The Role of miRNAs in Cisplatin-Resistant HeLa Cells

Chemotherapy is the main strategy in the treatment of cancer, however, the development of drug-resistance is the obstacle in long-term treatment of cervical cancer. Cisplatin is one of the most common drugs used in cancer therapy. Recently, accumulating evidence suggests that miRNAs are involved in various bioactivities in oncogenesis. It is not unexpected that miRNAs play a key role in acquiring of drug-resistance in the progression of tumor. In this study, we induced and maintained four levels of cisplatin-resistant HeLa cell lines (HeLa/CR1, HeLa/CR2, HeLa/CR3 and HeLa/CR4). According to the previous studies and exiting evidence, we selected five miRNAs (miR-183, miR-182, miR-30a, miR-15b and miR-16) and their potential target mRNAs as our research targets. The real-time RT-PCR was used to detect the relative expression of miRNAs and their mRNAs. The results show that miR-182 and miR-15b were up-regulated in resistant cell lines while miR-30a was significantly down-regulated. At the same time, the targets they regulated are related to the drug-resistance. The expression alteration of selected miRNAs in resistant cell lines compared to their parent HeLa cell line suggests that HeLa cell drug resistance is associated with distinct miRNAs, which indicates that miRNAs may be one of the therapy targets in the treatment of cervical cancer by sensitizing cell to chemotherapy.

[1]  A. Addario,et al.  Role of microRNAs in drug-resistant ovarian cancer cells. , 2008, Gynecologic oncology.

[2]  M. Lotze,et al.  The Beclin 1 network regulates autophagy and apoptosis , 2011, Cell Death and Differentiation.

[3]  Ivo Grosse,et al.  Functional microRNA targets in protein coding sequences , 2012, Bioinform..

[4]  Cem Kuscu Epigenetic Regulations and Promoter Characterization of CERIG (Cancer Endoplasmic Reticulum Gene-KIAA1199) , 2012 .

[5]  Susanna Cirera,et al.  MicroRNA expression profiles associated with development of drug resistance in Ehrlich ascites tumor cells. , 2011, Molecular pharmaceutics.

[6]  A. Dufour,et al.  Unraveling the role of KIAA1199, a novel endoplasmic reticulum protein, in cancer cell migration. , 2013, Journal of the National Cancer Institute.

[7]  Dietrich Büsselberg,et al.  Cisplatin as an Anti-Tumor Drug: Cellular Mechanisms of Activity, Drug Resistance and Induced Side Effects , 2011, Cancers.

[8]  Apeng Yang,et al.  Aberrant microRNA-182 expression is associated with glucocorticoid resistance in lymphoblastic malignancies , 2012, Leukemia & lymphoma.

[9]  Liu Hong,et al.  miR‐15b and miR‐16 modulate multidrug resistance by targeting BCL2 in human gastric cancer cells , 2008, International journal of cancer.

[10]  C. Croce,et al.  Human microRNA genes are frequently located at fragile sites and genomic regions involved in cancers. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[11]  C. Gong,et al.  Beclin 1 and autophagy are required for the tumorigenicity of breast cancer stem-like/progenitor cells , 2012, Oncogene.

[12]  Zhipeng Cai,et al.  A Computational Framework for Influenza Antigenic Cartography , 2010, PLoS Comput. Biol..

[13]  Francesca Aredia,et al.  Manipulation of autophagy in cancer cells: an innovative strategy to fight drug resistance. , 2013, Future medicinal chemistry.

[14]  T. Ørntoft,et al.  Repression of KIAA1199 attenuates Wnt-signalling and decreases the proliferation of colon cancer cells , 2011, British Journal of Cancer.

[15]  Hao Zhang,et al.  Programmed Cell Death 4 ( PDCD 4 ) Enhances the Sensitivity of Gastric Cancer Cells to TRAIL-Induced Apoptosis by Inhibiting the PI 3 K / Akt Signaling Pathway , 2012 .

