Signal transducer and activator of transcription 3 activation is associated with bladder cancer cell growth and survival

Chun-Liang Chen,Gong Cheng,Christina Chan,Jiayuh Lin,Ling Cen,Victor Huang,Jennifer Kohout,Brian Hutzen,Abbey Loy,Fu-Chuan Hsieh

doi:10.1186/1476-4598-7-78

Chun-Liang Chen, Gong Cheng + Show 8 more

Open Access

https://doi.org/10.1186/1476-4598-7-78

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Abstract

BackgroundConstitutive activation of signal transducer and activator of transcription 3 (Stat3) signaling pathway plays an important role in several human cancers. Activation of Stat3 is dependent on the phosphorylation at the tyrosine residue 705 by upstream kinases and subsequent nuclear translocation after dimerization. It remains unclear whether oncogenic Stat3 signaling pathway is involved in the oncogenesis of bladder cancer.ResultsWe found that elevated Stat3 phosphorylation in 19 of 100 (19%) bladder cancer tissues as well as bladder cancer cell lines, WH, UMUC-3 and 253J. To explore whether Stat3 activation is associated with cell growth and survival of bladder cancer, we targeted the Stat3 signaling pathway in bladder cancer cells using an adenovirus-mediated dominant-negative Stat3 (Y705F) and a small molecule compound, STA-21. Both prohibited cell growth and induction of apoptosis in these bladder cancer cell lines but not in normal bladder smooth muscle cell (BdSMC). The survival inhibition might be mediated through apoptotic caspase 3, 8 and 9 pathways. Moreover, down-regulation of anti-apoptotic genes (Bcl-2, Bcl-xL and survivin) and a cell cycle regulating gene (cyclin D1) was associated with the cell growth inhibition and apoptosis.ConclusionThese results indicated that activation of Stat3 is crucial for bladder cancer cell growth and survival. Therefore, interference of Stat3 signaling pathway emerges as a potential therapeutic approach for bladder cancer.

Highlights

Constitutive activation of signal transducer and activator of transcription 3 (Stat3) signaling pathway plays an important role in several human cancers
Results p-Stat3 was elevated in bladder cancer tissues Tissue microarray immunohistochemistry indicated that Stat3 phosphorylation was elevated in bladder cancer tissues
WH cells transduced with rAd/dominant negative Stat3 Y705F (dnStat3) had only 50.2 ± 13.5% (P < 0.05) and 16.1 ± 2.2% (P < 0.005) of cell growth compared to untransduced controls at day 2 postinfection; evenmore, at day 4 post-infection, cell growth of rAd/dnSTat3-transduced WH cells was decreased to only 1.1% and 0.5% of untransduced controls

Summary

Introduction

Constitutive activation of signal transducer and activator of transcription 3 (Stat3) signaling pathway plays an important role in several human cancers. Activation of Stat is dependent on the phosphorylation at the tyrosine residue 705 by upstream kinases and subsequent nuclear translocation after dimerization It remains unclear whether oncogenic Stat signaling pathway is involved in the oncogenesis of bladder cancer. Overactive FGFR3 and ERBB2 in bladder cancer presumably would activate Stat that is down-stream to these two receptor tyrosine kinases [10]. Another line of evidence is that overexpression of Stat3-regulated anti-apoptotic genes (Bcl-2, Bcl-xL and survivin) is found in bladder cancer. The role of activated Stat in bladder cancer remained speculative until the recent report showed that Stat activation correlated with malignant characteristics of T24 bladder cancer cells [19]. This implicates that activation of Stat may play a role in the development of bladder cancer

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