Gap junction intercellular communication (GJIC), which is performed by connexins, is crucial in the regulation of cellular functions. Connexin 43 (Cx43) is a general isoform expressed in most epithelial tissues especially in astrocytes. There were some studies indicated that Cx43 played a tumor suppressor which has been found in human tumors compared with adjacent normal tissues. Otherwise, there were some evidences showed that Cx43 overexpression affected metastasis. However, Cx43 plays a controversial role in tumor progression. Hypoxia, a hallmark of many solid tumors, is associated with angiogenesis and tumor progression. It activates a signal cascade that culminates in the stabilization of hypoxia-inducible factor 1 (HIF-1) transcription factor and activation of genes that possess hypoxia response elements (HRE). Herein, the loss of Cx43 was shown to stabilize HIF-1α, which is overexpressed in a majority of cancers and its overexpression correlates with poor prognosis and treatment failure. Meanwhile, we examined HIF-1α expression and activities in cancer cells with various Cx43 statuses. Loss of Cx43 expression in cancer cells resulted in increased HIF-1-dependent transcriptional activity and protein expression. In this study, we also found that Cx43 down-regulated VEGF and inhibited endothelial cell proliferation. Further work is warranted to understand the molecular mechanism leading to Cx43 effects by antiangiogenic signal pathway.

Citation Format: Man-Chin Chen, Che-Hsin Lee. Connexin 43 suppresses tumor angiogenesis by downregulation of vascular endothelial growth factor. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2636. doi:10.1158/1538-7445.AM2014-2636