Tan Shuran, Zhu Fang, Li Yi, Wen Xinxin, Yang Siyu, Liao Zexi, Duan Xuerui, Xiao Di, Zhang Yu
Department of Gynecology, Xiangya Hospital, Central South University, Changsha, Hunan, , 410008, PR China; Gynecological Oncology Research and Engineering Center of Hunan Province, XiangyaHospital, Changsha, Hunan, , 410008, PR China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Changsha, Hunan, 410008, PR China.
Department of Pharmacy, Xiangya Hospital, Central South University, Changsha, PR China; The Hunan Institute of Pharmacy Practice and Clinical Research, Changsha, PR China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Changsha, Hunan, 410008, PR China.
Transl Oncol. 2025 Jul;57:102416. doi: 10.1016/j.tranon.2025.102416. Epub 2025 May 17.
POLQ-like helicase (HELQ), an evolutionarily conserved 3'-5' DNA helicase, is markedly overexpressed in platinum-resistant ovarian cancer (OC), which is correlated with a poor prognosis. However, the mechanisms linking HELQ with resistance to platinum-based chemotherapy remain unkonwn. Our study presents both in vitro and in vivo evidence that elevated HELQ expression is linked to increased chemoresistance in OC models, with reduced HELQ levels enhancing their sensitivity to platinum agents. The expression of γH2AX, RPA1 and 53BP1 determined by immunofluorescence and western blot indicated that HELQ could promote platinum-induced DNA damage repair. HELQ was found to promote OC platinum resistance by regulating the expression of poly (ADP-ribose) polymerase 1(PARP1), which could be reversed by PARP1 downregulation. Furthermore, in vitro experiments showed that HELQ overexpression sensitizes OC cells to PARP inhibitors (PARPi). Immunohistochemical analysis indicates that diminished HELQ expression in tumor tissues correlates with disease progression in patients with first-line maintenance therapy with PARPi, whereby higher expression levels predict improved progression-free survival. Notably, we found a positive correlation between PARP1 and HELQ expression. In conclusion, HELQupregulats PARP1 to promote platinum resistance in OC and warrants consideration as an emerging biomarker for monitoring therapeutic responses to chemotherapy and PARPi treatment in ovarian cancer.
POLQ样解旋酶（HELQ）是一种进化上保守的3'-5' DNA解旋酶，在铂耐药卵巢癌（OC）中显著过表达，这与预后不良相关。然而，将HELQ与铂类化疗耐药联系起来的机制仍不清楚。我们的研究提供了体外和体内证据，表明HELQ表达升高与OC模型中化疗耐药性增加有关，降低HELQ水平可增强其对铂类药物的敏感性。通过免疫荧光和蛋白质印迹法测定的γH2AX、RPA1和53BP1的表达表明HELQ可促进铂诱导的DNA损伤修复。发现HELQ通过调节聚（ADP-核糖）聚合酶1（PARP1）的表达来促进OC铂耐药，PARP1下调可逆转这种情况。此外，体外实验表明HELQ过表达使OC细胞对PARP抑制剂（PARPi）敏感。免疫组织化学分析表明，在接受PARPi一线维持治疗的患者中，肿瘤组织中HELQ表达降低与疾病进展相关，即较高的表达水平预示着无进展生存期的改善。值得注意的是，我们发现PARP1与HELQ表达之间呈正相关。总之，HELQ上调PARP1以促进OC中的铂耐药，值得作为监测卵巢癌化疗和PARPi治疗反应性的新兴生物标志物加以考虑。
