Stat3 and Gap Junctions in Normal and Lung Cancer Cells

Abstract

Gap junctions are channels linking the interiors of neighboring cells. A reduction in gap junctional intercellular communication (GJIC) correlates with high cell proliferation, while oncogene products such as Src suppress GJIC, through the Ras/Raf/Erk and other effector pathways. High Src activity was found to correlate with high levels of the Src effector, Signal Transducer and Activator of Transcription-3 (Stat3) in its tyrosine-705 phosphorylated, i.e., transcriptionally activated form, in the majority of Non-Small Cell Lung Cancer lines examined. However, Stat3 inhibition did not restore GJIC in lines with high Src activity. In the contrary, Stat3 inhibition in normal cells or in lines with low Src activity and high GJIC eliminated gap junctional communication. Therefore, despite the fact that Stat3 is growth promoting and in an activated form acts like an oncogene, it is actually required for junctional permeability.

<p>GJA1 is a Prognostic Biomarker and Correlated with Immune Infiltrates in Colorectal Cancer</p>

“…It has been shown that down-regulation of GJA1 can result in aggressive growth of breast and lung cancer. [5][6][7] In contrast, forced expression of GJA1 in various tumor cells can restore normal cell phenotypes and well differentiation. 8 These findings indicated a possible role of GJA1 as a tumor suppressor.…”

Association of APC, GSTP1 and SOCS1 promoter methylation with the risk of hepatocellular carcinoma

“…Preliminary reports suggest that GSTP1 promoter region hypermethylation suppresses expression of the gene and contributes to an increase in the incidence of cancer (Bakker et al, 2002;Zhong et al, 2002;Jain et al, 2012). Moreover, the SOCS1 gene TSG located on chromosome 16p13.13 and the JAK-binding protein encoded by this gene are both regulated by the JAK/STAT signalling pathway, which is not only correlated with the regeneration of hepatocytes but is also relevant to the oncogenesis of various types of tumours, including HCC (Clark et al, 2013;Guy et al, 2014). In addition, SOCS1 promoter region methylation is related to decreased or abnormal expression of SOCS1 in human HCC (Yoshikawa et al, 2001), suggesting that the methylation of SOCS1 may participate in the development of HCC (Saelee et al, 2012).…”

Association of STAT3 with Cx26 and Cx43 in human uterine endometrioid adenocarcinoma

“…Coexistent activation of src and its effector molecule STAT3 is also observed in NSCLC cell lines. STAT3 deactivation results in a reduction in gap junctional communication exclusively in normal cells or in lines with low Src activity and high levels of gap junction communication (7). Similarly, STAT3 blockage abrogated junctional permeability in normal liver cells with high GJIC (3).…”

“…The study showed that gap junctions require the activation of STAT3 in order to maintain intracellular communication in non neoplastic and neoplastic lung cell lines. Cell proliferation is generally associated with a reduction in GJIC (7). Coexistent activation of src and its effector molecule STAT3 is also observed in NSCLC cell lines.…”

“…This evidence indicates a pleiotropic significance of STAT3: That it enables permeability of gap junctions and contributes to maintenance of gap junction communication (3,7). It should be emphasized that, besides Cx expression, STAT3 is an extraordinarily versatile mediator and it interacts with a number of molecules, including leptin and its receptor OB-R, IL-11 or oncostatin M that affect the invasive properties of malignant cells via their impact on cellular adhesion, motility and survival in gynecological cancers (10,(23)(24)(25)(26)(27).…”