Changes in Connexin43 Expression and Localization During Pancreatic Cancer Progression

Abstract

Gap junctions and gap junction communication have long been recognized to play roles in tissue organization and remodeling through both cell autonomous and intercellular means. We hypothesized that these processes become dysregulated during pancreas cancer progression. Molecular and histological characterization of the gap junction protein, connexin43, during progression of pancreatic ductal adenocarcinoma could yield insight into how these events may contribute to or be modulated during carcinogenesis. In a mouse model of pancreatic ductal adenocarcinoma generated through targeted endogenous expression of KrasG12D in the murine pancreas, we examined the evolving expression and localization of connex-in43. Overall, connexin43 expression increased over time, and its localization became more widespread. At early stages, connexin43 is found almost exclusively in association with the basolateral membrane of duct cells found in invasive lesions. Connexin43 became increasingly associated with the surrounding stroma over time. Connexin43 phosphorylation was also altered during tumorigenesis, as assessed by migrational changes of the protein in immunoblots. These data suggest a potential role for gap junctions and connexin43 in mediating interactions between and amongst the stromal and epithelial cells in pancreatic ductal adenocarcinoma.

Pathological Implications of Cx43 Down-regulation in Human Colon Cancer

“…In the present study, we explored the expression analysis of Cx43 in the human colon cancer in the Kashmiri population. The role of Cx43 in regulating cell growth has been established from the observation that different types of tumor cells and tumorigenic cell lines show decreased or altered connexin expression and/or localization (Solan et al, 2012). However, most of the previous studies have focused mostly on the expression of Cx43 in various human cancer cell lines (Leithe et al, 2006).…”

Autoregulation of Connexin43 Gap Junction Formation by Internally Translated Isoforms

“…Six C×43 molecules oligomerize to form transmembrane channels, termed connexons, which couple with apposing connexons on neighboring cells and coalesce into dense gap junction plaques (Unwin and Zampighi, 1980). Given the broad expression pattern of C×43, it is unsurprising that alterations in C×43 gap junction coupling are associated with diverse pathologies including heart disease (Akar et al, 2007; Beardslee et al, 2000; Luke and Saffitz, 1991; Smith et al, 1991), connective tissue disease (Paznekas et al, 2003), and cancer (Solan et al, 2012). In fact, altered C×43 trafficking contributes to the arrhythmias of sudden cardiac death (Kalcheva et al, 2007; Peters et al, 1997; Remo et al, 2011; Shaw and Rudy, 1997; Smyth et al, 2010).…”

Sulforaphane counteracts aggressiveness of pancreatic cancer driven by dysregulated Cx43-mediated gap junctional intercellular communication

“…These findings suggest that cytoplasmic localization of Cx43 induces the dysregulation of GJs by Cx43 withdrawal from the cell membrane during early tumor progression (BxPc-3-GEM), which may be followed by complete silencing of Cx43 expression in later tumor stages (AsPC-1). In this regard, changes in Cx43 expression and localization during pancreatic cancer progression have been recently described in the murine system and suggest a potential role for GJs and Cx43 in mediating interactions between and amongst the stromal and epithelial cells [32]. Another suggested mechanism for Cx43 translocation from the cell surface, along with the reduction of GJIC, involves the hypophosphorylation of Cx43, as demonstrated in oncogene-transformed rat liver epithelial cells and the occurrence of phosphorylated (P 1 , P 2 P 2 ´ , P 3 ) and unphosphorylated P 0 Cx43 immunoreactive bands in Western blot analysis [33].…”