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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-κB 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 3', 5'-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. Cancer Res; 77(12); 3306-16. ©2017 AACR. ©2017 American Association for Cancer Research.

Citation

Nidhi Jariwala, Devaraja Rajasekaran, Rachel G Mendoza, Xue-Ning Shen, Ayesha Siddiq, Maaged A Akiel, Chadia L Robertson, Mark A Subler, Jolene J Windle, Paul B Fisher, Arun J Sanyal, Devanand Sarkar. Oncogenic Role of SND1 in Development and Progression of Hepatocellular Carcinoma. Cancer research. 2017 Jun 15;77(12):3306-3316

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PMID: 28428278

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