Journal
CLINICAL CANCER RESEARCH
Volume 23, Issue 19, Pages 5892-5911Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1078-0432.CCR-17-0001
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Funding
- United States Department of Defense [W81XWH-15-1-0530, W81XWH-12-1-0223]
- Susan G. Komen for the Cure [BCTR0402892]
- Avon Foundation for Women [07-2007-070 01, 02-2011-104]
- NIH [CA16672]
- CPRIT [RP120348]
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Purpose: We investigated the role of the human endogenous retrovirus type K (HERV-K) envelope (env) gene in pancreatic cancer. Experimental Design: shRNA was employed to knockdown (KD) the expression of HERV-K in pancreatic cancer cells. Results: HERV-K env 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 (N = 106) than in normal donor sera (N = 40). Importantly, the in vitro and in vivo growth rates of three pancreatic cancer cell lines were significantly reduced after HERV-K KD by shRNA targeting HERV-K env, and there was reduced metastasis to lung after treatment. RNA-Seq results revealed changes in gene expression after HERV-K env 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. Conclusions: 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. (C) 2017 AACR.
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