Abstract
Connexins (Cxs) are critical for normal tissue development, differentiation, and cell proliferation. Normal expression and function of Cxs are considered to play a role in tumor suppression, but abnormal localization and abnormally increased expression of Cxs have been found in a variety of carcinomas. Of the Cx family, Cx43 is a most prevalent member and has been known as a downstream target of β-catenin, a key component of Wnt signaling pathway. We evaluated the expression of Cx43 in the colonic neoplasia progression sequence with additional attention to the stromal component. Resections of 50 colonic adenocarcinomas were stained immunohistochemically for Cx43 on paraffin embedded sections. Cx43 cytoplasmic expression increased progressively in the colonic adenocarcinoma sequence in both the epithelial [normal (4 ± 1), adenomatous (20 ± 2), cancerous (124 ± 10) (P < 0.01)], and stromal [normal (19 ± 1), cancerous (45 ± 4) (P < 0.01)] components. In the epithelial component, Cx43 was expressed lower in stage I adenocarcinomas (69 ± 12) compared to stage III/IV (158 ± 10, P < 0.01). Additionally, Cx43 was relatively increased in the adenocarcinoma at the invasive tumor front in all stages. Cx43 may play a critical role in the pathogenesis of colon cancer via gap junction or other gap junction independent mechanisms such as the Wnt/β-catenin pathway.
Highlights
Gap junctions are specific cell-to-cell channels formed by two hemichannels each of which is composed of six transmembrane proteins, called connexin (Cx)
The role of Cxs in carcinogenesis and metastasis remains controversial, because it is still unclear whether Cx expression is required for invasion and metastasizing [35]
The intercellular/membranous staining was rare and only sporadically seen in normal colonic epithelium, but cytoplasmic expression of Cx43 was frequently observed in colonic cancer cells
Summary
Gap junctions are specific cell-to-cell channels formed by two hemichannels each of which is composed of six transmembrane proteins, called connexin (Cx). While Cxs were initially thought to serve as putative tumor suppressors via normal functioning gap junctions [3,4,5,6], more recent studies have found aberrant increased expression of Cxs in a variety of carcinomas and sarcomas [7,8,9]. Because cell contactmediated signaling is important in carcinogenesis by regulating invasion and metastasis [10,11,12], we hypothesize that Cxs may serve a role in these processes through gap junction dependent or independent mechanisms. Because epithelial stromal interactions and signaling are critical for normal cell biology and cancer cell migration, we hypothesized that the expression of Cxs may be altered in the mesenchymal tissue in neoplastic progression
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