Abstract
Norcantharidin (NCTD), a demethylated analog of cantharidin derived from Chinese traditional medicine blister beetle, has been currently used as an anticancer drug for various cancers including hepatocellular carcinoma (HCC). In this study, for a more comprehensive understanding of the targets of NCTD in HCC, next-generation RNA-Seq was utilized. We revealed that the expression of FAM46C, which has been reported as a tumor suppressor for multiple myeloma, was enhanced after NCTD treatment. Re-analysis of TCGA (The Cancer Genome Atlas) LIHC (liver hepatocellular carcinoma) dataset demonstrated that FAM46C expression was significantly lower in HCC tissues than in normal liver tissues. NCTD injection or FAM46C overexpression could mitigate diethylnitrosamine (DEN)-initiated HCC in mice. Ectopic expression of FAM46C in two HCC cell lines, SMCC-7721 and SK-Hep-1, significantly repressed cell proliferation, and increased cells population in G2/M phase and cell apoptotic rate. We also found that FAM46C overexpression caused a notable decrease in Ras expression, MEK1/2 phosphorylation and ERK1/2 phosphorylation. More importantly, FAM46C knockdown significantly weakened the biological effects of NCTD on HCC cells, which suggested NCTD exerted the anticancer functions partially through up-regulating FAM46C. In conclusion, FAM46C, a tumor suppressor for HCC, is important for the anti-proliferation and proapoptotic effects of NCTD.
Highlights
Hepatocellular carcinoma (HCC) is one of the most common cancers in the world and remains one of the leading causes of cancer mortality[1,2]
The results showed that NCTD treatment time dependently reduced the proliferation of both hepatocellular carcinoma (HCC) cell lines (Fig. 1B)
By re-analyzing expression data of TCGA (The Cancer Genome Atlas) LIHC cohort, we found that FAM46C expression was significantly lower in HCC tissues than in the normal liver tissues (P < 0.0001, Fig. 2C), suggesting that FAM46C was a potential target for NCTD in HCC
Summary
Hepatocellular carcinoma (HCC) is one of the most common cancers in the world and remains one of the leading causes of cancer mortality[1,2]. In China, NCTD has been used to treat patients with HCC, breast cancer, colon cancer, leukemia, etc. NCTD exerts pro-apoptosis effects in colorectal cancer cells via the activation of the CD95 receptor/ligand system[17]. The activities of mitogen-activated protein kinase (MAPK) family members, such as extracellular signal-regulated kinase (ERK), p38MAPK or c-Jun N-terminal kinase (JNK) have been found involved in NCTD-induced apoptogenesis in breast cancer cells[12], colon cancer[10] and glioma cells[14]. The current study confirmed the anti-proliferation effects of NCTD on HCC cells through inducing cell-cycle arrest and cell apoptosis. In vitro experiments indicated the critical role of FAM46C in the anti-proliferation effects of NCTD on HCC cells
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