Abstract
Recurrence and metastasis are major challenges in the management of hepatocellular carcinoma (HCC) patients after resection. To identify a metastasis-associated gene signature, we performed comparative gene expression analysis with recurrent HCC tissues from HCC patients who underwent partial or total hepatectomy and from non-metastatic primary HCC tissues. From this, we were able to identify genes associated with HCC recurrence. TCIRG1 (T-Cell Immune Regulator 1) was one of the aberrantly overexpressed genes in patients with recurrent HCC who had undergone total hepatectomy. The significant overexpression of TCIRG1 was confirmed using the Liver Hepatocellular Carcinoma dataset from The Cancer Genome Atlas. High expression of TCIRG1 was significantly associated with poor 5-year disease-free and recurrence-free survival of HCC patients. TCIRG1 knockdown suppressed tumor cell growth and proliferation in HCC cell lines; caused a significant increase in the proportion of cells in the G1/S phase of cell cycle; induced cell death; suppressed the metastatic potential of HCC cells by selectively regulating the epithelial–mesenchymal transition (EMT) regulatory proteins E-cadherin, N-cadherin, Fibronectin, Snail and Slug; and significantly attenuated the metastatic potential of ras-transformed NIH-3T3 cells in vitro and in vivo. These findings suggest that TCIRG1 functions as a metastatic enhancer by modulating growth, death and EMT in HCC cells. TCIRG1 could be a therapeutic target for the treatment of liver malignancy and metastasis.
Highlights
Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide and the second most common cause of cancer-related death.[1]
Effective palliative treatment is hindered in HCC, which is frequently resistant to conventional chemotherapy and radiotherapy, because of toxicity in the presence of underlying liver disease.[3]
Randomized trials conducted with sorafenib have shown survival benefits in advanced HCC, which suggests that molecular-targeted therapies could be effective, and investigations are actively being conducted on the molecular pathogenesis and treatment of HCC.[4]
Summary
Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide and the second most common cause of cancer-related death.[1] The primary curative treatment for HCC is surgical resection in a minority of patients diagnosed at early stages, when curative treatments are feasible. Resection and percutaneous ablation are hampered by a recurrence rate of up to 70% at 5 years, which is closely linked to survival.[2] Effective palliative treatment is hindered in HCC, which is frequently resistant to conventional chemotherapy and radiotherapy, because of toxicity in the presence of underlying liver disease.[3] Only a minority of patients are eligible for curative treatment. There is an urgent need for new medical treatments. Randomized trials conducted with sorafenib have shown survival benefits in advanced HCC, which suggests that molecular-targeted therapies could be effective, and investigations are actively being conducted on the molecular pathogenesis and treatment of HCC.[4]
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