Department of Gynecology and Obstetrics, The First Affiliated Hospital of Xi'an Jiaotong University, 277 West Yanta Road, Xi'an, Shaanxi, P.R. China.
Department of Pathology, School of Basic Medical Sciences, Health Science Center, Xi'an Jiaotong University, 76 West Yanta Road, Xi'an, Shaanxi, P.R. China.
BMC Cancer. 2024 Sep 30;24(1):1213. doi: 10.1186/s12885-024-12969-1.
The main challenge in treating ovarian cancer is chemotherapy resistance. Previous studies have shown that PAK2 is highly expressed in various cancers. This research investigates whether increased PAK2 expression contributes to chemo-resistance and poor prognosis in ovarian cancer.
Initially, bioinformatics analysis was used to assess the importance of PAK2 mRNA up-regulation in ovarian cancer. This was then validated using tissue microarray to confirm PAK2 protein expression and localization in clinical samples. Univariate and multivariate logistic regression analyses were carried out to identify potential risk factors for chemo-resistance in serous epithelial ovarian cancer (EOC), while multivariate Cox regression and Kaplan-Meier analysis were conducted to ascertain prognostic factors for overall survival (OS) and disease-free survival (DFS) in patients with serous EOC. In vitro experiments were conducted to verify if inhibiting PAK2 expression could increase A2780/Taxol cells' sensitivity to paclitaxel, as shown by evaluating cell proliferation, apoptosis, transwell, and clone formation. Additionally, the interaction between PAK2, lnc-SNHG1, and miR-216b-5p was verified using RIP and luciferase reporter assays. Rescue experiments were undertaken to examine the influence of the lnc-SNHG1/miR-216b-5p/PAK2 axis on the development of paclitaxel resistance in A2780/Taxol cells.
The bioinformatics analysis indicated a notable increase in PAK2 expression in ovarian malignant tumors compared to adjacent tissues, particularly in patients with stage III-IV disease compared to those with stage I-II disease (P = 0.0056). Elevated levels of PAK2 were linked to reduced OS in ovarian cancer patients, although no significant association was observed with DFS. Immunohistochemistry findings further supported these results, showing positive PAK2 protein expression in chemo-resistant serous EOC tissues, predominantly localized in the cytoplasm, which correlated with poorer OS and DFS outcomes. In vitro experiments demonstrated that the downregulation of PAK2 in A2780/Taxol cells led to a reduction in colony formation, an increase in apoptosis, and a diminished capacity for cell invasion. Subsequent analysis confirmed that lnc-SNHG1 functions as a competitive endogenous RNA (ceRNA) by interacting with miR-216b-5p and regulating PAK2 expression. Rescue experiments demonstrated that lnc-SNHG1 induces resistance to paclitaxel in A2780/Taxol cells by modulating the miR-216b-5p/PAK2 axis.
PAK2 shows promise as a predictor of chemotherapy resistance and poor outcomes in ovarian cancer, indicating its potential use as a treatment target to overcome this resistance.
治疗卵巢癌的主要挑战是化疗耐药性。先前的研究表明 PAK2 在各种癌症中高表达。本研究旨在探讨 PAK2 表达增加是否导致卵巢癌的化疗耐药性和不良预后。
最初，使用生物信息学分析评估 PAK2mRNA 上调在卵巢癌中的重要性。然后使用组织微阵列验证 PAK2 蛋白在临床样本中的表达和定位。使用单变量和多变量逻辑回归分析确定浆液性上皮性卵巢癌（EOC）中化疗耐药的潜在危险因素，同时使用多变量 Cox 回归和 Kaplan-Meier 分析确定浆液性 EOC 患者总生存期（OS）和无病生存期（DFS）的预后因素。体外实验验证抑制 PAK2 表达是否能增加 A2780/Taxol 细胞对紫杉醇的敏感性，通过评估细胞增殖、凋亡、Transwell 和克隆形成来证明。此外，使用 RIP 和荧光素酶报告基因测定验证 PAK2、lnc-SNHG1 和 miR-216b-5p 之间的相互作用。进行挽救实验以研究 lnc-SNHG1/miR-216b-5p/PAK2 轴对 A2780/Taxol 细胞紫杉醇耐药发展的影响。
生物信息学分析表明，与邻近组织相比，卵巢恶性肿瘤中 PAK2 的表达显著增加，尤其是在 III-IV 期疾病患者中比 I-II 期疾病患者（P=0.0056）。卵巢癌患者中 PAK2 水平升高与 OS 降低有关，但与 DFS 无关。免疫组化结果进一步支持了这些结果，显示化疗耐药性浆液性 EOC 组织中 PAK2 蛋白表达阳性，主要定位于细胞质，与较差的 OS 和 DFS 结果相关。体外实验表明，下调 A2780/Taxol 细胞中的 PAK2 导致集落形成减少、凋亡增加和细胞侵袭能力降低。后续分析证实 lnc-SNHG1 通过与 miR-216b-5p 相互作用并调节 PAK2 表达作为竞争性内源 RNA（ceRNA）发挥作用。挽救实验表明，lnc-SNHG1 通过调节 miR-216b-5p/PAK2 轴诱导 A2780/Taxol 细胞对紫杉醇的耐药性。
PAK2 有望成为卵巢癌化疗耐药性和不良预后的预测因子，表明其可能作为克服这种耐药性的治疗靶点。