[16]  Michael Weller,et al.  Predicting response to cancer chemotherapy: the role of p53 , 1998, Cell and Tissue Research.

[17]  Martin Reczko,et al.  DIANA-microT web server v5.0: service integration into miRNA functional analysis workflows , 2013, Nucleic Acids Res..

[18]  Rende Guo,et al.  MicroRNA‐182 promotes cell growth, invasion, and chemoresistance by targeting programmed cell death 4 (PDCD4) in human ovarian carcinomas , 2013, Journal of cellular biochemistry.

[19]  William C Reinhold,et al.  MicroRNAs modulate the chemosensitivity of tumor cells , 2008, Molecular Cancer Therapeutics.

[20]  Jie Yang,et al.  Curcumin reduces the expression of Bcl-2 by upregulating miR-15a and miR-16 in MCF-7 cells , 2010, Medical oncology.

[21]  Y. Minagawa,et al.  Cisplatin‐resistant HeLa Cells Are Resistant to Apoptosis via p53‐dependent and ‐independent Pathways , 1999, Japanese journal of cancer research : Gann.

[22]  Fang-ling Ning,et al.  MicroRNA-182 modulates chemosensitivity of human non-small cell lung cancer to cisplatin by targeting PDCD4 , 2014, Diagnostic Pathology.

[23]  C. Croce,et al.  miR-15a and miR-16-1 in cancer: discovery, function and future perspectives , 2010, Cell Death and Differentiation.

[24]  Xiaofei Zheng,et al.  miR-183 inhibits TGF-β1-induced apoptosis by downregulation of PDCD4 expression in human hepatocellular carcinoma cells , 2010, BMC Cancer.

[25]  Yang Wang,et al.  MicroRNA-30a Sensitizes Tumor Cells to cis-Platinum via Suppressing Beclin 1-mediated Autophagy* , 2011, The Journal of Biological Chemistry.

[26]  Celia Quevedo,et al.  Biochemical mechanisms of cisplatin cytotoxicity. , 2007, Anti-cancer agents in medicinal chemistry.

[27]  Seiji Naito,et al.  Programmed cell death protein 4 down-regulates Y-box binding protein-1 expression via a direct interaction with Twist1 to suppress cancer cell growth. , 2009, Cancer research.

[28]  Hailin Tang,et al.  The miR-183/96/182 cluster regulates oxidative apoptosis and sensitizes cells to chemotherapy in gliomas. , 2013, Current cancer drug targets.

[29]  Zhiwei Wang,et al.  Implication of microRNAs in drug resistance for designing novel cancer therapy. , 2010, Drug resistance updates : reviews and commentaries in antimicrobial and anticancer chemotherapy.

[30]  Peter A. Jones,et al.  Epigenetic Activation of Tumor Suppressor MicroRNAs in Human Cancer Cells , 2006, Cell cycle.

[31]  E. Lam,et al.  FOXO and FOXM1 in cancer: the FOXO-FOXM1 axis shapes the outcome of cancer chemotherapy. , 2011, Current drug targets.

[32]  M. Bushell,et al.  microRNAs in cancer management. , 2012, The Lancet. Oncology.

[33]  P Vernon,et al.  Targeting microRNA-30a-mediated autophagy enhances imatinib activity against human chronic myeloid leukemia cells , 2012, Leukemia.

[34]  Xin Huang,et al.  Functional proteomic analysis reveals the involvement of KIAA1199 in breast cancer growth, motility and invasiveness , 2014, BMC Cancer.

[35]  Z. Huang,et al.  Autophagy and chemotherapy resistance: a promising therapeutic target for cancer treatment , 2013, Cell Death and Disease.

[36]  H. Miörner,et al.  Evaluation of a colorimetric assay based on 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) for rapid detection of rifampicin resistance in Mycobacterium tuberculosis. , 1998, The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease.