The Emerging Role of MicroRNAs in Regulating the Drug Response of Cholangiocarcinoma

Abstract

Cholangiocarcinoma (CCA) is the most common biliary malignancy, and has a poor prognosis. The median overall survival with the standard-of-care chemotherapy (Gemcitabine and cisplatin) in patients with advanced-stage CCA is less than one year. The limited efficacy of chemotherapy or targeted therapy remains a major obstacle to improving survival. The mechanisms involved in drug resistance are complex. Research efforts focusing on the distinct molecular mechanisms underlying drug resistance should prompt the development of treatment strategies that overcome chemoresistance or targeted drug resistance. MicroRNAs (miRNAs) are a class of evolutionarily conserved, short noncoding RNAs regulating gene expression at the post-transcriptional level. Dysregulated miRNAs have been shown to participate in almost all CCA hallmarks, including cell proliferation, migration and invasion, apoptosis, and the epithelial-to-mesenchymal transition. Emerging evidence demonstrates that miRNAs play a role in regulating responses to chemotherapy and targeted therapy. Herein, we present an overview of the current knowledge on the miRNA-mediated regulatory mechanisms underlying drug resistance among CCA. We also discuss the application of miRNA-based therapeutics to CCA, providing the basis for innovative treatment approaches.

A Brief Outlook on Pharmacogenetics (PGx): Focus in MicroRNAs (miRNAs) and Cancer Stem Cells (CSCs)

“…miRNA conserves of 21-25 nucleotides in length. miRNA has been reported to be able to down-regulate gene expression gene expression at the level of posttranscription (Zhang and Dolan, 2010). Not only in mammals, miRNAs can be found in genomes of plants, worms and flies (Zhang and Dolan, 2010;Lee, et al, 2007).…”

“…miRNA has been reported to be able to down-regulate gene expression gene expression at the level of posttranscription (Zhang and Dolan, 2010). Not only in mammals, miRNAs can be found in genomes of plants, worms and flies (Zhang and Dolan, 2010;Lee, et al, 2007). More than 700 miRNAs have been identified in humans based on experimental research and bioinformatic study (Zhang and Dolan, 2010;Griffiths-Jones, et al, 2008).…”

“…miRNA binds to the 3' untranslated regions (3'UTRs) of the gene traget and reduces gene expression at the level of posttranscription. (Zhang and Dolan, 2010;He and Gregory, 2004) miRNAs have been reported to be correlated with various cancers, including leukemia (Garzon, et al, 2008), prostate cancer (Ambs, et al, 2008), gastric cancer (Ueda, et al, 2010), lung cancer (Wu, et al, 2009), breast cancer (Khoshnaw, et al, 2009), and liver cancer (Mott, et al, 2009). miRNAs could affect the cancer in the initiation and progression stages (Garzon, et al, 2009).…”

“…miRNAs may also contribute to drug response, for example through regulating key drug metabolizing genes such as CYP. For example, the escape of miR-519c by 3'UTR truncation was found to enable drug-resistant cells to maintain high expression of ATP-binding cassette (ABC), subfamily G, member 2 (ABCG2), a transporter that is related to the absorption, distribution and excretion of drugs and cytotoxins (To, et al, 2009;Zhang and Dolan, 2010).…”

“…( 22) In another study, a SNP of miR-146a precursor was demonstrated to affect its binding to the 3'UTRs of breast cancer 1, early onset (BRCA1) as well as BRCA2 mRNAs, thus potentially modulating their expression. (Zhang and Dolan, 2010;Shen, et al, 2008).…”