Oncogenic Role of SND1 in Development and Progression of Hepatocellular Carcinoma

  • Cancer Res. 2017 Jun 15;77(12):3306-3316. doi: 10.1158/0008-5472.CAN-17-0298.
Nidhi Jariwala  1 ,  Devaraja Rajasekaran  1 ,  Rachel G Mendoza  1 ,  Xue-Ning Shen  1 ,  Ayesha Siddiq  1 ,  Maaged A Akiel  1 ,  Chadia L Robertson  1 ,  Mark A Subler  1 ,  Jolene J Windle  1 ,  Paul B Fisher  1  2  3 ,  Arun J Sanyal  4 ,  Devanand Sarkar  5  2  3
Affiliations
  • 1. Department of Human and Molecular Genetics, Virginia Commonwealth University, Richmond, Virginia.
  • 2. VCU Massey Cancer Center, Virginia Commonwealth University, Richmond, Virginia.
  • 3. VCU Institute of Molecular Medicine (VIMM), Virginia Commonwealth University, Richmond, Virginia.
  • 4. Department of Internal Medicine, Virginia Commonwealth University, Richmond, Virginia.
  • 5. Department of Human and Molecular Genetics, Virginia Commonwealth University, Richmond, Virginia. [email protected].
PMID: 28428278 DOI: 10.1158/0008-5472.CAN-17-0298
Abstract

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.

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