miR-548e Sponged by ZFAS1 Regulates Metastasis and Cisplatin Resistance of OC by Targeting CXCR4 and let-7a/BCL-XL/S Signaling Axis

Abstract

Ovarian cancer (OC) is a severe malignancy featuring a poor prognosis due to rapid metastasis and chemotherapy resistance. In this study, we extensively investigated the upstream and downstream mechanisms of miR-548e in regulating OC progression and cisplatin resistance. Our results indicated that ZFAS1 was highly expressed and promoted OC cell proliferation, migration, invasion, and cisplatin resistance by directly suppressing miR-548e expression. ZFAS1 co-localized with miR-548e in the cytosols of OC cells. miR-548e repressed CXCR4 expression, and elevated CXCR4 expression promoted OC cell proliferation, migration, invasion, and cisplatin resistance. Cisplatin resistance induced by ZFAS1 and CXCR4 overexpression in OC cells was mediated by their suppression on let-7a and elevation of BCL-XL/S expression. ZFAS1 knockdown and miR-548e and let-7a overexpression impaired cisplatin resistance and suppressed lung metastatic nodule formation in nude mice. In conclusion, ZFAS1 binds with miR-548e to enhance CXCR4 expression to promote OC cell proliferation and metastasis, which also enhances cisplatin resistance by suppressing let-7a and elevating BCL-XL/S protein expression.

<p>ZFAS1 Exerts an Oncogenic Role via Suppressing miR-647 in an m⁶A-Dependent Manner in Cervical Cancer</p>

“…19 Additionally, ZFAS1 is highly expressed and promotes ovarian cancer cell proliferation, migration, invasion, and cisplatin resistance by sponging miR-548e and elevating CXCR4 expression. 8 Here, we also identified miR-647 as a target of ZFAS1. ZFAS1 suppressed miR-647 expression and negatively correlated with miR-647 expression in CC tissues.…”

“…7 In ovarian cancer, ZFAS1 is highly expressed and accelerate cell proliferation, migration, invasion, and induces cisplatin resistance by directly suppressing miR-548e expression. 8 ZFAS1 was found to be downregulated in breast tumors compared to normal tissue. 9 However, the expression pattern, clinical significance and molecular mechanism of ZFAS1 has not been thoroughly studied in CC.…”

Aberrant Bcl-x splicing in cancer: from molecular mechanism to therapeutic modulation

“…Tolerability generated during chemotherapy such as apoptosis escape and Epithelial mesenchymal transformation (EMT), results in poor prognosis and is currently impeding the success of targeted therapies in cancer treatment [ 121 , 122 ]. Plenty of evidence suggested that Bcl-xL-dependent apoptotic inhibition was the main reason that promoted chemotherapy resistance in tumours in vitro and vivo (Table 2 ) [ 123 , 124 ]. A study on breast cancer showed that cells passed through EMT obtained therapeutic resistance by upregulating Bcl-xL transcripts.…”

“…Inhibiting Bcl-xL expression in breast cancer cells enhanced the cytotoxicity and apoptosis induced by T-DM1 [ 126 ]. Additionally, increased CXCR4 expression in ovarian cancer induced cisplatin resistance through promoting Bcl-xL/S [ 123 ]. Upregulated Bcl-xL expression was also found to be involved in resistance to therapy targeting Bcl-2 in mantle-cell lymphoma and Acute Myelocytic Leukemia [ 57 , 127 ].…”

Downregulation of lncRNA ZFAS1 inhibits the hallmarks of thyroid carcinoma via the regulation of miR‑302‑3p on cyclin&nbsp;D1

“…ZFAS1 serves a role in atherosclerosis (15) and a variety of cancer types (16)(17)(18)(19), such as ovarian cancer, breast cancer, prostate cancer and hepatocellular carcinoma. ZFAS1 is a candidate biomarker predictive of the prognosis of thyroid carcinoma (20).…”