TY - JOUR
T1 - Downregulation of human endogenous retrovirus type K (HERV-K) viral env RNA in pancreatic cancer cells decreases cell proliferation and tumor growth
AU - Li, Ming
AU - Radvanyi, Laszlo
AU - Yin, Bingnan
AU - Li, Jia
AU - Chivukula, Raghavender
AU - Lin, Kevin
AU - Lu, Yue
AU - Shen, Jian Jun
AU - Chang, David Z.
AU - Li, Donghui
AU - Johanning, Gary L.
AU - Wang-Johanning, Feng
N1 - Publisher Copyright:
© 2017 American Association for Cancer Research.
PY - 2017/10/1
Y1 - 2017/10/1
N2 - 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.
AB - 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.
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U2 - 10.1158/1078-0432.CCR-17-0001
DO - 10.1158/1078-0432.CCR-17-0001
M3 - Article
C2 - 28679769
AN - SCOPUS:85032298287
SN - 1078-0432
VL - 23
SP - 5892
EP - 5911
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 19
ER -