Abstract
The role of connexin proteins (Cx), which form gap junctions (GJ), in progression and chemotherapeutic sensitivity of cervical cancer (CaCx), is unclear. Using cervix specimens (313 CaCx, 78 controls) and CaCx cell lines, we explored relationships among Cx expression, prognostic variables and mechanisms that may link them. In CaCx specimens, Cx32 was upregulated and cytoplasmically localized, and three other Cx downregulated, relative to controls. Cx32 expression correlated with advanced FIGO staging, differentiation and increased tumor size. In CaCx cell lines, Cx32 expression suppressed streptonigrin/cisplatin-induced apoptosis in the absence of functional GJ. In CaCx specimens and cell lines, expression of Cx32 upregulated epidermal growth factor receptor (EGFR) expression. Inhibition of EGFR signaling abrogated the anti-apoptotic effect of Cx32 expression. In conclusion, upregulated Cx32 in CaCx cells produces anti-apoptotic, pro-tumorigenic effects in vivo and vitro. Abnormal Cx32 expression/localization in CaCx appears to be both a mechanism and biomarker of chemotherapeutic resistance.
Highlights
Introduction(GJ), which modulate essential cellular processes including electrical coupling, proliferation, differentiation and apoptosis.[1,2] Consistent with the idea of ‘contact growth inhibition’ originally proposed in the 1960s,3,4 GJ and Cx have been widely accepted as tumor suppressive; loss of GJ is characteristic of malignancy.[5,6,7] In malignant tumor cells, transfection with Cx enhances radiotherapy/chemotherapyinduced apoptosis in a GJ-dependent manner (toxic ‘bystander effect’).[1,8,9] Our recent work demonstrated that GJ facilitated cisplatin-induced apoptosis in cancerous cells, but suppressed apoptosis in normal cells.[10,11] Besides, other studies have shown that expression of Cx can induce cancer cell growth inhibition and apoptosis independent of GJ function.[12,13,14] It was reported that cytoplasmic Cx exerts pro-tumor effects during metastasis in many cancers, including colorectal, gastric, breast, prostate and liver,[15,16,17,18,19] and conducts chemoresistance in glioblastoma.[20,21] In contrast, it was recently reported that Cx suppressed metastasis of liver cancer cells.[22] the role of Cx expression, independent of GJs, in cancer pathogenesis is still controversial
It is well accepted that human papillomavirus (HPV) infection is highly correlated with cervical cancer.[25,26]
The results of the present study indicate that the specific upregulation and non-junctional localization of Cx32 in human CaCx cells contributes to tumor growth and chemoresistance
Summary
(GJ), which modulate essential cellular processes including electrical coupling, proliferation, differentiation and apoptosis.[1,2] Consistent with the idea of ‘contact growth inhibition’ originally proposed in the 1960s,3,4 GJ and Cx have been widely accepted as tumor suppressive; loss of GJ is characteristic of malignancy.[5,6,7] In malignant tumor cells, transfection with Cx enhances radiotherapy/chemotherapyinduced apoptosis in a GJ-dependent manner (toxic ‘bystander effect’).[1,8,9] Our recent work demonstrated that GJ facilitated cisplatin-induced apoptosis in cancerous cells, but suppressed apoptosis in normal cells.[10,11] Besides, other studies have shown that expression of Cx can induce cancer cell growth inhibition and apoptosis independent of GJ function.[12,13,14] It was reported that cytoplasmic Cx exerts pro-tumor effects during metastasis in many cancers, including colorectal, gastric, breast, prostate and liver,[15,16,17,18,19] and conducts chemoresistance in glioblastoma.[20,21] In contrast, it was recently reported that Cx suppressed metastasis of liver cancer cells.[22] the role of Cx expression, independent of GJs, in cancer pathogenesis is still controversial.
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