8: Investigating the role of Human endogenous retrovirus group E (HERV-E) in clear cell Renal Cell Carcinoma (ccRCC) through hypoxia and interferon signaling pathway

Background: HERVs are a family of viruses that represent remainders of ancestral exogenous retroviral infection into germ cell lines. Through negative selection, the majority of HERVs do not code functional proteins. However, HERV-E is a classified subtype that has been shown to produce transcripts selectively in ccRCC. Loss of von Hippel-Lindau (VHL) tumor suppressor gene, the most common causal event for ccRCC, has been related to increased expression of HERV-E. Here we aim to further investigate the pathophysiology for HERV-E in ccRCC.

Methods: ccRCC cancer cells were manipulated to re-express VHL to examine their impact on HERV-E expression. Multiple ccRCC cell lines and other organ cancer cell lines were treated with hypoxia-mimetic agents CoCl2 and DFO to study the role of hypoxia induction on HERV-E. HERV-E was suppressed through shRNA in ccRCC cell lines to examine their impact on interferon-stimulated gene factor 3 (ISGF3) pathway. Xenograft studies were performed to assess HERV-E’s effect on tumor growth.

Results: 1. ccRCC HERV-E is significantly suppressed by VHL in multiple ccRCC cell lines; 2. HERV-E is induced by hypoxia mimetic agents in ccRCC cell lines whereas no induction is seen in other organ cancer cell lines treated with equivalent hypoxia-mimetic agents; 3. HERV-E expression activates the ISGF3 pathway; 4. HERV-E +/+ RCC cell line results in significantly larger tumor growth in xenograft mouse model compared to HERV-E deficient ccRCC cell tumor.

Conclusions: Loss of VHL and hypoxia induction up-regulates the expression of HERV-E exclusively in ccRCC cancer cells. Despite the finding of HERV-E inducing ISGF3, a known tumor suppressor in ccRCC, larger tumors developed with HERV-E +/+ cancer cells compared to the HERV-E deficient Ren-02 cancer cells in xenograft mice models. This finding suggests that HERV-E suppression has context-dependent impact on tumor growth. Further investigation is required to examine a specific targeted pathway of HERV-E in ccRCC.