Human endogenous retrovirus-K envelope protein is aberrantly expressed in serous ovarian cancer and promotes chemosensitivity via NF-κB/P-glycoprotein pathway inhibition.

BACKGROUND: Approximately 100,000 human endogenous retroviruses (HERV) are integrated into the human genome. Most HERVs are not expressed; however, transcription within the family HERV-K, a class II beta-retrovirus, occurs in specific cancers. Herein, we investigated HERV-K env protein expression and its clinical and molecular significance in serous ovarian cancer. METHODS: Protein expression was assessed via immunohistochemistry and QuPath digital analysis in 24 normal, 10 benign, 13 borderline and 72 cancerous serous ovarian tissues. Clinicopathological parameters were obtained from medical records. Transcriptomes were evaluated using strand-specific reverse transcription-PCR and sequencing. Antiproliferative activities were explored using MTT and colony formation assays. A stable transfection expression system and siRNA gene silencing were used. Resistant cell lines were established using the paclitaxel concentration gradient method and chemoresponsiveness was evaluated by measuring the IC(50). RESULTS: HERV-K env was absent in normal ovarian epithelia and benign tumors but was detected in 37.5% (27 of 72) of serous carcinomas and 61.5% (8 of 13) of borderline tumors. Unexpectedly, HERV-K env was observed in lymphocytes only in a subset of HERV-K env-positive tumors: 18 of 27 invasive and 1 of 8 borderline tumors. HERV-K env-positivity was significantly associated with chemosensitivity, although the prognosis was unaffected. HERV-K type I (K101, K102, and K103) and II (K108 and K115) were transcribed in cultured ovarian cancer cells and tissues but not in their paclitaxel-resistant derivatives. Forced expression of HERV-K env in paclitaxel-resistant cells suppressed cellular proliferation and resensitized cells to paclitaxel by inhibiting NF-κB/P-glycoprotein. siRNA-mediated HERV-K env knockdown restored paclitaxel-resistance by recovering NF-κB/P-glycoprotein. CONCLUSION: HERV-K env was expressed in serous ovarian carcinoma and significantly associated with chemosensitivity. HERV-K env attenuated NF-κB/P-glycoprotein, a mechanism of chemoresistance. Hence, it could have therapeutic potential in chemoresistant ovarian cancers.