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The clinical and biological significance of STAT1 in esophageal squamous cell carcinoma.

Zhang Y, Molavi O, Su M, Lai R - BMC Cancer (2014)

Bottom Line: Furthermore, patients with STAT1-strong/weak tumors had a significantly longer survival compared to those with STAT1-negative tumors (33.6 months versus 13.1 months, p=0.019).In patients carrying tumors of aggressive cytology (n=50), those with STAT1-strong tumors survived significantly longer than those with STAT1-weak/negative tumors (34.6 months versus 20.5 months, p=0.011).To conclude, our findings suggest that STAT1 is a tumor suppressor in ESCC.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, Shantou University Medical College, 22 Xinling Road, Shantou 515031, Guangdong Province, China. minsu@stu.edu.cn.

ABSTRACT

Background: Loss of STAT1 (Signal Transducer and Activator of Transcription-1) has been implicated in the pathobiology of a number of cancer types. Nonetheless, the biological and clinical significance of STAT1 in esophageal squamous cell carcinomas (ESCC) has not been comprehensively studied.

Methods: Using immunohistochemistry, we detected the STAT1 expression in a cohort of ESCC patients; In-vitro experiments, we used enforced gene transfection of STAT1C into two STAT1- weak/negative ESCC cell lines and siRNA knockdown of STAT1 in two STAT1-strong ESCC cell lines to detect STAT1 function in ESCC.

Results: We found that the expression of STAT1 was heterogeneous in ESCC, with 64 (49.0%) strongly positive cases, 59 (45.0%) weakly positive cases and 8 (6.1%) negative cases. STAT1 expression inversely correlated with the depth of tumor invasion and tumor size (p=0.047 and p=0.029, respectively, Chi square). Furthermore, patients with STAT1-strong/weak tumors had a significantly longer survival compared to those with STAT1-negative tumors (33.6 months versus 13.1 months, p=0.019). In patients carrying tumors of aggressive cytology (n=50), those with STAT1-strong tumors survived significantly longer than those with STAT1-weak/negative tumors (34.6 months versus 20.5 months, p=0.011). Our in-vitro experiments revealed that STAT1 is proapoptotic and inhibitory to cell-cycle progression and colony formation. Lastly, we found evidence that STAT1 signaling in ESCC cells down-regulated the expression and/or activity of NF-κB and STAT3, both of which are known to have oncogenic potential.

Conclusion: To conclude, our findings suggest that STAT1 is a tumor suppressor in ESCC. Loss of STAT1, which is frequent in ESCC, contributes to the pathogenesis of these tumors.

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STAT1C inhibits NF-κB signaling. Western blot results showed a detectable down-regulation of total p65 and phospho-p65 after STAT1C transfection in EC1 and EC109 cells (A). In the same experiment, nuclear/cytoplasmic fractionation studies showed that STAT1C induced a substantial decrease in nuclear p65 and phospho-p65 (B). (C) Using a NF-κB/luciferase reporter, we found that STAT1C gene transfection induce a significant down-regulation of the NF-κB transcription activity in ESCC cells transfected with STAT1C cells were harvested 48 hours after the gene transfection. (*p < 0.05) (E.V.: empty vector).
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Fig6: STAT1C inhibits NF-κB signaling. Western blot results showed a detectable down-regulation of total p65 and phospho-p65 after STAT1C transfection in EC1 and EC109 cells (A). In the same experiment, nuclear/cytoplasmic fractionation studies showed that STAT1C induced a substantial decrease in nuclear p65 and phospho-p65 (B). (C) Using a NF-κB/luciferase reporter, we found that STAT1C gene transfection induce a significant down-regulation of the NF-κB transcription activity in ESCC cells transfected with STAT1C cells were harvested 48 hours after the gene transfection. (*p < 0.05) (E.V.: empty vector).

Mentions: Previous studies have shown that STAT1 can block NF-κB by downregulating TNF-α [16]. In view of the importance of NF-κB in the biology of ESCC [17, 18], we hypothesized that the biological effects of STAT1C in ESCC may be mediated by down-regulating the NF-κB signaling. In keeping with this concept, we found that transfection of STAT1C into EC1 and EC109 cells resulted in a substantial decrease in the phosphorylation of NF-κB p65, a marker of NF-κB activation [19] (Figure 6A). By subcellular fractionation, we also found that STAT1C transfection induced a dramatic decrease in the nuclear localization of NF-κB p65 or phospho-NF-κB p65 in both cell lines (Figure 6B). Lastly, we assessed the transcriptional activity of NF-κB using a commercially available luciferase reporter construct. As shown in Figure 6C, there was a significant down-regulation of NF-κB transcriptional activity after STAT1C transfection in both ESCC cells.Figure 6


The clinical and biological significance of STAT1 in esophageal squamous cell carcinoma.

