Antimetastatic effects of norcantharidin on hepatocellular carcinoma cells by up-regulating FAM46C expression.

Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related mortality worldwide. Norcantharidin (NCTD), a demethylated analog of cantharidin, possesses antimetastatic effects on HCC cells. The aim of this study was to identify target proteins of NCTD. In this study, we confirmed the antimetastatic effects of NCTD on SMMC-7721 and MHCC-97H cells. Through RNA sequencing, we found a non-canonical poly (A) polymerase, Family-with-sequence-similarity-46C (FAM46C) was up-regulated in response to NCTD exposure. Gene set enrichment analysis on The Cancer Genome Atlas liver HCC (LIHC) dataset revealed that metastasis down pathway was strongly associated with FAM46C expression. Overexpression of FAM46C in HCC cells suppressed cell migration and invasion via suppressing transforming growth factor-beta (TGF-beta)/Smad signaling and epithelial-mesenchymal transition (EMT) process. Additionally, the antimetastatic effects of NCTD on HCC cells were partially rescued by FAM46C knockdown. Collectively, our results suggested that FAM46C, up-regulated by NCTD treatment, played a critical role in promoting the migration and invasion of HCC cells via TGF-beta/Smad signaling. We identified a new therapeutic target of NCTD.