Downregulation of Talin1 promotes hepatocellular carcinoma progression through activation of the ERK1/2 pathway

• Published in: Cancer science Vol. 108; no. 6; pp. 1157 - 1168
• Main Authors: Chen, Peijuan, Lei, Ling, Wang, Jian, Zou, Xuejing, Zhang, Dongyan, Deng, Ling, Wu, Dehua
• Format: Journal Article
• Language: English
• Published: England John Wiley & Sons, Inc 01.06.2017; John Wiley and Sons Inc
• Subjects: Breast cancer; Carcinoma, Hepatocellular - genetics; Carcinoma, Hepatocellular - pathology; Cell adhesion & migration; Cell Line; Cell Line, Tumor; Cell Movement - genetics; Cirrhosis; Cytoskeleton; Disease Progression; Down-Regulation - genetics; Epithelial-Mesenchymal Transition - genetics; Epithelial–mesenchymal transition; ERK1/2 pathway; Extracellular signal-regulated kinase; Female; Gene Expression Regulation, Neoplastic - genetics; Growth factors; Hep G2 Cells; Hepatocellular carcinoma; Humans; Hyperplasia; Integrins; Kinases; Liver cancer; Liver diseases; Liver Neoplasms - genetics; Liver Neoplasms - pathology; Lymphatic system; Male; MAP Kinase Signaling System - genetics; Medical prognosis; Mesenchyme; Metabolic pathways; Metastases; Metastasis; Middle Aged; Original; prognostic biomarker; Proteins; Signal Transduction - genetics; Studies; Talin - genetics; Talin1; Tumor suppressor genes; United States > US; China; Epithelial-mesenchymal transition; prognostic biomarker; ERK1/2 pathway; Talin1; hepatocellular carcinoma
• ISSN: 1347-9032; 1349-7006
• DOI: 10.1111/cas.13247

Talin1 is an adaptor protein that conjugates integrins to the cytoskeleton and regulates integrins and focal adhesion signaling. Several studies have found that Talin1 is overexpressed in several tumor types and promotes tumor progression. However, the explicit role of Talin1 in hepatocellular carcinoma (HCC) progression is still unclear and its functional mechanism remains largely unknown. In this study, we showed a trend of gradually decreasing expression of Talin1 from normal liver tissues to hepatocirrhosis, liver hyperplasia, the corresponding adjacent non‐tumor, primary HCC, and eventually metastatic foci, indicating that Talin1 may correlate with HCC initiation to progression. Talin1 was significantly downregulated in HCC tissues compared with adjacent non‐tumor tissues and low Talin1 expression was associated with HCC progression and poor prognosis. Furthermore, Talin1 knockdown induced epithelial–mesenchymal transition and promoted migration and invasion in SK‐Hep‐1 cells and HepG2 cells. Mechanistically, we found that the ERK pathway was responsible for these promoting effects of Talin1 knockdown in HCC cells. The promoting effects of Talin1 knockdown on epithelial–mesenchymal transition, migration, and invasion were reversed by U0126, a specific ERK1/2 inhibitor. Taken together, our results suggested that Talin1 might serve as a tumor suppressor in HCC and a potential prognostic biomarker for HCC patients. In this study, we showed a trend of gradually decreasing expression of Talin1 from normal liver tissues to hepatocirrhosis, liver hyperplasia, the corresponding adjacent non‐tumor, primary hepatocellular carcinoma (HCC) and eventually metastatic foci. Furthermore, low Talin1 expression is significantly associated with tumor recurrence and poor prognosis in HCC patients. More importantly, we provided novel data to show that Talin1 inhibition can act as a positive regulator of EMT, migration and invasion in HCC cells via activation of the ERK1/2 pathway.