensitizes cells to chemotherapy and may be used in combination with chemotherapeutic agents such as gemcitabine to treat patients with pancreatic cancer.

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Cancer statistics, 2006.

Ahmedin Jemal, Rebecca Siegel, Elizabeth Ward … (2006)

Each year, the American Cancer Society estimates the number of new cancer cases and deaths expected in the United States in the current year and compiles the most recent data on cancer incidence, mortality, and survival based on incidence data from the National Cancer Institute and mortality data from the National Center for Health Statistics. Incidence and death rates are age-standardized to the 2000 US standard million population. A total of 1,399,790 new cancer cases and 564,830 deaths from cancer are expected in the United States in 2006. When deaths are aggregated by age, cancer has surpassed heart disease as the leading cause of death for those younger than age 85 since 1999. Delay-adjusted cancer incidence rates stabilized in men from 1995 through 2002, but continued to increase by 0.3% per year from 1987 through 2002 in women. Between 2002 and 2003, the actual number of recorded cancer deaths decreased by 778 in men, but increased by 409 in women, resulting in a net decrease of 369, the first decrease in the total number of cancer deaths since national mortality record keeping was instituted in 1930. The death rate from all cancers combined has decreased by 1.5% per year since 1993 among men and by 0.8% per year since 1992 among women. The mortality rate has also continued to decrease for the three most common cancer sites in men (lung and bronchus, colon and rectum, and prostate) and for breast and colon and rectum cancers in women. Lung cancer mortality among women continues to increase slightly. In analyses by race and ethnicity, African American men and women have 40% and 18% higher death rates from all cancers combined than White men and women, respectively. Cancer incidence and death rates are lower in other racial and ethnic groups than in Whites and African Americans for all sites combined and for the four major cancer sites. However, these groups generally have higher rates for stomach, liver, and cervical cancers than Whites. Furthermore, minority populations are more likely to be diagnosed with advanced stage disease than are Whites. Progress in reducing the burden of suffering and death from cancer can be accelerated by applying existing cancer control knowledge across all segments of the population.

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High-throughput cDNA microarray technology allows for the simultaneous analysis of gene expression levels for thousands of genes and as such, rapid, relatively simple methods are needed to store, analyze, and cross-compare basic microarray data. The application of a classical method of data normalization, Z score transformation, provides a way of standardizing data across a wide range of experiments and allows the comparison of microarray data independent of the original hybridization intensities. Data normalized by Z score transformation can be used directly in the calculation of significant changes in gene expression between different samples and conditions. We used Z scores to compare several different methods for predicting significant changes in gene expression including fold changes, Z ratios, Z and t statistical tests. We conclude that the Z score transformation normalization method accompanied by either Z ratios or Z tests for significance estimates offers a useful method for the basic analysis of microarray data. The results provided by these methods can be as rigorous and are no more arbitrary than other test methods, and, in addition, they have the advantage that they can be easily adapted to standard spreadsheet programs.

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William C. Hahn, Scott Dessain, Mary Brooks … (2002)

While it is clear that cancer arises from the accumulation of genetic mutations that endow the malignant cell with the properties of uncontrolled growth and proliferation, the precise combinations of mutations that program human tumor cell growth remain unknown. The study of the transforming proteins derived from DNA tumor viruses in experimental models of transformation has provided fundamental insights into the process of cell transformation. We recently reported that coexpression of the simian virus 40 (SV40) early region (ER), the gene encoding the telomerase catalytic subunit (hTERT), and an oncogenic allele of the H-ras gene in normal human fibroblast, kidney epithelial, and mammary epithelial cells converted these cells to a tumorigenic state. Here we show that the SV40 ER contributes to tumorigenic transformation in the presence of hTERT and oncogenic H-ras by perturbing three intracellular pathways through the actions of the SV40 large T antigen (LT) and the SV40 small t antigen (ST). LT simultaneously disables the retinoblastoma (pRB) and p53 tumor suppressor pathways; however, complete transformation of human cells requires the additional perturbation of protein phosphatase 2A by ST. Expression of ST in this setting stimulates cell proliferation, permits anchorage-independent growth, and confers increased resistance to nutrient deprivation. Taken together, these observations define the elements of the SV40 ER required for the transformation of human cells and begin to delineate a set of intracellular pathways whose disruption, in aggregate, appears to be necessary to generate tumorigenic human cells.

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Author and article information

Journal

Journal ID (nlm-ta): Int J Oncol

Journal ID (iso-abbrev): Int. J. Oncol

Journal ID (publisher-id): IJO

Title: International Journal of Oncology

Publisher: D.A. Spandidos

ISSN (Print): 1019-6439

ISSN (Electronic): 1791-2423

Publication date Collection: May 2018

Publication date (Electronic): 14 March 2018

Publication date PMC-release: 14 March 2018

Volume: 52

Issue: 5

Pages: 1491-1503

Affiliations

[1 ]Department of Colorectal and Anal Surgery, The First Hospital of Jilin University, Changchun, Jilin 130000

[2 ]Department of Ultrasound, The China-Japan Union Hospital of Jilin University, Changchun, Jilin 130000

[3 ]Center for Private Medical Service and Healthcare, The First Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510080

[4 ]Department of Hepatobiliary and Pancreas Surgery, The First Hospital of Jilin University, Changchun, Jilin 130000, P.R. China

Author notes

Correspondence to: Professor Ping Zhang, Department of Hepatobiliary and Pancreas Surgery, The First Hospital of Jilin University, 71 Xinmin Street, Changchun, Jilin 130000, P.R. China, E-mail: azhangpinga@ 123456126.com

Article

Publisher ID: ijo-52-05-1491

DOI: 10.3892/ijo.2018.4315

PMC ID: 5873836

PubMed ID: 29568910

SO-VID: 3ebf6183-452b-4922-b007-784e1f052e7d

License:

This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

History

Date received : 31 October 2017

Date accepted : 06 February 2018

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Downregulation of miR-374b-5p promotes chemotherapeutic resistance in pancreatic cancer by upregulating multiple anti-apoptotic proteins

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Most cited references 43

Cancer statistics, 2006.

Analysis of microarray data using Z score transformation.

Enumeration of the simian virus 40 early region elements necessary for human cell transformation.

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