Non-junctional Cx32 mediates anti-apoptotic and pro-tumor effects via epidermal growth factor receptor in human cervical cancer cells

Yi-fan ZHAO,Yong-chang LAI,Hui GE,Yun-quan GUO,Xue FENG,JiaSONG,Qin WANG,Li-xia FAN,Andrew L HARRIS,Xi-yan WANG,Liang TAO

(1.Department of Anesthesiology,Sun Yat-Sen Memorial Hospital,Sun Yat-Sen University,Guangzhou 510120,China;2.Department of Pharmacology,Zhongshan School of Medicine,Sun Yat-Sen University,Guangzhou 510080,China;3.Tumor Research Institute,Xinjiang Medical University Affiliated Tumor Hospital，Urumqi 830000,China;4.Department of Pathology,Xinjiang Medical University Affiliated Tumor Hospital,Urumqi 830000,China;5.Department of Pharmacology,Physiology and Neuroscience,New Jersey Medical School-Rutgers University,Newark,NJ 07103,United State of America)

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Non-junctional Cx32 mediates anti-apoptotic and pro-tumor effects via epidermal growth factor receptor in human cervical cancer cells

Yi-fan ZHAO1,Yong-chang LAI2,Hui GE3,Yun-quan GUO4,Xue FENG3,JiaSONG3,Qin WANG2,Li-xia FAN2,Andrew L HARRIS5,Xi-yan WANG3,Liang TAO2

(1.Department of Anesthesiology,Sun Yat-Sen Memorial Hospital,Sun Yat-Sen University,Guangzhou 510120,China;2.Department of Pharmacology,Zhongshan School of Medicine,Sun Yat-Sen University,Guangzhou 510080,China;3.Tumor Research Institute,Xinjiang Medical University Affiliated Tumor Hospital，Urumqi 830000,China;4.Department of Pathology,Xinjiang Medical University Affiliated Tumor Hospital,Urumqi 830000,China;5.Department of Pharmacology,Physiology and Neuroscience,New Jersey Medical School-Rutgers University,Newark,NJ 07103,United State of America)

OBJECTIVETo investigate the role of connexin proteins(Cx),which form gap junctions(GJ),in progression and chemotherapeutic sensitivity of cervical cancer(CaCx).METHODSWe analyze the expression of Cx26,Cx30,Cx32 and Cx43 in human specimens consisting of:Normal cervix(n=78),CaCx FIGO stageⅠ(n=148),CaCx FIGO stageⅡ(n=165).InCaCx cell lines,Hela-Cx32(induced expression by doxycycline),C-33A(endogenously express Cx32)and siHa(transiently transfected plasmid with Cx32),we detected the role of Cx32 against tostreptonigrin/cisplatin-induced apopotosisin presence or absence of functional GJ through using GJ inhibitors or low density cultural.Furtherly,we observed the relativity of Cx32 and EGFR expression in human specimens.Also,we detected the role of EGFR signaling pathway in the process of Cx32 anti-apoptosis through suppressed EGFR expression by inhibitors or siRNA sequences in cell lines.RESULTSWe firstly demonstrated the expression of Cx32 was highly upregulated and accumulated in cytoplasm in the CaCx specimens,and the degree of upregulation correlated with advanced FIGO stages.Thus,in three human cervical cell lines,Cx32 was shown to suppress apoptosis when GJ formation is inhibited.No matter in cases of CaCx or cell lines,Cx32 expression was highly correlated with expression of EGFR and the EGFR pathway is an essential component of the Cx32-induced anti-apoptotic effect.CONCLUSIONCx32,traditionally tumor suppressive protein,was shown to be tumor protective against chemotherapy through EGFR pathway in a GJ-independent way.

gap-junction;connexin;cervical cancer;apoptosis;epidermal growth factor receptor

The project supported by National Nature Science Foundation of China(U1303221);National Natural Science Foundation of China(81373439,81473234);and Construction of Technique Plate for Evaluation of the Pharmacodynamics of New Drugs in Xinjiang from the Department of Science and Technology of Xinjiang Province(201233150)

Liang TAO,Tel:(020)87335468,E-mail:taol@mail.sysu.edu.cn