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

• Published in: Clinical cancer research 2017-10, Vol.23 (19), p.5892-5911
• Main Authors: Li, Ming, Radvanyi, Laszlo, Yin, Bingnan, Rycaj, Kiera, Li, Jia, Chivukula, Raghavender, Lin, Kevin, Lu, Yue, Shen, JianJun, Chang, David Z, Li, Donghui, Johanning, Gary L, Wang-Johanning, Feng
• Format: Article
• Language: English
• Subjects: AKT protein; Alternative splicing; Antigen (tumor-associated); Antigens; Biomarkers; Biotechnology; Cancer; Carcinogenesis - genetics; Cell culture; Cell Line, Tumor; Cell proliferation; Cell Proliferation - genetics; Culture media; Endogenous Retroviruses - genetics; Endogenous Retroviruses - pathogenicity; Env gene; Experimental design; Gene expression; Gene Expression Regulation, Neoplastic; Gene Expression Regulation, Viral; Gene Knockdown Techniques; Growth rate; Host-Pathogen Interactions - genetics; Humans; Immunotherapy; Lungs; Metastases; p53 Protein; Pancreatic cancer; Pancreatic Neoplasms - genetics; Pancreatic Neoplasms - pathology; Pancreatic Neoplasms - virology; Proteins; Recombinant Fusion Proteins - genetics; Ribonucleic acid; RNA; RNA, Small Interfering - genetics; RNA-directed DNA polymerase; Signal transduction; Signal Transduction - genetics; Target detection; Tissues; Transduction; Tumor cell lines; Tumorigenesis; Tumors; Viral envelope proteins; Viral Envelope Proteins - genetics; Virus-like particles; Viruses
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-17-0001

We investigated the role of the human endogenous retrovirus type K (HERV-K) envelope ( ) gene in pancreatic cancer. shRNA was employed to knockdown (KD) the expression of HERV-K in pancreatic cancer cells. HERV-K 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 ( = 106) than in normal donor sera ( = 40). Importantly, the and growth rates of three pancreatic cancer cell lines were significantly reduced after HERV-K KD by shRNA targeting HERV-K , and there was reduced metastasis to lung after treatment. RNA-Seq results revealed changes in gene expression after HERV-K 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. 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. .