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

Abstract

Purpose We investigated the role of the human endogenous retrovirus type K (HERV-K) envelope (env) gene in pancreatic cancer (PC). Experimental Design shRNA was employed to knockdown (KD) the expression of HERV-K in PC cells. Results HERV-K env expression was detected in seven PC cell lines and in 80% of PC patient biopsies, but not in two normal pancreatic cell lines or uninvolved normal tissues. A new HERV-K splice variant was discovered in several PC cell lines. RT 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 PC patient sera (N=106) than in normal donor sera (N=40). Importantly, the in vitro and in vivo growth rates of three PC 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 PC cells or tumors. Conclusion These results demonstrate that HERV-K influences signal transduction via the RAS-ERK-RSK pathway in PC. Our data highlight the potentially important role of HERV-K in tumorigenesis and progression of PC, 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 PC.

Disruption by SaCas9 Endonuclease of HERV-Kenv, a Retroviral Gene with Oncogenic and Neuropathogenic Potential, Inhibits Molecules Involved in Cancer and Amyotrophic Lateral Sclerosis

“…We focused on HERV-K because, of the dozens of HERV families, only HERV-W and HERV-K were repeatedly reported to have potentially pathogenic properties, both linked to the proteins coded by their env genes. The HERV-W is linked to multiple sclerosis [ 49 , 50 ], and the HERV-K to cancer [ 5 , 51 ] and amyotrophic lateral sclerosis [ 52 , 53 , 54 ].…”

“…Presently, increased HERV-K expression in tumors is associated with shorter relapse-free survival [ 58 ]. The HERV-K Env protein was shown to promote key signaling pathways, involved in cellular movements, cancer, cell death/survival, and cell proliferation, with a central role in regulating the RAS-ERK-RSK signaling pathway [ 39 , 52 ]. After HERV-K knockdown, breast cancer cells undergo a reversion to a non-tumorigenic phenotype, with a major downregulation of EGF-R and NF-κB [ 39 ].…”

Expressional activation and functional roles of human endogenous retroviruses in cancers

“…Elevated HERV‐K gag expression in PBMC was associated with prostate cancer diagnosis particularly in older men and smokers who tend to develop a more aggressive disease . Recently, HERV‐K env expression was detected in pancreatic cancer cell lines and in 80% of pancreatic cancer patient biopsies, but not in normal pancreatic cell lines or uninvolved normal tissues . The significantly elevated expression of numerous HERV elements in various cancers has accelerated their use as biomarkers for cancer aggressiveness and malignancy.…”

Elevated HERV-K Expression in Soft Tissue Sarcoma Is Associated with Worsened Relapse-Free Survival

“…Among the different families, retroviral sequences of the HERV-K family (HML-2) were the latest acquired, therefore they are the most complete and biologically active family ( Bannert and Kurth, 2004 ; Hughes and Coffin, 2004 , 2005 ). HERV-K expression was detected in several tumor entities, among them chronic myeloid leukemia ( Brodsky et al, 1993 ), renal cell carcinoma ( Florl et al, 1999 ; Kreimer et al, 2013 ), breast carcinoma ( Wang-Johanning et al, 2003 ), prostate carcinoma ( Wallace et al, 2014 ), pancreatic cancer ( Li et al, 2017 ), and melanoma ( Serafino et al, 2009 ). In melanoma, HERV-K expression is suggested to be an early event in tumorigenesis, seemingly enhancing the pathological process of tumor formation ( Serafino et al, 2009 ; Cegolon et al, 2013 ).…”

“…In melanoma, HERV-K expression is suggested to be an early event in tumorigenesis, seemingly enhancing the pathological process of tumor formation ( Serafino et al, 2009 ; Cegolon et al, 2013 ). Most recently, it was demonstrated that shRNA-mediated downregulation of HERV-K in pancreatic cancer cell lines suppressed growth rates and metastases as well as the expression of several proliferation-related genes ( Li et al, 2017 ). However, it is worth mentioning that the above described associations between HERV expression and tumor tissues are correlative.…”