Abstract
Calcium activated Chloride Channel A4 (CLCA4), as a tumor suppressor, was reported to contribute to the progression of several malignant tumors, yet little is known about the significance of CLCA4 in invasion and prognosis of hepatocellular carcinoma (HCC). CLCA4 expression was negatively correlated with tumor size, vascular invasion and TNM stage. Kaplan-Meier analysis showed that CLCA4 was an independent predictor for overall survival (OS) and time to recurrence (TTR). In addition, CLCA4 status could act as prognostic predictor in different risk of subgroups. Moreover, combination of CLCA4 and serum AFP could be a potential predictor for survival in HCC patients. Furthermore, CLCA4 may inhibit cell migration and invasion by suppressing epithelial-mesenchymal transition (EMT) via PI3K/ATK signaling. Knockdown of CLCA4 significantly increased the migration and invasion of HCC cells and changed the expression pattern of EMT markers and PI3K/AKT phosphorylation. An opposite expression pattern of EMT markers and PI3K/AKT phosphorylation was observed in CLCA4-transfected cells. Additionally, immunohistochemistry and RT-PCR results further confirmed this correlation. Taken together, CLCA4 contributes to migration and invasion by suppressing EMT via PI3K/ATK signaling and predicts favourable prognosis of HCC. CLCA4/AFP expression may help to distinguish different risks of HCC patients after hepatectomy.
Highlights
Hepatocellular carcinoma (HCC) is one of the commonest malignant tumors and a leading cause of cancer-related death [1, 2]
In order to explore the clinical significance of Chloride Channel A4 (CLCA4) in hepatocellular carcinoma (HCC) patients, we detected the expression of CLCA4 in 186 HCC tissues and their matched adjacent nontumorous liver samples by immunohistochemistry
CLCA4 expression had no significance with gender, age, AFP level, HBsAg, gammaglutamyltransferase (GGT), liver cirrhosis, tumor number, satellite nodule, tumor differentiation and Barcelona Clinic Liver Cancer (BCLC) stage
Summary
Hepatocellular carcinoma (HCC) is one of the commonest malignant tumors and a leading cause of cancer-related death [1, 2]. CLCA proteins play an important role in chloride conductance in epithelial cells [11]. More and more evidence found that the expression of CLCA proteins was abnormal in a variety of cancers, such as CLCA1, CLCA2 and CLCA4, which could be potential predictors for patients. CLCA1 could inhibit the proliferation of colorectal cancer cells, which is correlated with beneficial prognosis of colorectal cancer patients [13]. CLCA2 is a p53-inducible inhibitor of cell proliferation, and could be a marker of differentiated epithelium that is downregulated with tumor progresssion. Low CLCA2 expression promoted cell proliferation and metastasis which was caused by driving epithelial to mesenchymal transition (EMT) signaling pathway [14, 15]
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