Abstract
Downregulation of deleted in liver cancer 1 (DLC1) is associated with poor prognosis of various cancers, but its functional mechanisms in hepatocellular carcinoma (HCC) remains unclear. In the present study, we investigated the roles of DLC1 in tumor progression and autophagy of HCC. We found that DLC1 was frequently downregulated in HCC tissues. Underexpression of DLC1 correlated with AFP level, vascular invasion, poor differentiation, and poor prognosis. In vitro assays revealed that DLC1 not only suppressed the proliferation, migration, and invasion of HCC cells, but also inhibited autophagy of HCC cells. Mechanistic investigation revealed that DLC1 decreased TCF4 expression and the interaction between β-catenin and TCF4, then inactivated Wnt/β-catenin signaling. Additionally, DLC1 suppressed the ROCK1 activity and the dissociation of the Beclin1-Bcl2 complex, thereby inhibiting autophagy of HCC cells. In conclusion, our findings imply that loss of DLC1 contributes to the progression and oncogenic autophagy of HCC.Deleted in liver cancer 1 (DLC1) is frequently down-regulated in hepatocellular carcinoma tissue and correlates with α-fetoprotein levels, vascular invasion, poor differentiation and poor prognosis. The authors show that DLC1 suppresses the proliferation, migration, invasion and autophagy of hepatocellular carcinoma cells through inactivating Wnt/β-catenin signaling and inhibition of the serine/threonine kinase ROCK1.
Highlights
Hepatocellular carcinoma (HCC) is the fifth most common malignancies and the third leading cause of cancer-related deaths around the world [1]
We found that deleted in liver cancer 1 (DLC1) was significantly decreased in 64.9% (61/94) HCC tumor tissues compared to matched non-tumor tissues (Fig. 1a)
Downregulation of DLC1 was found in various human cancers due to gene deletion or epigenetic silence, such as lung cancer, breast cancer, and liver cancer [6, 26]
Summary
Hepatocellular carcinoma (HCC) is the fifth most common malignancies and the third leading cause of cancer-related deaths around the world [1]. Despite the significant improvement of surgical and adjuvant treatment approaches, the 5-year survival rate of HCC remains unsatisfactory due to the the high rate of intrahepatic and extrahepatic. DLC1 is a multidomain protein that contains sterile alpha motif (SAM), Rho GTPase-activating protein (RhoGAP), and steroidogenic acute regulatory protein-related lipid transfer (START) domains. Rho GTPases and DLC1 are dysregulated in several cancers and have been found to play opposite roles in tumorigenesis and tumor metastasis [10, 11]
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