PIAS3, SHP2 and SOCS3 Expression patterns in Cervical Cancers: Relevance with activation and resveratrol-caused inactivation of STAT3 signaling

• Published in: Gynecologic oncology 2015-12, Vol.139 (3), p.529-535
• Main Authors: Zhang, Peng, Yang, Bin, Yao, Yuan-Yuan, Zhong, Li-Xia, Chen, Xiao-Yan, Kong, Qing-You, Wu, Mo-Li, Li, Cong, Li, Hong, Liu, Jia
• Format: Article
• Language: English
• Subjects: Adenocarcinoma - chemistry; Adenocarcinoma - genetics; Adenocarcinoma - metabolism; Antineoplastic Agents, Phytogenic - pharmacology; Carcinoma, Squamous Cell - chemistry; Carcinoma, Squamous Cell - genetics; Carcinoma, Squamous Cell - metabolism; Cell Proliferation - drug effects; Cell Survival - drug effects; Cervical cancers; Cyclin D1 - analysis; Female; Gene Expression - drug effects; HeLa Cells; Hematology, Oncology and Palliative Medicine; Humans; Inhibitor of Apoptosis Proteins - analysis; Molecular Chaperones - analysis; Molecular Chaperones - genetics; Molecular Chaperones - metabolism; Obstetrics and Gynecology; Phosphorylation; PIAS3; Protein Inhibitors of Activated STAT - analysis; Protein Inhibitors of Activated STAT - genetics; Protein Inhibitors of Activated STAT - metabolism; Protein Tyrosine Phosphatase, Non-Receptor Type 11 - analysis; Protein Tyrosine Phosphatase, Non-Receptor Type 11 - genetics; Protein Tyrosine Phosphatase, Non-Receptor Type 11 - metabolism; Proto-Oncogene Proteins c-myc - analysis; Resveratrol; RNA, Neoplasm - metabolism; SHP2; Signal Transduction - drug effects; SOCS3; STAT3 signaling pathway; STAT3 Transcription Factor - analysis; STAT3 Transcription Factor - drug effects; STAT3 Transcription Factor - metabolism; Stilbenes - pharmacology; Suppressor of Cytokine Signaling 3 Protein; Suppressor of Cytokine Signaling Proteins - analysis; Suppressor of Cytokine Signaling Proteins - genetics; Suppressor of Cytokine Signaling Proteins - metabolism; Uterine Cervical Neoplasms - chemistry; Uterine Cervical Neoplasms - genetics; Uterine Cervical Neoplasms - metabolism; Vascular Endothelial Growth Factor A - analysis
• ISSN: 0090-8258; 1095-6859
• DOI: 10.1016/j.ygyno.2015.09.087

Abstract Objective Resveratrol inhibits cervical cancer (CC) cells by blocking STAT3 signaling. However, the mechanism of resveratrol-induced STAT3 inactivation remains largely unknown. SHP2, PIAS3, and SOCS3 are STAT3 negative regulators; therefore, their statuses in cervical adenocarcinoma (HeLa) and squamous cell carcinoma (SiHa and C33A) cell lines without and with resveratrol treatment and their correlation with STAT3 activation in CC specimens were investigated. Methods MTT and TUNEL assays were used to check the resveratrol sensitivity of CC cells, and immunocytochemical staining, Western blotting, and RT-PCR were used to analyze SHP2, PIAS3, and SOCS3 expression and the intracellular distribution of STAT3. Tissue microarray based immunohistochemical staining was performed to investigate potential correlations between SHP2, PIAS3, and SOCS3 expression and STAT3 activation. Results PIAS3 and SOCS3 were found to be weakly expressed in CC cells and upregulated by resveratrol; this was accompanied by inhibition of STAT3 signaling. The SHP2 level remained unchanged in all three cell lines after resveratrol treatment. STAT3 nuclear translocation was more frequent in adenocarcinomas and squamous cell carcinomas than that of their noncancerous counterparts. The SOCS3 level and detection rate were higher in noncancerous squamous cells (but not in glandular epithelia) compared with their cancerous counterparts. The phospho-SHP2 detection rate was similar in noncancerous and tumor tissues of squamous and glandular origins; however, PIAS3 levels were distinct. Conclusions Of the three STAT3 negative regulators, PIAS3 correlated most negatively with STAT3 nuclear translocation and may inhibit STAT3 signaling in both histological CC subtypes. PIAS3 responsiveness may reflect greater resveratrol sensitivity and improved therapeutic outcome in CCs.