Abstract
Non-coding RNAs (ncRNAs) have been implicated in most cellular functions. The disruption of their function through somatic mutations, genomic imprinting, transcriptional and post-transcriptional regulation, plays an ever-increasing role in cancer development. ncRNAs, including notorious microRNAs, have been thus proposed to function as tumor suppressors or oncogenes, often in a context-dependent fashion. In parallel, ncRNAs with altered expression in cancer have been reported to exert a key role in determining drug sensitivity or restoring drug responsiveness in resistant cells. Acquisition of resistance to anti-cancer drugs is a major hindrance to effective chemotherapy and is one of the most important causes of relapse and mortality in cancer patients. For these reasons, non-coding RNAs have become recent focuses as prognostic agents and modifiers of chemo-sensitivity. This review starts with a brief outline of the role of most studied non-coding RNAs in cancer and then highlights the modulation of cancer drug resistance via known ncRNAs based mechanisms. We identified from literature 388 ncRNA-drugs interactions and analyzed them using an unsupervised approach. Essentially, we performed a network analysis of the non-coding RNAs with direct relations with cancer drugs. Within such a machine-learning framework we detected the most representative ncRNAs-drug associations and groups. We finally discussed the higher integration of the drug-ncRNA clusters with the goal of disentangling effectors from downstream effects and further clarify the involvement of ncRNAs in the cellular mechanisms underlying resistance to cancer treatments.
Highlights
Reviewed by: Francesco Russo, Novo Nordisk Foundation Center for Protein Research, University of Copenhagen, Denmark Ajaikumar B
Other miRNAs are found either within exons, including 3′ UTRs of mRNAs, or clustered with other miRNA genes [11]. Since their discovery [12, 13], the number of annotated miRNAs in the human genome has grown rapidly and they regulate a variety of cellular processes, including apoptosis [14], differentiation [15] and cell proliferation. miRNA deregulation has been demonstrated in cancer [16,17,18,19]
One of the firsts observation on a possible link between miRNAs and drug resistance was reported in breast cancer (BC) suggesting that increased sensitivity of patients to anthracyclinebased chemotherapy was related to deletion of chromosome 11q, a region containing MIR125B1 [41]
Summary
Reviewed by: Francesco Russo, Novo Nordisk Foundation Center for Protein Research, University of Copenhagen, Denmark Ajaikumar B. MiR-16 expression is affected by several drugs: in gastric cancer cell lines etoposide and 5-Fluorouracil could increase the levels of miR-16, both in vitro and in vivo, and the up-regulation of miR-16 is modulated by p38 MAPK signaling pathway [175]. MiR-224 promoted cisplatin sensitivity in ncRNAs and Drugs Interactions in Cancer osteosarcoma resistant cells by targeting Rac1 [238].
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