2706

GJB2

gap junction protein, beta 2, 26kDa;GJB2;gap junction protein, beta 2, 26kDa

connexin 26|gap junction beta-2 protein|gap junction protein beta 2

13q11-q12

protein-coding

PURPOSE: Connexin 26 (Cx26) is one of the gap junction-forming family members classically considered to be tumor suppressors. However, recent studies show association of elevated expression of Cx26 with poor prognosis in several human malignancies. Furthermore, Cx26 has been observed to be indispensable to spontaneous metastasis of melanoma cells. Here, we assessed Cx26 expression in primary colorectal cancer (CRC) and the metastatic lesions to elucidate its role in metastasis. EXPERIMENTAL DESIGN: Cx26 expression was assessed in 25 adenomas, 167 CRCs, and normal mucosa, together with the metastatic lesions. RESULTS: Normal mucosa and adenomatous tissue expressed Cx26 mainly in the plasma membrane, whereas cancer cells mostly contained Cx26 in the cytoplasm. The incidence of aberrant Cx26 expression varied widely in CRC (mean, 49.5 +/- 35.5%), and the expression levels were confirmed by Western blot and quantitative reverse transcription-PCR. Clinicopathologic survey revealed association of high expression with less differentiated histology and venous invasion (P = 0.0053 and P = 0.0084, respectively). Notably, high Cx26 expression was associated with shorter disease-free survival and shorter lung metastasis-free survival in 154 curatively resected CRC sets (P = 0.041 and P = 0.028, respectively). Survey of metastatic lesions revealed that lung metastasis, but not liver and lymph nodes metastases, expressed higher Cx26 than the CRC series or corresponding primary CRCs (P < 0.0001 and P = 0.0001, respectively). CONCLUSIONS: These findings suggest that aberrant expression of Cx26 plays an essential role in lung metastasis. Thus, Cx26 is a promising therapeutic target, particularly for CRC patients who develop lung metastasis.

BACKGROUND: Failure of gap junction formation affects the development of various types of cancer. We aimed to clarify the clinicopathologic outcome and prognostic significance of connexin (Cx) 26 in human esophageal squamous cell carcinoma (ESCC). METHODS: Immunohistochemical staining for Cx26 was performed on surgical specimens obtained from 123 patients with ESCC. RESULTS: There was no positive staining for Cx26-specific expression in normal esophageal squamous cells. Primary ESCC with Cx26-positive expression was detected in the cytoplasm of cancer cell nests in 60 cases. Cx26 expression was correlated with N (lymph node metastasis, P = 0.014) and the number of metastatic lymph nodes (P = 0.047). The 5-year survival rates of ESCC patients with Cx26-positive expression were significantly lower than those with Cx26-negative expression (positive, 39.7%; negative, 65.7%; P = 0.007). By multivariate analysis, tumor-node-metastasis (TNM) clinical classification (T, P < 0.001; N, P = 0.002; M, P = 0.046) and Cx26 (P = 0.024) were independent prognosis predictors of ESCC. CONCLUSIONS: These results suggest that abnormal expression of Cx26 participates in the progress of ESCC.

BACKGROUND: Connexins form the intercellular channels of the gap junction and play an integral part in a variety of biological functions, such as maintaining tissue homeostasis, cell growth control, and development. Previously it was demonstrated that the expression of connexin 26 (Cx26) can increase the metastatic potential of mouse melanoma cells. The objective of the study was to investigate the role Cx26 plays in the metastasis of human melanoma cells, focusing on the communication between melanoma cells and endothelial cells. METHODS: Immunostaining was used to examine Cx26 expression in the melanoma lesions and in the endothelial cells around the melanoma cell nests. In all, 33 melanomatous tissue samples from 16 patients were studied, as well as nevocellular nevus (NCN) and normal skin samples. Cx26 mRNA and protein expression was also examined in the cultured endothelial cells. A dye-transfer assay was performed to examine gap junction formation between melanoma cells and endothelial cells. RESULTS: Immunohistochemistry demonstrated that Cx26 was clearly expressed by the endothelial cells of the small vessels surrounding the melanoma cell nests as well as the melanoma cells. Cx26 mRNA and protein expression was detected in cultured endothelial cells. In a coculture system with human malignant melanoma cell line (HMY-1) and endothelial cells (HMVEC), immunohistochemistry indicated Cx26 expression in both types of cells and dye-transfer assay demonstrated dye-coupling from HMY-1 into HMVEC. CONCLUSIONS: Cx26 may contribute to the metastasis of melanoma by facilitating communication between melanoma cells and their surrounding endothelial cells.