Downregulation of Human Endogenous Retrovirus Type K (HERV-K) Viral <i>env</i> RNA in Pancreatic Cancer Cells Decreases Cell Proliferation and Tumor Growth.

Abstract

<b>Purpose:</b> We investigated the role of the human endogenous retrovirus type K (HERV-K) envelope (<i>env</i>) gene in pancreatic cancer.<b>Experimental Design:</b> shRNA was employed to knockdown (KD) the expression of HERV-K in pancreatic cancer cells.<b>Results:</b> HERV-K <i>env</i> expression was detected in seven pancreatic cancer cell lines and in 80% of pancreatic cancer patient biopsies, but not in two normal pancreatic cell lines or uninvolved normal tissues. A new HERV-K splice variant was discovered in several pancreatic cancer cell lines. Reverse transcriptase activity and virus-like particles were observed in culture media supernatant obtained from Panc-1 and Panc-2 cells. HERV-K viral RNA levels and anti-HERV-K antibody titers were significantly higher in pancreatic cancer patient sera (<i>N</i> = 106) than in normal donor sera (<i>N</i> = 40). Importantly, the <i>in vitro</i> and <i>in vivo</i> growth rates of three pancreatic cancer cell lines were significantly reduced after HERV-K KD by shRNA targeting HERV-K <i>env</i>, and there was reduced metastasis to lung after treatment. RNA-Seq results revealed changes in gene expression after HERV-K <i>env</i> KD, including RAS and TP53. Furthermore, downregulation of HERV-K Env protein expression by shRNA also resulted in decreased expression of RAS, p-ERK, p-RSK, and p-AKT in several pancreatic cancer cells or tumors.<b>Conclusions:</b> These results demonstrate that HERV-K influences signal transduction via the RAS-ERK-RSK pathway in pancreatic cancer. Our data highlight the potentially important role of HERV-K in tumorigenesis and progression of pancreatic cancer, and indicate that HERV-K viral proteins may be attractive biomarkers and/or tumor-associated antigens, as well as potentially useful targets for detection, diagnosis, and immunotherapy of pancreatic cancer. <i>Clin Cancer Res; 23(19); 5892-911. ©2017 AACR</i>.