journal contribution
posted on 2023-03-31, 01:23 authored by Akira Ooki, Maria Del Carmen Rodriguez Pena, Luigi Marchionni, Wikum Dinalankara, Asma Begum, Noah M. Hahn, Christopher J. VandenBussche, Zeshaan A. Rasheed, Shifeng Mao, George J. Netto, David Sidransky, Mohammad O. Hoque Supplemental information includes Supplemental Figure S1. The characterization of SOX2 as an oncogene in bladder cancer, Supplemental Figure S2. Stem cell-related molecules associated with SOX2 expression, Supplemental Figure S3. CD24+/CD133+ as a potential marker for SOX2-expressing CSCs, Supplemental Figure S4. COX2/PGE2 signaling pathway in regulating SOX2, Supplemental Figure S5. The association of PGE2 expression with apoptosis in YAP1-LV or YAP1-sh cells, Supplemental Figure S6. Correlation among SOX2, YAP1, and COX2 expression in human UCB samples, Supplemental Figure S7. CSC expansion following CDDP treatment suppressed by combination treatment with verteporfin and celecoxib, Supplemental Figure S8. The EGFR-regulated YAP1 expression via PI3K signaling in basal-type UCB, and Supplementary Materials and Methods.
Funding
Flight Attendant Medical Research Institute Young Clinical Scientist Award
SPORE
Allegheny Health Network-Johns Hopkins Cancer Research Fund
History
ARTICLE ABSTRACT
Overcoming acquired drug resistance remains a core challenge in the clinical management of human cancer, including in urothelial carcinoma of the bladder (UCB). Cancer stem-like cells (CSC) have been implicated in the emergence of drug resistance but mechanisms and intervention points are not completely understood. Here, we report that the proinflammatory COX2/PGE2 pathway and the YAP1 growth-regulatory pathway cooperate to recruit the stem cell factor SOX2 in expanding and sustaining the accumulation of urothelial CSCs. Mechanistically, COX2/PGE2 signaling induced promoter methylation of let-7, resulting in its downregulation and subsequent SOX2 upregulation. YAP1 induced SOX2 expression more directly by binding its enhancer region. In UCB clinical specimens, positive correlations in the expression of SOX2, COX2, and YAP1 were observed, with coexpression of COX2 and YAP1 particularly commonly observed. Additional investigations suggested that activation of the COX2/PGE2 and YAP1 pathways also promoted acquired resistance to EGFR inhibitors in basal-type UCB. In a mouse xenograft model of UCB, dual inhibition of COX2 and YAP1 elicited a long-lasting therapeutic response by limiting CSC expansion after chemotherapy and EGFR inhibition. Our findings provide a preclinical rationale to target these pathways concurrently with systemic chemotherapy as a strategy to improve the clinical management of UCB.Significance: These findings offer a preclinical rationale to target the COX2 and YAP1 pathways concurrently with systemic chemotherapy to improve the clinical management of UCB, based on evidence that these two pathways expand cancer stem-like cell populations that mediate resistance to chemotherapy. Cancer Res; 78(1); 168–81. ©2017 AACR.
