Rivera-Serrano Mariela, Flores-Colón Marienid, Valiyeva Fatima, Meléndez Loyda M, Vivas-Mejía Pablo E
Department of Biology, University of Puerto Rico-Rio Piedras Campus, San Juan 00925, Puerto Rico.
Department of Biochemistry, University of Puerto Rico-Medical Sciences Campus, San Juan 00936, Puerto Rico.
Int J Mol Sci. 2025 Apr 24;26(9):4012. doi: 10.3390/ijms26094012.
Most women with ovarian cancer (OC) develop resistance to platinum chemotherapy, posing a significant challenge to treatment. Matrix metalloproteinase 3 (MMP3) is overexpressed in High-Grade Serous Ovarian Cancer (HGSOC) and is associated with poor survival outcomes; however, its role in platinum resistance remains underexplored. We evaluated the baseline and cisplatin-induced MMP3 transcript and protein levels in cisplatin-resistant OC cells, revealing significantly higher MMP3 levels in cisplatin-resistant cells than in cisplatin-sensitive cells. siRNA-mediated MMP3 knockdown in cisplatin-resistant OC cells significantly reduced viability, proliferation, and invasion, and these effects were further enhanced when combined with cisplatin treatment, indicating a possible synergistic impact on reducing cancer cell aggressiveness; however, chemical MMP3 inhibition did not replicate these effects. RNA sequencing of MMP3-siRNA-treated cisplatin-resistant HGSOC cells revealed 415 differentially expressed genes (DEGs) compared to the negative control, with an additional 440 DEGs identified in MMP3-siRNA HGSOC cells treated in combination with cisplatin. These DEGs were enriched in pathways related to cell cycle regulation, apoptosis, metabolism, stress response, and extracellular matrix organization. Co-immunoprecipitation-coupled mass spectroscopy (IP-MS) identified MMP3-interacting proteins that may contribute to cell survival and chemoresistance in cisplatin-resistant OC. While MMP3-siRNA monotherapy did not reduce tumor growth in vivo, its combination with cisplatin significantly inhibited tumor growth in a cisplatin-resistant HGSOC xenograft model. These findings underscore the multifaceted role of MMP3 in cisplatin resistance, suggesting its involvement in critical cellular processes driving chemoresistance and highlighting the challenges associated with direct MMP3 targeting in therapeutic strategies.
大多数卵巢癌（OC）患者会对铂类化疗产生耐药性，这给治疗带来了重大挑战。基质金属蛋白酶3（MMP3）在高级别浆液性卵巢癌（HGSOC）中过度表达，且与不良生存结果相关；然而，其在铂类耐药中的作用仍未得到充分研究。我们评估了顺铂耐药OC细胞中MMP3转录本和蛋白质的基线水平以及顺铂诱导后的水平，发现顺铂耐药细胞中的MMP3水平显著高于顺铂敏感细胞。在顺铂耐药OC细胞中，通过小干扰RNA（siRNA）介导的MMP3敲低显著降低了细胞活力、增殖和侵袭能力，并且当与顺铂治疗联合使用时，这些作用进一步增强，表明对降低癌细胞侵袭性可能具有协同作用；然而，化学抑制MMP3并未重现这些效果。对MMP3-siRNA处理的顺铂耐药HGSOC细胞进行RNA测序发现，与阴性对照相比，有415个差异表达基因（DEG），在联合顺铂处理的MMP3-siRNA HGSOC细胞中又鉴定出另外440个DEG。这些DEG富集于与细胞周期调控、凋亡、代谢、应激反应和细胞外基质组织相关的通路。免疫共沉淀耦合质谱（IP-MS）鉴定出了与MMP3相互作用的蛋白质，这些蛋白质可能在顺铂耐药OC中促进细胞存活和化疗耐药。虽然MMP3-siRNA单药治疗在体内并未减少肿瘤生长，但在顺铂耐药HGSOC异种移植模型中，其与顺铂联合使用显著抑制了肿瘤生长。这些发现强调了MMP3在顺铂耐药中的多方面作用，表明其参与了驱动化疗耐药的关键细胞过程，并突出了在治疗策略中直接靶向MMP3所面临的挑战。
