Abstract
Cancer stem-like cells (CSCs) contribute to bladder cancer chemotherapy resistance and progression, but the associated mechanisms have not been elucidated. This study determined whether blocking an autocrine signaling loop in CSCs improves the therapeutic effects of cis-platinum on bladder cancer. The expression of the epithelial marker OV6 and other markers in human bladder cancer specimens was examined by IHC. The CSC properties of magnetic-activated cell sorting (MACS)-isolated OV6+ and OV6- bladder cancer cells were examined. Molecular mechanisms were assessed through RNA-Seq, cytokine antibody arrays, co-immunoprecipitation (co-IP), chromatin immunoprecipitation (ChIP) and other assays. An orthotopic bladder cancer mouse model was established to evaluate the in vivo effects of a YAP inhibitor (verteporfin) and a PDGFR inhibitor (CP-673451) on the cis-platinum resistance of OV6+ CSCs in bladder cancer. Upregulated OV6 expression positively associated with disease progression and poor prognosis for bladder cancer patients. Compared with OV6- cells, OV6+ bladder cancer cells exhibited strong CSC characteristics, including self-renewal, tumor initiation in NOD/SCID mice, and chemotherapy resistance. YAP, which maintains the stemness of OV6+ CSCs, triggered PDGFB transcription by recruiting TEAD1. Autocrine PDGF-BB signaling through its receptor PDGFR stabilized YAP and facilitated YAP nuclear translocation. Furthermore, blocking the YAP/TEAD1/PDGF-BB/PDGFR loop with verteporfin or CP-673451 inhibited the cis-platinum resistance of OV6+ bladder cancer CSCs in an orthotopic bladder cancer model. OV6 could be a helpful indicator of disease progression and prognosis for patients with bladder cancer, and targeting the autocrine YAP/TEAD1/PDGF-BB/PDGFR loop might serve as a remedy for cis-platinum resistance in patients with advanced bladder cancer.
Highlights
Bladder cancer is one of the most frequently diagnosed and lethal cancers worldwide, with an estimated 429,800 new cases and 165,100 deaths in 2012 [1]
OV6 could be a helpful indicator of disease progression and prognosis for patients with bladder cancer, and targeting the autocrine Yes-associated protein (YAP)/TEAD1/PDGF-BB/PDGFR loop might serve as a remedy for cis-platinum resistance in patients with advanced bladder cancer
On the basis of the previous studies that OV6 closely associates with progression and prognosis of patients with tumors [22,23,24], we examined whether the epithelial marker OV6 is associated with the clinicopathologic characteristics and prognosis of patients with bladder cancer
Summary
Bladder cancer is one of the most frequently diagnosed and lethal cancers worldwide, with an estimated 429,800 new cases and 165,100 deaths in 2012 [1]. Surgical resection is the preferred treatment for patients with bladder cancer, most tumors recur and progress to muscle-invasive bladder cancers (MIBC) and metastatic bladder cancer, which are prone to develop chemotherapy resistance after treatment and are associated with poor prognosis [2, 3]. Cancer stem-like cells (CSCs) are a small sub-. Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/).
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