MiR-34c Downregulation Leads to SOX4 Overexpression and Cisplatin Resistance in Nasopharyngeal Carcinoma

Abstract

Background : A major cause of disease-related death in nasopharyngeal carcinoma (NPC) is the development of distant metastasis (DM) despite combination chemoradiotherapy treatment. We previously identified and validated a four microRNA (miRNA) signature that is prognostic for DM. In this study, characterization of a key component of this signature, miR-34c, revealed its role in chemotherapy resistance. Methods: 246 NPC patient biopsy samples were subject to comprehensive miRNA profiling and immunohistochemistry (IHC). Two human normal nasopharyngeal cell lines (immortalized; NP69 and NP460), as well as the NPC cell line C666-1, were used to generate pre-miR-34c (gain-of-function) and anti-miR-34c (loss-of-function) cells. Signaling pathways were assessed using quantitative real-time PCR (qRT-PCR) and Western blot. Cell viability was measured using the ATPlite assay. Results: MiR-34c was downregulated in NPC patient samples, and confirmed in vitro to directly target SOX4, a master regulator of epithelial-to-mesenchymal transition (EMT). MiR-34c downregulation triggered EMT-representative changes in NP69 and NP460 whereby Snail, ZEB1, CDH2, and SOX2 were upregulated, while Claudin-1 and CDH1 were downregulated. Phenotypically, inhibition of miR-34c led to cisplatin resistance, whereas miR-34c over-expression sensitized NPC cells to cisplatin. TGFβ1 decreased miR-34c and increased SOX4 expression in vitro . The TGFβ receptor 1 inhibitor SB431542 reduced SOX4 expression and increased cisplatin sensitivity. Finally, IHC revealed that lower SOX4 expression was associated with improved overall survival in chemotherapy-treated NPC patients. Conclusion: miR-34c downregulation correlates with higher incidence of DM. Repression of miR-34c was shown to increase SOX4 expression, which leads to cisplatin resistance, while TGFβ1 was found to repress miR-34c expression. Taken together, our study demonstrates that inhibition of the TGFβ1 pathway could be a strategy to restore cisplatin sensitivity in NPC.

Curcumin and its derivatives in cancer therapy: Potentiating antitumor activity of cisplatin and reducing side effects

“…Besides, the iron-starvation response followed by increasing intracellular accumulation of iron could increase the CP cytotoxicity against head and neck tumors (Lee, You, Shin, & Roh, 2020). Some ncRNAs, including miRNAs, cir-cRNAs, and lncRNAs affect CP response in tumors (Bissey et al, 2020;Ren et al, 2020;Yang, Zhang, & Guan, 2020). Because CP resistance is an increasing challenge in oncology (Zampieri et al, 2020), some other antitumor agents have been tested to reverse CP resistance (Y. D. Li, Mao, et al, 2020;D.…”

Overexpression of SOX4 indicates poor prognosis and promotes progression of hypopharyngeal carcinoma

“…In the current research, we examine the SOX4 expression in HPC and its relationship to clinicopathological traits using IHC and western blot analysis. According to the date, the SOX4 expression was signi cantly higher compare with para-cancerous tissues and its expression level was connected with differentiation, clinical stage, tumor size, lymph node, metastasis, treatment and Ki-67 expression, which is similar to the study of some malignant tumor including nasopharyngeal Carcinoma 12,24 , prostate cancer 15,25 , oral squamous cell carcinoma 26,27 , As we known it is important for tumor patients to take precise prediction of prognosis. In breast cancer, high SOX4 expression predictes poor prognosis 13 .…”