MYC-Induced miR-203b-3p and miR-203a-3p Control Bcl-xL Expression and Paclitaxel Sensitivity in Tumor Cells

Abstract

Taxanes are chemotherapeutic agents used in the treatment of solid tumors, particularly of breast, ovarian, and lung origin. However, patients show divergent therapy responses, and the molecular determinants of taxane sensitivity have remained elusive. Especially the signaling pathways that promote death of the taxane-treated cells are poorly characterized. Here we describe a novel part of a signaling route in which c-Myc enhances paclitaxel sensitivity through upregulation of miR-203b-3p and miR-203a-3p; two clustered antiapoptosis protein Bcl-xL controlling microRNAs. In vitro, the miR-203b-3p decreases the expression of Bcl-xL by direct targeting of the gene's mRNA 3’UTR. Notably, overexpression of the miR-203b-3p changed the fate of paclitaxel-treated breast and ovarian cancer cells from mitotic slippage to cell death. In breast tumors, high expression of the miR-203b-3p and MYC was associated with better therapy response and patient survival. Interestingly, in the breast tumors, MYC expression correlated negatively with BCL2L1 expression but positively with miR-203b-3p and miR-203a-3p. Finally, silencing of MYC suppressed the transcription of both miRNAs in breast tumor cells. Pending further validation, these results may assist in patient stratification for taxane therapy.

MicroRNA-based potential diagnostic, prognostic and therapeutic applications in triple-negative breast cancer

“…Multidrug resistance (MDR) is generally considered to be a major factor in the failure of many forms of chemotherapy. Recently, growing body of reports have suggested that several miRNAs are closely associated with MDR and they can modulate drug sensitivity in TNBC [78][79][80][81][82][83][84]. Tan et al [79] found that miR-638 can affect DNA repair and sensitivity to UV and cisplatin.…”

Bcl‐xL expression following articular cartilage injury and its effects on the biological function of chondrocytes

“…Although Bcl-xL serves as a promoter of various types of cancers due to its antiapoptotic effects, requiring targeted knockdown therapy [17][18][19], it has also been found to inhibit inflammation in some diseases due to its antiapoptotic effects [20,21]. The purpose of this study was to investigate the expression of Bcl-xL in cartilage damage caused by osteoarthritis and determine its effect on chondrocytes.…”

Downregulation of hsa-microRNA-204-5p and identification of its potential regulatory network in non-small cell lung cancer: RT-qPCR, bioinformatic- and meta-analyses

“…Apart from binding competition of miRNA towards hub genes, the combined ways of TFs with miR-204-5p and genes were still in doubt due to lack of database prediction, experimental proof and literature confirmation directly repressing E2F1, a MYC-collaborating molecule [52]. In breast tumor, MYC expression correlates positively with miR-203b-3p and miR-203a-3p but negatively with BCL2L1 expression, resulting in formation of a TF-FFL [113]. MIR7-3HG restrains MYC dephosphorylation by downregulation of AMBRA1 to form a positive feedback loop for its own expression and further contributing significantly to autophagic control [114].…”