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    • In an immunohistochemical analysis of gastric cancer samples

    2021-10-15

    In an immunohistochemical analysis of 117 gastric cancer samples, reduced Cx43 and E-cadherin expression were shown to contribute to the development of primary gastric cancer; however, increased Cx43 and E-cadherin expression contributed to lymph node metastasis [13]. In primary urothelial guanabenz cancer, enhanced Cx43 expression was associated with poor patient prognosis [3]. The study examined tissue samples from 174 patients in tissue microarray format, and Cx43 expression was evaluated semi-quantitatively (0, 1+, and 2+) by immunohistochemical analysis. Of 174 patient samples, 31 samples (17.8%) showed high (2+) Cx43 expression, which was associated with higher tumor grade, increased proliferation, and shorter progression-free survival [3]. In an in silico analysis of the gene expression profiles of breast cancer tissues, increased Cx43 and Cx26 expression in primary breast cancers was associated with recurrence and poor patient survival. In contrast, in a tissue microarray study of 483 cases of invasive breast cancer, none of the connexin markers (Cx26, Cx32, and Cx43) correlated with patient survival or tumor grade [14]. In melanoma patients, increased Cx43 and Cx26 expression correlated with metastasis and poor patient survival. Furthermore, in brain metastases from primary breast cancers, Cx43 was only overexpressed in the metastases but not in healthy brain tissue [4]. These data strongly suggest that breast cancer and melanoma cells use Cx43 to initiate metastasis formation at distant sites. In support of this, Cx43 knockdown in 4T-1 cells decreased micro-tumor formation by approximately three-fold, and Cx43 was required to form functional gap junctions with endothelial cells necessary for microtumor formation [4]. Human breast cancer cells expressing Twist and with increased Cx43 expression rapidly extravasated and formed more microtumors compared with controls. Consistent with these findings, Tsai et al. over-expressed Cx43 in breast cancer cell lines and observed that transfected cells migrated at a significantly higher rate than their non-transfected counterparts [5], in keeping with Cx43 contributing to metastatic disease and cancer progression. In a study of oral squamous cell carcinoma tissue biopsies from 35 patients analyzed for Cx26, Cx43, and Cx45 expression, high tumor cell membrane Cx43 expression was prognostic for short overall survival. There was no association between overall survival and Cx26 and Cx45 expression [2]. Similar results were found when biopsies from 98 patients with esophageal squamous cell carcinoma were analyzed. Patients with a higher degree of Cx43 expression had a survival rate of 40% at 60 months. In contrast, patients with low Cx43 expression had an 80% survival rate at 60 months [8]. An immunohistochemical analysis of Cx43 expression in colorectal adenomas was performed using a two point scale. Samples were considered negative when less than 10% of cells were Cx43 positive and positive when more than 10% of cells were Cx43 positive. Cx43 expression was correlated with patient characteristics and histopathological features. Increased Cx43 expression was found in the mucosa surrounding adenomas with high-grade dysplasia [15]. In the case of thyroid cancer, metastasis seemed to be associated with low Cx43 expression [16] in a Cx43 mRNA study of 120 patients (60 with benign thyroid disease and 60 with malignant thyroid cancer). Cx43 and cadherin expression was decreased in 78.3% of primary gastric cancers [17] and was associated with advanced pathological stage and lymph node metastasis. Similarly, Cx43 was significantly downregulated in chronic B cell leukemia patients (n = 113) compared to cells from healthy donors [18]. In the case of astrocytic brain tumors, two independent studies reported that Cx43 protein expression decreased with increasing tumor grade. Pu et al. noted a decrease in Cx43 expression from 100% Cx43-positive samples in grade I glioma to 14.3% Cx43-positive samples in grade IV glioma, suggesting that loss of functional Cx43 results in more malignant phenotypes [19]. However, while Caltabiano at el. also reported that Cx43 protein expression decreased in grade III and IV tumors, Cx43 mRNA levels remain high [20].