MP57-07\u2003LONG NON-CODING RNA SOX2OT PROMOTES STEMNESS CHARACTERISTICS AND DRUG-RESISTANCE OF BLADDER CANCER CELLS BY MODULATING SOX2

Abstract

INTRODUCTION AND OBJECTIVES: Cancer stem cells are considered responsible for many important aspects of tumors such as their self-renewal, tumor-initiating, metastasis and drug-resistance. SOX2 overlapping transcript (SOX2OT) is a novel long non-coding RNA that acts as a potential biomarker and involves in development of multiple cancers. Here, we elucidated the function and possible molecular mechanisms of the effect of SOX2OT on the biological behaviors of bladder cancer cells. METHODS: The expression level of SOX2OT was determined by RT-qPCR in a total of 106 patients with urothelial bladder cancer and validated by online datasets. Bladder cancer stem cells (BCSCs) were isolated from bladder cancer cells using flow cytometry based on the stem cell markers CD44 and ALDH1. After the construction of SOX2OT knockdown cell lines, the malignant phenotypes (self-renewal, metastasis, drug-resistance and tumourigenicity) of BCSCs were determined by using different assay. Downstream targets of SOX2OT were investigated by RNA-FISH, bioinformatics analysis, dual-luciferase reporter assay and western blot. RESULTS: SOX2OT was highly expressed in bladder cancer and positively correlated with higher histological grade, advanced TNM stage and poor prognosis. Inhibition of SOX2OT repressed self-renewal, metastasis and drug-resistance (Cisplatin) in vitro. Moreover, inhibition of SOX2OT also elicited delayed tumor growth of xenograft and a decrease in the number and size of lung metastases in vivo. Mechanistically, the bio-information analysis revealed that SOX2OT expression positively correlated with SOX2 expression and RNA-FISH results revealed that SOX2OT was mainly distributed in the cytoplasm of BCSC. Further experimental results demonstrated that SOX2OT functions as a miRNA sponge to positively regulate SOX2 expression by sponging the miR-200 cluster. Furthermore, overexpression of SOX2 reversed the malignant phenotype inhibition of BCSCs induced by silencing SOX2OT. CONCLUSIONS: Taken together, SOX2OT is a promising novel prognosis biomarker in bladder cancer. That SOX2OT promotes stemness characteristics and drug-resistance of bladder cancer cells through regulating SOX2 may represent a target for clinical intervention. Figure. No caption available. Source of Funding: This work was supported by the National Key R&D Program of China (2016YFC0902601); the National Natural Science Foundation of China (81672546, 81602253, 81772703); the Natural Science Foundation of Beijing (71772219, 7152146).