Background: Hepatocellular carcinoma (HCC) is one of the most common and malignant tumors in the digestive tract. Tumor Suppressor Candidate 3 (TUSC3) is one subunit of the endoplasmic reticulum Oligosaccharyl transferase (OST) complex, which plays an important role in N-glycosylation during the protein folding process. However, the role of TUSC3 in the initiation and progression of HCC has not been mentioned yet. In the present study, we aim to investigate the effects of TUSC3 on the initiation and progression of HCC.
Methods: Immunohistochemical assay and qRT-PCR were used to detect the expression of TUSC3 and lipase C hepatic type (LIPC) in HCC tissue and cells. Loss-of-function and gain-of-function were applied to detect the function of TUSC3 and LIPC in vivo and in vitro. Immunofluorescence assay and co-immunoprecipitation were used to detect the relationship between TUSC3 and LPC. Western blot was applied to detect the expression of epithelial-mesenchymal transition (EMT) markers and the Akt signaling pathway.
Results: TUSC3 was aberrantly decreased in hepatocellular carcinoma tissues compared to the matched adjacent normal tissues, which resulted in bigger size of tumor (P = 0.001, Table 2), worse differentiation (P = 0.006, Table 2) and an advanced BCLC stage. Down-regulation of TUSC3 led to the enhanced proliferation and migration of hepatocellular carcinoma cells in vivo and vitro, whereas the opposite effect could be observed in the TUSC3-overexpression group. The analysis of TUSC3 microarray showed that LIPC, a glycoprotein primarily synthesized and secreted by hepatocytes, was a downstream target of TUSC3, and it negatively modulated the development of HCC. The morphological changes in HCC cells indicated that TUSC3 regulated the epithelial-mesenchymal transition (EMT). Mechanistically, TUSC3 inhibited EMT progression through the LIPC/AKT axis.
Conclusion: Down-regulation of TUSC3 promotes EMT progression by activating AKT signaling via targeting LIPC in HCC, which is probably the possible mechanism driving TUSC3-deficient hepatocellular carcinoma cells toward a malignant phenotype.
Keywords: Epithelial–mesenchymal transition; Hepatocellular carcinoma; LIPC; TUSC3.
© 2022. The Author(s).