Connexin 43 expression is associated with poor survival in patients with esophageal squamous cell carcinoma

Abstract

Connexin 43 (Cx43) is an important gap junction protein in vertebrates, which has been reported to function as a tumor suppressor in a number of organs. However, the mechanism underlying the effect of Cx43 on tumor progression remains unknown, with only a limited number of studies reporting on the role of Cx43 in esophageal cancer. In the present study, Cx43 expression was analyzed by immunohistochemical staining and the associations between Cx43 expression and clinicopathological characteristics or prognosis were evaluated. Cx43 was expressed at a high frequency in patients with esophageal squamous cell carcinoma (ESCC). Of the 98 ESCC cases investigated, positivity for Cx43 was observed in 62 cases (63.26%). In patients with high Cx43 expression, the survival rates were significantly reduced compared with those in patients with low Cx43 expression. Moreover, the overexpression of Cx43, as measured by immunohistochemistry, was an independent prognostic indicator of ESCC. Thus, our data indicated that Cx43 may be a candidate molecular prognostic marker and molecular target for the development of an effective therapeutic intervention for patients with esophageal cancer.

Gap junctions and cancer: communicating for 50 years

“…Over a dozen studies in the last decade correlate high connexin expression with a significantly better prognosis (e.g., Cx43 in prostate 39 , pancreatic 40 , breast 41 , head and neck SCC 42 , non-small-cell lung 43 , and colorectal 44 cancers; and Cx26 in colorectal 45 and intestinal type-gastric 46 cancers). In contrast, more than a dozen studies correlate high connexin expression with a poor prognosis (e.g., Cx43 in oral SCC 47 , esophageal SCC 48 and non-muscle invasive urothelial bladder cancer 49 ; and Cx26 in breast cancer 50,51 , lung SCC 52 , esophageal SCC 53 , colorectal cancer 37 and papillary and follicular thyroid cancer 54 ). The complexity of these mixed findings may be partly explained by the connexin family member being assessed not only in the tumour but also in the host tissue.…”

Connexins in cancer: bridging the gap to the clinic

“…Correlation identified between Cx26 and recurrence, histology and p53 expression ( P < 0.05)Nomura et al [195]Cx26UHigh Cx26 = shorter patient survival P = 0.02Cx26 associated with a higher tumour grade ( P = 0.02)Knosel et al [196]Cx43FLoss of Cx43 expression = shorter relapse-free survival and OS P = 0.017Depends on subcellular Cx43 staining. Not significant if more advanced stage III and IV tumours are analysedSirnes et al [38]Oesophageal SCCCx26UHigh levels = reduced OS P = 0.007Correlated with lymph node metastasis ( P = 0.014) and the number of metastatic lymph nodes ( P = 0.047)Inose et al [197]Cx43UHigh levels = reduced OS P = 0.018Independent prognostic indicatorTanaka et al [198]GastricCx26FHigh Cx26 = better OS P = 0.002Negative associations between Cx26 expression and clinicopathologic features (all P < 0.05). High Cx26 associated with histological intestinal-type ( P = 0.017) and early-stage gastric carcinoma.…”

The Potential Impact of Connexin 43 Expression on Bcl-2 Protein Level and Taxane Sensitivity in Head and Neck Cancers–In Vitro Studies

“…This was confirmed by Puzzo et al in laryngeal cancers [24]. However, other studies found inverse association between Cx43 expression and overall survival suggesting, that Cx43 has different role in certain tumor types (esophageal, oropharyngeal) or localization (cytoplasm and nucleus vs. membrane) [25][26][27]. Dubina et al also found frame-shift mutations at the carboxyl-terminal region of Cx43 in human colon adenocarcinomas, which affects its phosphorylation, localization and function of the protein and also its staining with different antibodies [28].…”