Stat3 Activation in Urothelial Stem Cells Leads to Direct Progression to Invasive Bladder Cancer

Ho, Philip Levy; Lay, Erica Julianne; Jian, Weiguo; Parra, Diana; Chan, Keith S.

doi:10.1158/0008-5472.can-11-3195

Cited by 116 publications

(91 citation statements)

References 20 publications

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“…The pathological characteristics of the mouse bladder tumors suggest that these mice could represent a bona fide NMIBC model. Also, the mouse tumors display activation of MAPK/Erk, Stat3 and S6 pathways, which have been previously involved in human BC (36-38). …”

Section: Discussionmentioning

confidence: 77%

In Vivo Disruption of an Rb–E2F–Ezh2 Signaling Loop Causes Bladder Cancer

et al. 2014

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Bladder cancer (BC) is a highly prevalent human disease in which retinoblastoma (Rb) pathway inactivation and epigenetic alterations are common events. However, the connection between these two processes is still poorly understood. Here we show that the in vivo inactivation of all Retinoblastoma (Rb) family genes in the mouse urothelium is sufficient to initiate BC development. The characterization of the mouse tumors revealed multiple molecular features of human BC, including the activation of E2F transcription factor and subsequent Ezh2 expression, and the activation of several signaling pathways previously identified as highly relevant in urothelial tumors. These mice represent a genetically defined model for human high-grade superficial BC. Whole transcriptional characterizations of mouse and human bladder tumors revealed a significant overlap and confirm the predominant role for Ezh2 in the downregulation of gene expression programs. Importantly, the increased tumor recurrence and progression in human superficial BC patients is associated with increased E2F and Ezh2 expression and Ezh2-mediated gene expression repression. Collectively, our studies provide a genetically defined model for human high-grade superficial BC and demonstrate the existence of an Rb-E2F-Ezh2 axis in bladder whose disruption can promote tumor development.

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Section: Discussionmentioning

confidence: 77%

In Vivo Disruption of an Rb–E2F–Ezh2 Signaling Loop Causes Bladder Cancer

et al. 2014

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“…It also has multiple protumorigenic functions, including the promotion of tumor cell proliferation, survival, invasion, metastasis and angiogenesis (24,25). IL-6 induces EMT changes in tumor cells via activation of the STAT3 signaling pathway and STAT3-knockdown reverses these changes (26).…”

Section: Discussionmentioning

confidence: 99%

Expression of interleukin-6 is associated with epithelial-mesenchymal transition and survival rates in gallbladder cancer

Zhang

Gong

Zhang

et al. 2014

Molecular Medicine Reports

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Abstract. The present study aimed to investigate the expression of interleukin-6 (IL-6) in gallbladder cancer (GBC) tissues and its correlation with survival rate. The association between IL-6 and epithelial-mesenchymal transition (EMT)-associated markers was also examined. Using immunohistochemistry, reverse transcription quantitative polymerase chain reaction (RT-qPCR) and western blot analysis, the protein and mRNA expression levels of IL-6, Twist, E-cadherin and Vimentin in 20 GBC tissues were analyzed. The IL-6, Twist and Vimentin proteins were overexpressed in 40, 20 and 70% of the human GBC samples, respectively. The protein expression of E-cadherin was higher in only 5% of the GBC samples. These differences were significant (P<0.05). Western blot analysis also revealed overexpression of IL-6, Twist and Vimentin and underexpression of E-cadherin in the GBC samples with poor differentiation, local invasion and a higher tumor-node-metastasis (TNM) stage (P<0.05). Higher mRNA expression levels of IL-6, Twist and Vimentin and a reduced expression level of E-cadherin were also demonstrated in the GBC tissues (P<0.05). The degree of differentiation, local invasion, lymph node metastasis and clinical stage were significantly associated with the mRNA expression levels of IL-6, Twist and E-cadherin. The increased expression levels of IL-6 and Twist and the reduced expression of E-cadherin correlated with shorter median survival rates (P<0.05). Line regression results revealed correlation among the mRNA expression levels of IL-6, Twist, E-cadherin and Vimentin. To the best of our knowledge, the present study is the first to demonstrate that IL-6 is associated with EMT-associated markers, tumor differentiation, local invasion, TNM stage and survival rates in GBC.

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“…Using the ingenuity pathway analysis (IPA) upstream regulators tool, we searched for transcription factors that were predicted to be activated in basal cancers [23 & ]. The results identified active signal transducer and activator of transcription-3 (STAT3), DNp63a, NFkB, and HIF1 in the basal gene expression signature, and all of them had been implicated in the control of EMT and bladder cancer 'stemness' [32,33] …”

Section: Intrinsic Basal and Luminal Subtypes Of Bladder Cancermentioning

confidence: 99%

“…Basal MIBCs are also enriched with gene expression signatures predictive of active STAT3 [39], and preclinical studies have directly implicated STAT3 in basal bladder cancer tumorigenesis [32]. Direct inhibitors of STAT3 are still in preclinical development, and these agents would be predicted to be most active in basal cancers.…”

Section: Candidate Biological Targets In Basal Cancersmentioning

confidence: 99%

Genetic subtypes of invasive bladder cancer

McConkey

Choi

Dinney

2015

Current Opinion in Urology

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Like their breast cancer counterparts, basal bladder cancers are characterized by poor clinical outcomes in the absence of effective systemic therapy, but a large fraction of them do respond to neoadjuvant chemotherapy, suggesting that the tumors should be managed aggressively. On the contrary, tumors that belong to the 'p53-like' subtype tend to be chemoresistant, so patients with these tumors should probably be managed differently. It seems likely that prospective identification of tumor intrinsic subtype membership could complement the use of DNA-based biomarkers to identify the groups of patients who will benefit the most from chemotherapy and targeted agents.

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Stat3 Activation in Urothelial Stem Cells Leads to Direct Progression to Invasive Bladder Cancer

Cited by 116 publications

References 20 publications

In Vivo Disruption of an Rb–E2F–Ezh2 Signaling Loop Causes Bladder Cancer

In Vivo Disruption of an Rb–E2F–Ezh2 Signaling Loop Causes Bladder Cancer

Expression of interleukin-6 is associated with epithelial-mesenchymal transition and survival rates in gallbladder cancer

Genetic subtypes of invasive bladder cancer

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