Department of Pathophysiology, College of Basic Medical Science, China Medical University, Shenyang, Liaoning Province, 110122, P.R. China.
Department of Biomedical Engineer, School of Intelligent Medicine, China Medical University, Shenyang, Liaoning Province, 110122, P.R. China.
Cell Commun Signal. 2024 Mar 27;22(1):194. doi: 10.1186/s12964-024-01585-y.
Chemoresistance is associated with tumor relapse and unfavorable prognosis. Multiple mechanisms underlying chemoresistance have been elucidated, including stemness and DNA damage repair. Here, the involvement of the WNT receptor, FZD5, in ovarian cancer (OC) chemoresistance was investigated.
OC cells were analyzed using in vitro techniques including cell transfection, western blot, immunofluorescence and phalloidin staining, CCK8 assay, colony formation, flowcytometry, real-time PCR, and tumorisphere formation. Pearson correlation analysis of the expression levels of relevant genes was conducted using data from the CCLE database. Further, the behavior of OC cells in vivo was assessed by generation of a mouse xenograft model.
Functional studies in OC cells showed that FZD5 contributes to epithelial phenotype maintenance, growth, stemness, HR repair, and chemoresistance. Mechanistically, FZD5 modulates the expression of ALDH1A1, a functional marker for cancer stem-like cells, in a β-catenin-dependent manner. ALDH1A1 activates Akt signaling, further upregulating RAD51 and BRCA1, to promote HR repair.
Taken together, these findings demonstrate that the FZD5-ALDH1A1-Akt pathway is responsible for OC cell survival, and targeting this pathway can sensitize OC cells to DNA damage-based therapy.
化疗耐药与肿瘤复发和预后不良有关。已经阐明了化疗耐药的多种机制，包括干性和 DNA 损伤修复。在这里，研究了 WNT 受体 FZD5 在卵巢癌 (OC) 化疗耐药中的作用。
使用体外技术分析 OC 细胞，包括细胞转染、western blot、免疫荧光和鬼笔环肽染色、CCK8 测定、集落形成、流式细胞术、实时 PCR 和肿瘤球体形成。使用 CCLE 数据库中的数据对相关基因的表达水平进行 Pearson 相关性分析。此外，通过生成小鼠异种移植模型来评估 OC 细胞在体内的行为。
在 OC 细胞中的功能研究表明，FZD5 有助于上皮表型维持、生长、干性、HR 修复和化疗耐药。在机制上，FZD5 通过 β-catenin 依赖性方式调节癌症干细胞样细胞的功能性标志物 ALDH1A1 的表达。ALDH1A1 激活 Akt 信号通路，进一步上调 RAD51 和 BRCA1，促进 HR 修复。
综上所述，这些发现表明 FZD5-ALDH1A1-Akt 通路负责 OC 细胞的存活，靶向该通路可以使 OC 细胞对基于 DNA 损伤的治疗敏感。
