Abstract
BackgroundHepatocellular carcinoma (HCC) is now the second leading cause of cancer death worldwide and lacks effectual therapy due to its high rate of tumor recurrence and metastasis. The aim of this study was to investigate the effects of L antigen family member 3 (LAGE3, a member of the LAGE gene family involved in positive transcription) on the progression of HCC.MethodsThe expression of LAGE3 was detected by quantitative real-time polymerase chain reaction. 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, colony formation assay, EdU, and cell cycle analysis assay were employed to evaluate the proliferation of HCC cells. Annexin V-FITC/PI and TUNEL assay were used to assess the apoptosis rate of HCC cells. Wound healing and transwell assay were used to investigate the migration and invasion of HCC cells. A xenograft model of HCC was established with 2 × 106 Hep3B or SK-HEP1 cells to investigate the in vivo effects of LAGE3. Then, the protein levels of LAGE3, p-p38, p-38, c-Jun N-terminal kinase (JNK),p-JNK, extracellular signal-regulated kinase (ERK), and p-ERK were detected by western blot.ResultsWe found that LAGE3 was upregulated in HCC tissues compared to adjacent tissues, and its high expression was correlated with poor overall survival by bioinformatics analysis. Next, we manually regulated the expression of LAGE3 in HCC cells. The knockdown of LAGE3 inhibited the proliferation of HCC cells by arresting the cell cycle in G1 phase. Also the downregulation of LAGE3 inhibited cell migration and invasion and induced apoptosis of HCC cells, while overexpression of LAGE3 promoted the malignant phenotypes of HCC. These results were further confirmed by the in vivo growth of HCC xenografts and the inhibition of apoptosis of HCC tumor cells. Furthermore, we found that LAGE3 exerted cancer-promoting effects by potentiating the JNK and ERK signaling pathway. An ERK inhibitor (10 μM SCH772984) or JNK inhibitor (25 μM SP600125) repressed the upregulated LAGE3-induced proliferation, migration, and invasion of HCC cells.ConclusionsLAGE3 enhanced the malignant phenotypes of HCC by promoting the JNK and ERK signaling pathway.
Highlights
Hepatocellular carcinoma (HCC) is the second leading cause of cancer death worldwide and lacks effectual therapy due to its high rate of tumor recurrence and metastasis
L antigen family member 3 (LAGE3) enhanced the malignant phenotypes of HCC by promoting the Jun N-terminal kinase (JNK) and extracellular signal-regulated kinase (ERK) signaling pathway
We found that LAGE3 was upregulated in HCC tissues compared to adjacent tissues
Summary
Hepatocellular carcinoma (HCC) is the second leading cause of cancer death worldwide and lacks effectual therapy due to its high rate of tumor recurrence and metastasis. HCC is common in patients with unhealthy alcohol intake, non-alcoholic fatty liver disease, infection with hepatitis B and C, as well as advanced hepatic fibrosis or cirrhosis [4] They promote hepatic inflammation and aberrant hepatocyte regeneration, leading to a series of genetic and epigenetic events. Surgical treatment is the most effective therapy of HCC only for patients in the early stage of the disease, but about 60–70% of patients are not diagnosed until late stages [7]. In this case, the efficacy of radiotherapy and chemotherapy is limited [7]. There is an urgent need to deeply investigate the mechanism of HCC and explore effectual molecules targeting the treatment of this fatal malignancy
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