Nguyen Que Thanh Thanh, Shin Soo-Gui, Nguyen Tra Tran Thu, Lee Kyoung Yul, McClelland Michael, Lee Eun-Ju
Department of Obstetrics and Gynecology, Chung-Ang University School of Medicine, Seoul, 06974, Republic of Korea.
Department of Pathology, Kangwon National University Hospital, Chuncheon, Republic of Korea.
J Ovarian Res. 2025 Jul 4;18(1):146. doi: 10.1186/s13048-025-01722-2.
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.
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.
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.
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.
约100,000个人类内源性逆转录病毒（HERV）整合到人类基因组中。大多数HERV不表达；然而，II类β逆转录病毒HERV-K家族内的转录在特定癌症中发生。在此，我们研究了HERV-K env蛋白表达及其在浆液性卵巢癌中的临床和分子意义。
通过免疫组织化学和QuPath数字分析评估24例正常、10例良性、13例交界性和72例癌性浆液性卵巢组织中的蛋白表达。临床病理参数从病历中获取。使用链特异性逆转录PCR和测序评估转录组。使用MTT和集落形成试验探索抗增殖活性。使用稳定转染表达系统和siRNA基因沉默。使用紫杉醇浓度梯度法建立耐药细胞系，并通过测量IC评估化学敏感性。
HERV-K env在正常卵巢上皮和良性肿瘤中不存在，但在37.5%（72例中的27例）浆液性癌和61.5%（13例中的8例）交界性肿瘤中检测到。出乎意料的是，仅在HERV-K env阳性肿瘤的一个子集中在淋巴细胞中观察到HERV-K env：27例浸润性肿瘤中的18例和8例交界性肿瘤中的1例。HERV-K env阳性与化学敏感性显著相关，尽管预后不受影响。HERV-K I型（K101、K102和K103）和II型（K108和K115）在培养的卵巢癌细胞和组织中转录，但在其紫杉醇耐药衍生物中不转录。在紫杉醇耐药细胞中强制表达HERV-K env可抑制细胞增殖，并通过抑制NF-κB/P-糖蛋白使细胞对紫杉醇重新敏感。siRNA介导的HERV-K env敲低通过恢复NF-κB/P-糖蛋白恢复紫杉醇耐药性。
HERV-K env在浆液性卵巢癌中表达，并与化学敏感性显著相关。HERV-K env减弱了NF-κB/P-糖蛋白，这是一种化学耐药机制。因此，它在化学耐药性卵巢癌中可能具有治疗潜力。
