Sung Hye Youn, Han Jihye, Ju Woong, Kang Jihee Lee, Park Ae Kyung, Ahn Jung-Hyuck
Department of Biochemistry, College of Medicine, Ewha Womans University, Seoul 07804, Korea.
Department of Obstetrics and Gynecology, College of Medicine, Ewha Womans University, Seoul 07804, Korea.
BMB Rep. 2025 May;58(5):224-231. doi: 10.5483/BMBRep.2024-0167.
Although cisplatin is an effective anticancer agent for treating ovarian cancer, it encounters significant resistance. A full understanding of the mechanisms behind cisplatin resistance has not been achieved. This study identifies MBNL2 as a crucial regulator of cellular responses to cisplatin, examining variations in gene expression and methylation profiles between cisplatinsensitive and -resistant ovarian cancer cells. Cells resistant to cisplatin exhibited increased MBNL2 mRNA expression and significant demethylation at promoter CpG sites. Treating ovarian cancer cell lines with a DNA demethylating agent significantly raised MBNL2 mRNA expression, indicating that epigenetic mechanisms involving DNA methylation control MBNL2 expression. Modulating MBNL2 levels altered the response to cisplatin through survival pathways that shield cells from cisplatin-induced apoptosis. Overexpressing MBNL2 enhanced resistance, while its depletion heightened cisplatin sensitivity. Furthermore, MBNL2 mRNA levels differed among patients based on their response to platinum-based chemotherapeutics. Patients resistant to these drugs had higher MBNL2 mRNA levels, effectively distinguishing them from those who were sensitive (AUC = 0.89, P = 0.0308). A meta-analysis of seventeen datasets confirmed that lower MBNL2 expression levels are associated with a better chemotherapy response and longer relapse-free survival. Conversely, higher MBNL2 expression levels correlated with increased recurrence rates and reduced survival. Thus, MBNL2 may serve as a promising prognostic and therapeutic target for overcoming cisplatin resistance. [BMB Reports 2025; 58(5): 224-231].
尽管顺铂是治疗卵巢癌的一种有效抗癌药物，但它会遇到显著的耐药性。目前尚未完全了解顺铂耐药背后的机制。本研究确定MBNL2是细胞对顺铂反应的关键调节因子，研究了顺铂敏感和耐药卵巢癌细胞之间基因表达和甲基化谱的差异。对顺铂耐药的细胞表现出MBNL2 mRNA表达增加以及启动子CpG位点显著去甲基化。用DNA去甲基化剂处理卵巢癌细胞系可显著提高MBNL2 mRNA表达，表明涉及DNA甲基化的表观遗传机制控制MBNL2表达。调节MBNL2水平通过保护细胞免受顺铂诱导的凋亡的生存途径改变对顺铂的反应。过表达MBNL2增强耐药性，而敲低MBNL2则提高顺铂敏感性。此外，根据患者对铂类化疗药物的反应，MBNL2 mRNA水平存在差异。对这些药物耐药的患者MBNL2 mRNA水平较高，可有效将他们与敏感患者区分开来（AUC = 0.89，P = 0.0308）。对17个数据集的荟萃分析证实，较低的MBNL2表达水平与更好的化疗反应和更长的无复发生存期相关。相反，较高的MBNL2表达水平与复发率增加和生存率降低相关。因此，MBNL2可能是克服顺铂耐药性的一个有前景的预后和治疗靶点。[《BMB报告》2025年；58(5): 224 - 231]
