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Downregulation of TUSC3 promotes EMT and hepatocellular carcinoma progression through LIPC/AKT axis
Ruxia Deng1,2,3, Xiansheng Lu1,2,3, Chang Hong1,2,3
1Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, Guangdong, People's Republic of China.
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.
Insights
Reduced Tumor Suppressor Candidate 3 (TUSC3) expression in hepatocellular carcinoma (HCC) promotes tumor growth and metastasis. TUSC3 inhibits epithelial-mesenchymal transition (EMT) via the lipase C hepatic type (LIPC)/AKT pathway, suggesting TUSC3 as a potential therapeutic target for HCC.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Hepatocellular carcinoma (HCC) is a highly malignant digestive tract tumor.
- Tumor Suppressor Candidate 3 (TUSC3), an N-glycosylation enzyme subunit, has an unestablished role in HCC.
- This study investigates TUSC3's function in HCC initiation and progression.
Purpose of the Study:
- To elucidate the role of TUSC3 in hepatocellular carcinoma (HCC) development.
- To determine the molecular mechanisms underlying TUSC3's function in HCC.
- To explore TUSC3 as a potential therapeutic target for HCC.
Main Methods:
- Detected TUSC3 and lipase C hepatic type (LIPC) expression using immunohistochemistry and qRT-PCR.
- Utilized loss-of-function and gain-of-function assays to assess TUSC3 and LIPC roles in vitro and in vivo.
- Investigated TUSC3-LIPC interaction via immunofluorescence and co-immunoprecipitation.
- Analyzed epithelial-mesenchymal transition (EMT) markers and the Akt signaling pathway using Western blot.
Main Results:
- TUSC3 expression was significantly decreased in HCC tissues, correlating with larger tumor size, poorer differentiation, and advanced BCLC stage.
- TUSC3 downregulation enhanced HCC cell proliferation and migration, while TUSC3 overexpression inhibited these processes.
- TUSC3 targets LIPC, a glycoprotein that negatively modulates HCC development.
- TUSC3 inhibited EMT progression through the LIPC/AKT signaling axis.
Conclusions:
- TUSC3 downregulation promotes HCC progression by activating AKT signaling via LIPC, driving malignant cell phenotype.
- TUSC3 plays a critical role in suppressing HCC initiation and progression.
- Targeting the TUSC3/LIPC/AKT pathway may offer a novel therapeutic strategy for HCC.
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