Oncogenic circular RNA circ_0007534 contributes to paclitaxel resistance in endometrial cancer by sponging miR-625 and promoting ZEB2 expression

Abstract

Circular RNAs (circRNAs) and epithelial to mesenchymal transition (EMT) have been implicated in the development of human cancer and paclitaxel resistance. CircRNA circ_0007534 has been described as a key oncogenic circular RNA that is upregulated in a variety of cancer tissues. However, whether circ_0007534 causes EMT and paclitaxel resistance in endometrial cancer is still unknown. In this work, we revealed that circ_0007534 levels were significantly higher in endometrial cancer tissues, and that high circ_0007534 expression was associated with poor differentiation, advanced tumor stage, cancer invasion, cancer metastasis, and poor prognosis in endometrial cancer patients. Overexpression of circ_0007534 boosted endometrial cancer cell proliferation, invasion, EMT, and paclitaxel resistance. Knockdown of circ_0007534 restored paclitaxel sensitivity and reversed EMT in endometrial cancer cells. We also showed that circ_0007534 enhanced endometrial cancer aggressiveness, progression, and paclitaxel resistance by sponging microRNA-625 (miR-625) and subsequently increasing the expression of the miR-625 target gene ZEB2. Our cell functional studies demonstrated that inhibiting miR-625 or increasing ZEB2 mimicked the effects of circ_0007534 overexpression. Consequently, our data show that circ_0007534 plays a crucial role in EMT and paclitaxel resistance through miR-625/ZEB2 signaling. Targeting the circ_0007534/miR-625/ZEB2 pathway might be an effective strategy for overcoming paclitaxel resistance in endometrial cancer.

Circular RNAs in EMT-driven metastasis regulation: modulation of cancer cell plasticity, tumorigenesis and therapy resistance

“…Overexpression of circ-0007534 in endometrial tumor results in paclitaxel resistance. The circ-0007534 elevates ZEB2 level via miR-625 inhibition to accelerate EMT and accelerate paclitaxel insensitivity [ 121 ]. Docetaxel functions similarly to paclitaxel and prevents the depolymerization of microtubules to suppress cancer.…”

“…Circ-0007534 stimulates EMT in endometrial cancer and, in this way, promotes the progression of tumor cells to mediate paclitaxel resistance. Circ-0007534 increases ZEB2 expression via miR-625 inhibition to trigger the EMT mechanism and paclitaxel resistance [ 121 ]. According to these studies, circRNAs regulate ZEB1 and ZEB2, and more research is needed to understand ZEB2 regulation by circRNAs in cancers.…”

The emerging role and clinical significance of circRNAs in papillary thyroid cancer

“…Furthermore, circCPM promoted resistance to 5-FU in gastric cancer and modulated autophagy by targeting PRKAA2 ( 106 ). In endometrial cancer, resistance to paclitaxel was found to be mediated by the key oncogenic circ0007534 ( 107 ). These studies suggest that circRNA-targeted therapy may have a role in reversing cancer chemoresistance.…”

Circular RNAs in gynecologic cancers: mechanisms and implications for chemotherapy resistance

“…Overexpression of circ_0007534 in EC cells enhances cell proliferation, aggression, epithelial-mesenchymal transition (EMT), and PTX resistance. The outcomes of mechanistic experiments show that circ_0007534 promotes EC invasiveness, progression, and PTX resistance by sponging miR-625 and promoting zinc finger E-box binding homeobox 2 (ZEB2) expression ( Yi et al, 2022b ). In contrast, the knockdown of circ_0039569 in EC cells restrains cell growth and invasion, leading to PTX sensitivity.…”