MicroRNA-34a Attenuates Paclitaxel Resistance in Prostate Cancer Cells via Direct Suppression of JAG1/Notch1 Axis

Abstract

Background/Aims: Treatment options for metastatic castrate-resistant prostate cancer (mCRPC) are limited and typically centered on paclitaxel-based chemotherapy. In this study, we aimed to evaluate whether miR-34a attenuates chemoresistance to paclitaxel by regulating target genes associated with drug resistance. Methods: We used data from The Cancer Genome Atlas to compare miR-34a expression levels in prostate cancer (PC) tissues with normal prostate tissues. The effects of miR-34a inhibition and overexpression on PC proliferation were evaluated in vitro via Cell Counting Kit-8 (CCK-8) proliferation, colony formation, apoptosis, and cell-cycle assays. A luciferase reporter assay was employed to identify the interactions between miR-34a and specific target genes. To determine the effects of up-regulation of miR-34a on tumor growth and chemo-resistance in vivo, we injected PC cells overexpressing miR-34a into nude mice subcutaneously and evaluated the rate of tumor growth during paclitaxel treatment. We examined changes in the expression levels of miR-34a target genes JAG1 and Notch1 and their downstream genes via miR-34a transfection by quantitative reverse transcription PCR (qRT-PCR) and western blot assay. Results: miR-34a served as an independent predictor of reduced patient survival. MiR-34a was down-regulated in PC-3PR cells compared with PC-3 cells. The CCK-8 assay showed that miR-34a overexpression resulted in increased sensitivity to paclitaxel while miR-34a down-regulation resulted in chemoresistance to paclitaxel in vitro. A study of gain and loss in a series of functional assays revealed that PC cells expressing miR-34a were chemosensitive. Furthermore, the overexpression of miR-34a increased the sensitivity of PC-3PR cells to chemotherapy in vivo. The luciferase reporter assay confirmed that JAG1 and Notch1 were directly targeted by miR-34a. Interestingly, western blot analysis and qRT-PCR confirmed that miR-34a inhibited the Notch1 signaling pathway. We found that miR-34a increased the chemosensitivity of PC-3PR cells by directly repressing the TCF1/ LEF1 axis. Conclusion: Our results showed that miR-34a is involved in the development of chemosensitivity to paclitaxel. By regulating the JAG1/Notch1 axis, miR-34a or its target genes JAG1 or Notch1 might serve as potential predictive biomarkers of response to paclitaxel-based chemotherapy and/or therapeutic targets that will help to overcome chemoresistance at the mCRPC stage.

Mechanisms of Taxane Resistance

“…For example, miR-143 targets KRAS, involved in the activation of the oncogenic MAPK/Ras pathway, and its overexpression can sensitize cells to DTX [419]. miR-34a normally inhibits NOTCH (involved in the BCL-2 family pro-survival pathway), but downregulation resulted in PTX resistance in in vitro models [420]. miR-148 also restored sensitivity to PTX by transfecting ectopic miR-148 into resistant cells [305,413,417].…”

Roles of MicroRNA-34a in Epithelial to Mesenchymal Transition, Competing Endogenous RNA Sponging and Its Therapeutic Potential

“…Treatment options for metastatic castrate-resistant prostate cancer (mCRPC) are limited and typically centered on paclitaxel-based chemotherapy. Liu et al [72] found that miR-34a attenuates chemoresistance to paclitaxel by regulating target genes, JAG1 and Notch1 , which are associated with drug resistance. NFIX circular RNA (circNFIX), which regulates NOTCH1 to promote glioma progression by sponging miR-34a-5p via the Notch signaling pathway, will be discussed in the latter portion of this review [73].…”

<p>SNHG15 Contributes To Cisplatin Resistance In Breast Cancer Through Sponging miR-381</p>

“…For instance, miR-34a has been discovered to be down-regulated and contributed to DDP resistance in DDP-resistant prostate cancer cells. 17 miR-381 could overcome cisplatin resistance in non-small cell lung cancer (NSCLC) cells through inactivating nuclear factor-κB signaling. 18 Moreover, miR-381 overexpression could improve DDP sensitivity of breast cancer cells through targeting MDR1.…”