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

Chen CL, Cen L, Kohout J, Hutzen B, Chan C, Hsieh FC, Loy A, Huang V, Cheng G, Lin J - Mol. Cancer (2008)

Bottom Line: Activation of Stat3 is dependent on the phosphorylation at the tyrosine residue 705 by upstream kinases and subsequent nuclear translocation after dimerization.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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Center for Childhood Cancer, The Research Institute at Nationwide Children's Hospital, Columbus, OH 43205, USA. Chun-Liang.Chen@nationwidechildrens.org

ABSTRACT

Background: Constitutive 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.

Results: We 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.

Conclusion: These 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.

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Related in: MedlinePlus

p-Stat3 was elevated in bladder cancer tissues. (A) normal tissue, (B) squamous cell carcinoma (Stage II), (C) urothelial carcinoma (stage III), (D) urothelial carcinoma (stage IV). Normal tissues appeared negative in p-Stat3 staining. The nuclei were counterstained with hematoxylin blue. Image magnification was 100×.
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Figure 1: p-Stat3 was elevated in bladder cancer tissues. (A) normal tissue, (B) squamous cell carcinoma (Stage II), (C) urothelial carcinoma (stage III), (D) urothelial carcinoma (stage IV). Normal tissues appeared negative in p-Stat3 staining. The nuclei were counterstained with hematoxylin blue. Image magnification was 100×.

Mentions: Tissue microarray immunohistochemistry indicated that Stat3 phosphorylation was elevated in bladder cancer tissues. Three representative bladder cancer tissues with p-Stat3 positive immunostaining (scale 2–3) are shown (Figure 1B–D), whereas normal bladder tissues were negative or very weak (scale 0–1) with immunostaining (Figure 1A). The elevated p-Stat3 in the bladder cancer tissues was scored and summarized according to immunostaining intensities. Two of the bladder cancer tissues were not included for immunostaining scoring because no staging information is available. Nineteen out of 100 bladder cancer tissues were positive for p-Stat3 immunostaining (scale 2–3).


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

Chen CL, Cen L, Kohout J, Hutzen B, Chan C, Hsieh FC, Loy A, Huang V, Cheng G, Lin J - Mol. Cancer (2008)

p-Stat3 was elevated in bladder cancer tissues. (A) normal tissue, (B) squamous cell carcinoma (Stage II), (C) urothelial carcinoma (stage III), (D) urothelial carcinoma (stage IV). Normal tissues appeared negative in p-Stat3 staining. The nuclei were counterstained with hematoxylin blue. Image magnification was 100×.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2577686&req=5

Figure 1: p-Stat3 was elevated in bladder cancer tissues. (A) normal tissue, (B) squamous cell carcinoma (Stage II), (C) urothelial carcinoma (stage III), (D) urothelial carcinoma (stage IV). Normal tissues appeared negative in p-Stat3 staining. The nuclei were counterstained with hematoxylin blue. Image magnification was 100×.
Mentions: Tissue microarray immunohistochemistry indicated that Stat3 phosphorylation was elevated in bladder cancer tissues. Three representative bladder cancer tissues with p-Stat3 positive immunostaining (scale 2–3) are shown (Figure 1B–D), whereas normal bladder tissues were negative or very weak (scale 0–1) with immunostaining (Figure 1A). The elevated p-Stat3 in the bladder cancer tissues was scored and summarized according to immunostaining intensities. Two of the bladder cancer tissues were not included for immunostaining scoring because no staging information is available. Nineteen out of 100 bladder cancer tissues were positive for p-Stat3 immunostaining (scale 2–3).

Bottom Line: Activation of Stat3 is dependent on the phosphorylation at the tyrosine residue 705 by upstream kinases and subsequent nuclear translocation after dimerization.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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Center for Childhood Cancer, The Research Institute at Nationwide Children's Hospital, Columbus, OH 43205, USA. Chun-Liang.Chen@nationwidechildrens.org

ABSTRACT

Background: Constitutive 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.

Results: We 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.

Conclusion: These 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.

Show MeSH
Related in: MedlinePlus