期刊
CANCER RESEARCH
卷 77, 期 12, 页码 3306-3316出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/0008-5472.CAN-17-0298
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资金
- NCI [R21 CA183954]
- National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) [1R01DK107451-01A1]
- National Institute of Diabetes and Digestive and Kidney Diseases [T32DK007150]
- VCU Massey Cancer Center Transgenic/Knock-out Mouse Facility
- VCU Massey Cancer Center flow cytometry core facility
- NIH-NCI Cancer Center Support grant [P30 CA016059]
SND1, a subunit of the miRNA regulatory complex RISC, has been implicated as an oncogene in hepatocellular carcinoma (HCC). In this study, we show that hepatocyte-specific SND1 transgenic mice (Alb/SND1 mice) develop spontaneous HCC with partial penetrance and exhibit more highly aggressive HCC induced by chemical carcinogenesis. Livers from Alb/SND1 mice exhibited a relative increase in inflammatory markers and spheroid-generating tumor-initiating cells (TIC). Mechanistic investigations defined roles for Akt and NF-kappa B signaling pathways in promoting TIC formation in Alb/SND1 mice. In human xenograft models of subcutaneous or orthotopic HCC, administration of the selective SND1 inhibitor 30, 50-deoxythymidine bisphosphate (pdTp), inhibited tumor formation without effects on body weight or liver function. Our work establishes an oncogenic role for SND1 in promoting TIC formation and highlights pdTp as a highly selective SND1 inhibitor as a candidate therapeutic lead to treat advanced HCC. (C)2017 AACR.
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