title: PIAS3, SHP2 and SOCS3 Expression patterns in Cervical Cancers: Relevance with activation and resveratrol-caused inactivation of STAT3 signaling.
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.
authors.affiliation: Liaoning Laboratory of Cancer Genetics and Epigenetics and Department of Cell Biology, College of Basic Medical Sciences, Dalian Medical University, Dalian 116044, China.
authors.forename: Peng
authors.initials: P
authors.lastname: Zhang
authors.affiliation: Department of Gynaecological Surgery, Sheng-Jing Hospital, China Medical University, Shenyang 110004, China.
authors.forename: Bin
authors.initials: B
authors.lastname: Yang
authors.affiliation: Liaoning Laboratory of Cancer Genetics and Epigenetics and Department of Cell Biology, College of Basic Medical Sciences, Dalian Medical University, Dalian 116044, China.
authors.forename: Yuan-Yuan
authors.initials: YY
authors.lastname: Yao
authors.affiliation: Department of Clinical Oncology, Second Affiliated Hospital of Dalian Medical University, Dalian 110042, China.
authors.forename: Li-Xia
authors.initials: LX
authors.lastname: Zhong
authors.affiliation: Liaoning Laboratory of Cancer Genetics and Epigenetics and Department of Cell Biology, College of Basic Medical Sciences, Dalian Medical University, Dalian 116044, China.
authors.forename: Xiao-Yan
authors.initials: XY
authors.lastname: Chen
authors.affiliation: Liaoning Laboratory of Cancer Genetics and Epigenetics and Department of Cell Biology, College of Basic Medical Sciences, Dalian Medical University, Dalian 116044, China.
authors.forename: Qing-You
authors.initials: QY
authors.lastname: Kong
authors.affiliation: Liaoning Laboratory of Cancer Genetics and Epigenetics and Department of Cell Biology, College of Basic Medical Sciences, Dalian Medical University, Dalian 116044, China.
authors.forename: Mo-Li
authors.initials: ML
authors.lastname: Wu
authors.affiliation: Liaoning Laboratory of Cancer Genetics and Epigenetics and Department of Cell Biology, College of Basic Medical Sciences, Dalian Medical University, Dalian 116044, China.
authors.forename: Cong
authors.initials: C
authors.lastname: Li
authors.affiliation: Liaoning Laboratory of Cancer Genetics and Epigenetics and Department of Cell Biology, College of Basic Medical Sciences, Dalian Medical University, Dalian 116044, China. Electronic address: lihongmcn@dlmedu.edu.cn.
authors.forename: Hong
authors.initials: H
authors.lastname: Li
authors.affiliation: Liaoning Laboratory of Cancer Genetics and Epigenetics and Department of Cell Biology, College of Basic Medical Sciences, Dalian Medical University, Dalian 116044, China. Electronic address: jialiudl@aliyun.com.
authors.forename: Jia
authors.initials: J
authors.lastname: Liu
mesh_terms: D000230:Adenocarcinoma / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D002294:Carcinoma, Squamous Cell / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D019938:Cyclin D1 / Q000032:analysis; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D006367:HeLa Cells; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000032:analysis; D018832:Molecular Chaperones / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D050828:Protein Inhibitors of Activated STAT / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11 / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D016271:Proto-Oncogene Proteins c-myc / Q000032:analysis; D012334:RNA, Neoplasm / Q000378:metabolism; D000077185:Resveratrol; D050796:STAT3 Transcription Factor / Q000032:analysis / Q000187:drug effects / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013267:Stilbenes / Q000494:pharmacology*; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D000077022:Survivin; D002583:Uterine Cervical Neoplasms / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A / Q000032:analysis
chemical_list: D000972:Antineoplastic Agents, Phytogenic; C107489:BIRC5 protein, human; D051034:Inhibitor of Apoptosis Proteins; C489427:MYC protein, human; D018832:Molecular Chaperones; C484745:PIAS3 protein, human; D050828:Protein Inhibitors of Activated STAT; D016271:Proto-Oncogene Proteins c-myc; D012334:RNA, Neoplasm; C106644:SOCS3 protein, human; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D013267:Stilbenes; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D000077022:Survivin; D042461:Vascular Endothelial Growth Factor A; D019938:Cyclin D1; C516724:PTPN11 protein, human; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D000077185:Resveratrol
keywords: Cervical cancers;; PIAS3;; Resveratrol;; SHP2;; SOCS3;; STAT3 signaling pathway