A miRNA-200c/cathepsin L feedback loop determines paclitaxel resistance in human lung cancer A549 cells in vitro through regulating epithelial–mesenchymal transition

Abstract

Cathepsin L (CTSL), a cysteine protease, is closely related to tumor occurrence, development, and metastasis, and possibly regulates cancer cell resistance to chemotherapy. miRNAs, especially the miR-200 family, have been implicated in drug-resistant tumors. In this study we explored the relationship of CTSL, miRNA-200c and drug resistance, and the potential regulatory mechanisms in human lung cancer A549 cells and A549/TAX cells in vitro. A549/TAX cells were paclitaxel-resistant A549 cells overexpressing CTSL and characterized by epithelial-mesenchymal transition (EMT). We showed that miRNA-200c and CTSL were reciprocally linked in a feedback loop in these cancer cells. Overexpression of miRNA-200c in A549/TAX cells decreased the expression of CTSL, and enhanced their sensitivity to paclitaxel and suppressed EMT, whereas knockdown of miRNA-200c in A549 cells significantly increased the expression of CTSL, and decreased their sensitivity to paclitaxel and induced EMT. Overexpression of CTSL in A549 cells significantly decreased the expression of miRNA-200c, and reduced their sensitivity to paclitaxel and induced EMT, but these effects were reversed by miRNA-200c, whereas knockdown of CTSL in A549/TAX cells attenuated paclitaxel resistance and remarkably inhibited EMT, but the inhibition of miRNA-200c could reverse these effects. Therefore, miRNA-200c may be involved in regulating paclitaxel resistance through CTSL-mediated EMT in A549 cells, and CTSL and miRNA-200c are reciprocally linked in a feedback loop.

MicroRNA‑212‑3p inhibits paclitaxel resistance through regulating epithelial‑mesenchymal transition, migration and invasion by targeting ZEB2 in human hepatocellular carcinoma

“…The expression levels of EMT markers showed that EMT was induced in Huh7/PTX cells, suggesting that EMT was positively associated with PTX resistance. This is consistent with a previous study that also indicated the association between EMT and PTX resistance by regulating the expression levels of E-cadherin, cytokeratin 18, N-cadherin and vimentin (20). Moreover, it was found that miR-212-3p inhibited PTX resistance by regulating EMT.…”

Resveratrol, curcumin, paclitaxel and miRNAs mediated regulation of PI3K/Akt/mTOR pathway: go four better to treat bladder cancer

“…However, miRNAs can reduce the paclitaxel resistance. It has come to limelight less lately that miR-200c can overcome paclitaxel resistance via modulation of the cathepsin L (CTSL)- mediated epithelial-mesenchymal transition in A549 cells via feedback loop system [ 131 ]. Also, paclitaxel resistance was reversed by the overexpression of miR-107 in A549/Taxol cells.…”

‘Patchiness’ and basic cancer research: unravelling the proteases

“…Similarly, Cathepsin A transcription was targeted by expressed mir106b-5p causing suppression of Colorectal Carcinoma (CRC) cell migration and invasion [76]. Interestingly, mir200c overexpression reduced Cathepsin L expression in lung A549 cells, resulting in enhanced susceptibility to Paclitaxel-mediated cell death and EMT suppression [77]. While, such recent studies link Cathepsin transcriptional expression to an alternative mode of regulation through the miRNAs, more importantly, such studies also highlight the relative importance of miRNA as a potential therapeutic in overcoming Cathepsin-mediated chemoresistance and Cathepsin-mediated EMT regulation [77].…”

“…Interestingly, mir200c overexpression reduced Cathepsin L expression in lung A549 cells, resulting in enhanced susceptibility to Paclitaxel-mediated cell death and EMT suppression [77]. While, such recent studies link Cathepsin transcriptional expression to an alternative mode of regulation through the miRNAs, more importantly, such studies also highlight the relative importance of miRNA as a potential therapeutic in overcoming Cathepsin-mediated chemoresistance and Cathepsin-mediated EMT regulation [77]. As seen previously, mir152 has been linked to regulating Wnt-mediated EMT inhibition [78] and mir106b-5p with the regulation of key signaling intermediates such as GSK3B, VEGFA and PTK2 in colon and cervical cancers [79] and in both of which, Cathepsins A and L are seen to play a vital regulatory role.…”