Impact of SOX2 function and regulation on therapy resistance in bladder cancer

Abstract

Bladder cancer (BC) is a malignant disease with high rates of recurrence and mortality. It is mainly classified as non-muscle-invasive BC and muscle-invasive BC (MIBC). Often, MIBC is chemoresistant, which, according to cancer stem cells (CSCs) theory, is linked to the presence of bladder cancer stem cells (BCSCs). Sex-determining region Y- (SRY) Box transcription factor 2 (SOX2), which is a molecular marker of BCSCs, is aberrantly over-expressed in chemoresistant BC cell lines. It is one of the standalone prognostic factors for BC, and it has an inherently significant function in the emergence and progression of the disease. This review first summarizes the role of SRY-related high-mobility group protein Box (SOX) family genes in BC, focusing on the SOX2 and its significance in BC. Second, it discusses the mechanisms relevant to the regulation of SOX2. Finally, it summarizes the signaling pathways related to SOX2 in BC, suggests current issues to be addressed, and proposes potential directions for future research to provide new insights for the treatment of BC.

Therapeutic Potential of Regorafenib in Cisplatin-Resistant Bladder Cancer with High Epithelial–Mesenchymal Transition and Stemness Properties

“…The cytotoxicity of cisplatin results in DNA damage and, hence, blocks proliferation and initiates cell death [8,9]. It has been further suggested that the possible mechanisms of cisplatin resistance development potentially include the abnormal activation of (i) the DNA repair system (such as actin-like 6A and nucleotide excision repair proteins) [38,39]; (ii) downstream signaling molecules (such as EGFR) [7,31]; and (iii) cancer stem cell-like characters (many stemness markers identified in earlier studies and our present study) [17,19,20].…”

“…Some reports suggest that the EMP status of bladder cancer could affect its metastatic and stemness properties [17][18][19]. Furthermore, cancer stem cell-like phenotypic transformation in bladder cancer may be associated with the EMT and dedifferentiation transitions, as well as the hypoxic microenvironmental conditions [19,20]. Hence, this study proposed the need for an improved understanding of the EMP effect, namely EMT and stemness promotion, their role in the development of cisplatin resistance in bladder cancer cells, and subsequent therapeutic studies.…”

Clinicopathological significance of cancer stem cell marker CD44/SOX2 in esophageal squamous cell carcinoma (ESCC) patients and construction of a nomogram to predict overall survival

“…It is identified as one of the CSCs markers, including Nanog and SALL4, of which its overexpression enhances the properties of tumor stem cells ( 18 ). In various cancers such as bladder cancer, enhanced expression of SOX2 has been found to be associated with an increase in tumor cell stemness and the maintenance of their self-renewal capacity ( 19 ). The long non-coding RNA (lncRNA) SOX2-OT, localized in the cytoplasm, has been found to promote SOX2 expression, thereby augmenting bladder tumor cell stemness and progression ( 20 ).…”