Emerging roles of gap junction proteins connexins in cancer metastasis, chemoresistance and clinical application

Jun-I Wu,Lu-Hai Wang

doi:10.1186/s12929-019-0497-x

Abstract

Connexin, a four-pass transmembrane protein, contributes to assembly of gap junctions among neighboring cells and thus facilitates gap junctional intercellular communication (GJIC). Traditionally, the roles of connexins were thought to mediate formation of hemichannels and GJIC assembly for transportation of ions and small molecules. Many studies have observed loss of GJIC, due to reduced expression or altered cytoplasmic localization of connexins, in primary tumor cells. Connexins are generally considered tumor-suppressive. However, recent studies of clinical samples suggested a different role of connexins in that expression levels and membrane localization of connexins, including Connexin 43 (Cx43, GJA1) and Connexin 26 (Cx26, GJB2), were found to be enhanced in metastatic lesions of cancer patients. Cx43- and Cx26-mediated GJIC was found to promote cancer cell migration and adhesion to the pulmonary endothelium. Regulatory circuits involved in the induction of connexins and their functional effects have also been reported in various types of cancer. Connexins expressed in stromal cells were correlated with metastasis and were implicated in regulating metastatic behaviors of cancer cells. Recent studies have revealed that connexins can contribute to cellular phenotypes via multiple ways, namely 1) GJIC, 2) C-terminal tail-mediated signaling, and 3) cell-cell adhesion during gap junction formation. Both expression levels and the subcellular localization could participate determining the functional roles of connexins in cancer. Compounds targeting connexins were thus tested as potential therapeutics intervening metastasis or chemoresistance. This review focuses on the recent findings in the correlation between the expression of connexins and patients’ prognosis, their roles in metastasis and chemoresistance, as well as the implications and concerns of using connexin-targeting drugs as anti-metastatic therapeutics. Overall, connexins may serve as biomarkers for cancer prognosis and as therapeutic targets for intervening metastasis and chemoresistance.

Highlights

Cancer is the second leading cause of mortality worldwide [1]
Cancer is a disease of dysregulated cell growth [14], and gap junctional intercellular communication (GJIC) is frequently lost in primary tumor cells via reduced expression and/or cytoplasmic localization of connexins [15,16,17,18,19]
We found that Connexin 30 or GJB6 (Cx30).3 had no GJIC function, its oncogenesis promoting functions must be resulted from other Cx30.3-mediated signaling pathways, the precise subcellular localization of C30.3 remains to be characterized [83]

Summary

Introduction

Cancer is the second leading cause of mortality worldwide [1]. While early-diagnosed cancer patients are possible for curative surgery and favorable long-term survival, patients diagnosed with metastasis have much lower survival rates [2]. Cancer is a disease of dysregulated cell growth [14], and GJIC is frequently lost in primary tumor cells via reduced expression and/or cytoplasmic localization of connexins [15,16,17,18,19]. Cx43 was only expressed in the cytoplasm of most primary tumor cells and was reversely correlated with lymph node metastasis [19].

Results

Conclusion