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. 2014 Sep;35(9):2074-83.
doi: 10.1093/carcin/bgu114. Epub 2014 May 23.

Elevated HERV-K mRNA Expression in PBMC Is Associated With a Prostate Cancer Diagnosis Particularly in Older Men and Smokers

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Free PMC article

Elevated HERV-K mRNA Expression in PBMC Is Associated With a Prostate Cancer Diagnosis Particularly in Older Men and Smokers

Tiffany A Wallace et al. Carcinogenesis. .
Free PMC article

Abstract

Aberrant expression of subgroup k human endogenous retroviruses (HERV-K) has been observed in prostate cancer. This subgroup is unique because it encodes sequences in the human genome containing open reading frames for near intact retroviruses. We hypothesized that HERV-K reactivation could serve as a non-invasive early disease detection marker for prostate cancer. We evaluated HERV-K gag messenger RNA (mRNA) expression in blood samples of African-American and European-American men using a case-control design via quantitative real-time PCR. Additionally, we examined HERV-K envelope protein expression in prostate tumors by immunohistochemistry. HERV-K envelope protein was commonly upregulated in prostate tumors, but more so in tumors of African-American than European-American patients (61% versus 40%, P < 0.01). Examining HERV-K gag expression in peripheral blood mononuclear cells (PBMC) from 294 cases and 135 healthy men, we found that the abundance of HERV-K gag message was significantly higher in cases than controls and was associated with increased plasma interferon-γ. Men with gag expression in the highest quartile had >12-fold increased odds {odds ratio = 12.87 [95% confidence interval 6.3-26.25]} of being diagnosed with prostate cancer than those in the lowest quartile. Moreover, our results showed that HERV-K expression may perform better as a disease biomarker in older than younger men (whereas the sensitivity of prostate-specific antigen (PSA) testing decreases with age) and in men with a smoking history compared with never smokers. Combining non-invasive HERV-K testing with PSA testing may improve the efficacy of prostate cancer detection specifically among older men and smokers who tend to develop a more aggressive disease.

Figures

Fig. 1.
Fig. 1.
Comparison of HERV-K gag mRNA expression in PBMC isolated from the blood of healthy controls (n = 135) and prostate cancer patients (n = 294) using previously published gag mRNA primer set. (a) HERV-K gag mRNA was significantly elevated in PBMC isolated from prostate cancer patients compared with the control population (Mann–Whitney test, P < 0.001). (b) HERV-K gag mRNA is significantly elevated in PBMC from African-American (AA) controls compared with European-American (EA) controls (Mann–Whitney test, P < 0.001), whereas there was no significant difference in the levels of HERV-K gag between African-American and European-American patients (Mann–Whitney test, P = 0.44). HERV-K gag was significantly elevated in patients compared with population controls in both African-Americans (Mann–Whitney test, P < 0.001) and European-Americans (Mann–Whitney test, P < 0.001).
Fig. 2.
Fig. 2.
Association between high HERV-K gag mRNA expression and elevated plasma IFNγ and IP10 levels. Plasma IFNγ (a) and its downstream mediator IP10 (b) were significantly increased in patients with high gag expression compared with controls with high gag expression (Mann–Whitney test IFNγ, P < 0.001; Mann–Whitney test IP10, P = 0.02). Additionally, cases with high gag expression had significantly higher levels of plasma IFNγ compared with cases with low gag expression. No significant association of gag expression with tumor necrosis factor-α (c) or IL-1β (d) was observed.
Fig. 3.
Fig. 3.
HERV-K expression in human prostate adenocarcinomas. Shown is IHC analysis of four invasive adenocarcinomas for expression of HERV-K envelope (env) protein using the monoclonal anti-envelope antibody, 6H5. (a) Scattered positivity for HERV-K env expression in the tumor epithelium, showing a low to moderate antigen expression as indicated by the brown chromogen deposits. (bd) Locally intensive staining for env expression in the tumor epithelium. Staining shows a cytosolic to membrane distribution with a more intensive staining of cancer cells toward the luminal side of the cancerous gland (c and d). a and b: Magnification: ×100. c and d: Magnification: ×400. Inset: higher resolution image for the env protein-positive tumor epithelium. Counterstain: Hematoxylin. (e) Immunostaining for env protein in human prostate tumors using a tissue microarray that included tumors from both African-American (n = 105) and European-American patients (n = 272). On average, tumors from African-American patients showed a higher expression of the HERV-K env protein than tumors from European-Americans (Student’s t-test, P < 0.001). (f) HERV-K gag and env protein expression were detected in human prostate cancer cell lines (CWR22, 22Rv1, PC-3 and DU145) but were not detected in the non-tumorigenic human prostate cell line, RWPE1. An extract from the HERV-K-positive T47D human breast cancer cell line were included as a positive control.

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