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Repression of Dicer is associated with invasive phenotype and chemoresistance in ovarian cancer.

ABSTRACT: Dicer is a key enzyme that processes microRNA (miRNA) precursors into their mature form, enabling them to regulate gene expression. However, the effects of Dicer on the biological behavior of cancer cells remain largely unclear. In this study, it was demonstrated that Dicer down-regulation promoted cell proliferation, migration and cell cycle progression in A2780 and SKOV3 ovarian cancer cells. Furthermore, Dicer expression was significantly decreased in cisplatin-resistant A2780 cells (A2780/DDP) compared with parental A2780 cells. Knockdown of Dicer by RNA interference decreased the sensitivity of A2780 cells to cisplatin. Moreover, EZH2 depletion by short hairpin RNA (shRNA) increased the expression of Dicer in vitro. Our data suggest that Dicer is involved in numerous biological/pathological processes, including drug resistance in ovarian cancer, and that its expression may be regulated by EZH2.

SUBMITTER: Kuang Y

PROVIDER: S-EPMC3629258 | biostudies-literature | 2013 Apr

REPOSITORIES: biostudies-literature

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Repression of Dicer is associated with invasive phenotype and chemoresistance in ovarian cancer.

Kuang Yan Y Cai Jing J Li Donglin D Han Qin Q Cao Jin J Wang Zehua Z

Oncology letters 20130128 4

Dicer is a key enzyme that processes microRNA (miRNA) precursors into their mature form, enabling them to regulate gene expression. However, the effects of Dicer on the biological behavior of cancer cells remain largely unclear. In this study, it was demonstrated that Dicer down-regulation promoted cell proliferation, migration and cell cycle progression in A2780 and SKOV3 ovarian cancer cells. Furthermore, Dicer expression was significantly decreased in cisplatin-resistant A2780 cells (A2780/DD ...[more]

PMID: 23599754

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Project description:Mechanical factors in the tumor microenvironment play an important role in response to a variety of cellular activities in cancer cells. Here, we utilized polyacrylamide hydrogels with varying physical parameters simulating tumor and metastatic target tissues to investigate the effect of substrate stiffness on the growth, phenotype, and chemotherapeutic response of ovarian cancer cells (OCCs). We found that increasing the substrate stiffness promoted the proliferation of SKOV-3 cells, an OCC cell line. This proliferation coincided with the nuclear translocation of the oncogene Yes-associated protein. Additionally, we found that substrate softening promoted elements of epithelial-mesenchymal transition (EMT), including mesenchymal cell shape changes, increase in vimentin expression, and decrease in E-cadherin and β-catenin expression. Growing evidence demonstrates that apart from contributing to cancer initiation and progression, EMT can promote chemotherapy resistance in ovarian cancer cells. Furthermore, we evaluated tumor response to standard chemotherapeutic drugs (cisplatin and paclitaxel) and found antiproliferation effects to be directly proportional to the stiffness of the substrate. Nanomechanical studies based on atomic force microscopy (AFM) have revealed that chemosensitivity and chemoresistance are related to cellular mechanical properties. The results of cellular elastic modulus measurements determined by AFM demonstrated that Young's modulus of SKOV-3 cells grown on soft substrates was less than that of cells grown on stiff substrates. Gene expression analysis of SKOV-3 cells showed that mRNA expression can be greatly affected by substrate stiffness. Finally, immunocytochemistry analyses revealed an increase in multidrug resistance proteins, namely, ATP binding cassette subfamily B member 1 and member 4 (ABCB1 and ABCB4), in the cells grown on the soft gel resulting in resistance to chemotherapeutic drugs. In conclusion, our study may help in identification of effective targets for cancer therapy and improve our understanding of the mechanisms of cancer progression and chemoresistance.

Project description:BackgroundOvarian cancer is associated with poor long-term survival due to late diagnosis and development of chemoresistance. Tumour hypoxia is associated with many features of tumour aggressiveness including increased cellular proliferation, inhibition of apoptosis, increased invasion and metastasis, and chemoresistance, mostly mediated through hypoxia-inducible factor (HIF)-1α. While HIF-1α has been associated with platinum resistance in a variety of cancers, including ovarian, relatively little is known about the importance of the duration of hypoxia. Similarly, the gene pathways activated in ovarian cancer which cause chemoresistance as a result of hypoxia are poorly understood. This study aimed to firstly investigate the effect of hypoxia duration on resistance to cisplatin in an ovarian cancer chemoresistance cell line model and to identify genes whose expression was associated with hypoxia-induced chemoresistance.MethodsCisplatin-sensitive (A2780) and cisplatin-resistant (A2780cis) ovarian cancer cell lines were exposed to various combinations of hypoxia and/or chemotherapeutic drugs as part of a 'hypoxia matrix' designed to cover clinically relevant scenarios in terms of tumour hypoxia. Response to cisplatin was measured by the MTT assay. RNA was extracted from cells treated as part of the hypoxia matrix and interrogated on Affymetrix Human Gene ST 1.0 arrays. Differential gene expression analysis was performed for cells exposed to hypoxia and/or cisplatin. From this, four potential markers of chemoresistance were selected for evaluation in a cohort of ovarian tumour samples by RT-PCR.ResultsHypoxia increased resistance to cisplatin in A2780 and A2780cis cells. A plethora of genes were differentially expressed in cells exposed to hypoxia and cisplatin which could be associated with chemoresistance. In ovarian tumour samples, we found trends for upregulation of ANGPTL4 in partial responders and down-regulation in non-responders compared with responders to chemotherapy; down-regulation of HER3 in partial and non-responders compared to responders; and down-regulation of HIF-1α in non-responders compared with responders.ConclusionThis study has further characterized the relationship between hypoxia and chemoresistance in an ovarian cancer model. We have also identified many potential biomarkers of hypoxia and platinum resistance and provided an initial validation of a subset of these markers in ovarian cancer tissues.

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Repression of Dicer is associated with invasive phenotype and chemoresistance in ovarian cancer.

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Repression of Dicer is associated with invasive phenotype and chemoresistance in ovarian cancer.

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