Zhang Y, Molavi O, Su M, Lai R - BMC Cancer (2014)

STAT1C inhibits NF-κB signaling. Western blot results showed a detectable down-regulation of total p65 and phospho-p65 after STAT1C transfection in EC1 and EC109 cells (A). In the same experiment, nuclear/cytoplasmic fractionation studies showed that STAT1C induced a substantial decrease in nuclear p65 and phospho-p65 (B). (C) Using a NF-κB/luciferase reporter, we found that STAT1C gene transfection induce a significant down-regulation of the NF-κB transcription activity in ESCC cells transfected with STAT1C cells were harvested 48 hours after the gene transfection. (*p < 0.05) (E.V.: empty vector).
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4233059&req=5

Fig6: STAT1C inhibits NF-κB signaling. Western blot results showed a detectable down-regulation of total p65 and phospho-p65 after STAT1C transfection in EC1 and EC109 cells (A). In the same experiment, nuclear/cytoplasmic fractionation studies showed that STAT1C induced a substantial decrease in nuclear p65 and phospho-p65 (B). (C) Using a NF-κB/luciferase reporter, we found that STAT1C gene transfection induce a significant down-regulation of the NF-κB transcription activity in ESCC cells transfected with STAT1C cells were harvested 48 hours after the gene transfection. (*p < 0.05) (E.V.: empty vector).
Mentions: Previous studies have shown that STAT1 can block NF-κB by downregulating TNF-α [16]. In view of the importance of NF-κB in the biology of ESCC [17, 18], we hypothesized that the biological effects of STAT1C in ESCC may be mediated by down-regulating the NF-κB signaling. In keeping with this concept, we found that transfection of STAT1C into EC1 and EC109 cells resulted in a substantial decrease in the phosphorylation of NF-κB p65, a marker of NF-κB activation [19] (Figure 6A). By subcellular fractionation, we also found that STAT1C transfection induced a dramatic decrease in the nuclear localization of NF-κB p65 or phospho-NF-κB p65 in both cell lines (Figure 6B). Lastly, we assessed the transcriptional activity of NF-κB using a commercially available luciferase reporter construct. As shown in Figure 6C, there was a significant down-regulation of NF-κB transcriptional activity after STAT1C transfection in both ESCC cells.Figure 6

Bottom Line: Furthermore, patients with STAT1-strong/weak tumors had a significantly longer survival compared to those with STAT1-negative tumors (33.6 months versus 13.1 months, p=0.019).In patients carrying tumors of aggressive cytology (n=50), those with STAT1-strong tumors survived significantly longer than those with STAT1-weak/negative tumors (34.6 months versus 20.5 months, p=0.011).To conclude, our findings suggest that STAT1 is a tumor suppressor in ESCC.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, Shantou University Medical College, 22 Xinling Road, Shantou 515031, Guangdong Province, China. minsu@stu.edu.cn.

ABSTRACT

Background: Loss of STAT1 (Signal Transducer and Activator of Transcription-1) has been implicated in the pathobiology of a number of cancer types. Nonetheless, the biological and clinical significance of STAT1 in esophageal squamous cell carcinomas (ESCC) has not been comprehensively studied.

Methods: Using immunohistochemistry, we detected the STAT1 expression in a cohort of ESCC patients; In-vitro experiments, we used enforced gene transfection of STAT1C into two STAT1- weak/negative ESCC cell lines and siRNA knockdown of STAT1 in two STAT1-strong ESCC cell lines to detect STAT1 function in ESCC.

Results: We found that the expression of STAT1 was heterogeneous in ESCC, with 64 (49.0%) strongly positive cases, 59 (45.0%) weakly positive cases and 8 (6.1%) negative cases. STAT1 expression inversely correlated with the depth of tumor invasion and tumor size (p=0.047 and p=0.029, respectively, Chi square). Furthermore, patients with STAT1-strong/weak tumors had a significantly longer survival compared to those with STAT1-negative tumors (33.6 months versus 13.1 months, p=0.019). In patients carrying tumors of aggressive cytology (n=50), those with STAT1-strong tumors survived significantly longer than those with STAT1-weak/negative tumors (34.6 months versus 20.5 months, p=0.011). Our in-vitro experiments revealed that STAT1 is proapoptotic and inhibitory to cell-cycle progression and colony formation. Lastly, we found evidence that STAT1 signaling in ESCC cells down-regulated the expression and/or activity of NF-κB and STAT3, both of which are known to have oncogenic potential.

Conclusion: To conclude, our findings suggest that STAT1 is a tumor suppressor in ESCC. Loss of STAT1, which is frequent in ESCC, contributes to the pathogenesis of these tumors.

Show MeSH
Related in: MedlinePlus