Jin Jiahui, Zhao Peng, Dai Chengcheng, Li Jie, Huang Ziyi, Zhang Tongsong, Ma Xuezhen
College of Medicine, Qingdao University, Qingdao, 266071, China.
Department of Molecular Pathology, Qingdao Central Hospital，University of Health and Rehabilitation Sciences, Qingdao, 266042, China.
Mol Cell Biochem. 2025 Sep 3. doi: 10.1007/s11010-025-05369-x.
Keratin 15 (KRT15) promotes tumor progression in several cancers, but its engagement in breast cancer is seldom uncovered. This study aimed to explore the impact of KRT15 modification on breast cancer growth, mobility, radiosensitivity, ferroptosis, and Wnt/β-catenin signaling pathway. A lentiviral vector containing short hairpin RNA or complementary DNA targeting KRT15 was transfected into MDA-MB-231 and MCF-7 cells in vitro. The transfected MCF-7 cells were further proposed to irradiation treatment. In vivo, female BALB/c nude mice were used to establish xenograft model with KRT15-overexpressed MDA-MB-231 cells and treated by irradiation. KRT15 overexpression promoted cell proliferation, migration, invasion, colony number, epithelial-mesenchymal transition (EMT, reflected by E-Cadherin, N-Cadherin, and Vimentin expressions), and S-stage cell cycle arrest in MDA-MB-231 and MCF-7 cells, but repressed cell apoptosis and ferroptosis (reflected by DMT1, SLC7A11, FTH1, and GPX4 expressions); while KRT15 knockdown exhibited the opposite effects. Importantly, KRT15 overexpression enhanced irradiation resistance in MCF-7 cells reflected by cell proliferation, migration, invasion, colony number, cell cycle, and cell apoptosis detections. Besides, KRT15 overexpression increased EMT and activated Wnt/β-catenin signaling pathway (reflected by β-catenin, TCF-1, c-Myc, CCND1, MMP7 expressions) in MCF-7 cells with or without irradiation. In vivo experiments further validated that KRT15 overexpression promoted tumor growth, EMT, Wnt/β-catenin signaling pathway, and irradiation resistance, but repressed the ferroptosis. Collectively, KRT15 may facilitate tumor growth, invasion, EMT, and radioresistance but represses ferroptosis in a Wnt/β-catenin signaling-related way, suggesting its potency as a treatment target for breast cancer management.
角蛋白15（KRT15）在多种癌症中促进肿瘤进展，但其在乳腺癌中的作用鲜有报道。本研究旨在探讨KRT15修饰对乳腺癌生长、迁移、放射敏感性、铁死亡及Wnt/β-连环蛋白信号通路的影响。体外将携带靶向KRT15的短发夹RNA或互补DNA的慢病毒载体转染至MDA-MB-231和MCF-7细胞中。对转染后的MCF-7细胞进一步进行放射治疗。在体内，使用雌性BALB/c裸鼠建立过表达KRT15的MDA-MB-231细胞异种移植模型并进行放射治疗。KRT15过表达促进MDA-MB-231和MCF-7细胞的增殖、迁移、侵袭、集落形成、上皮-间质转化（EMT，通过E-钙黏蛋白、N-钙黏蛋白和波形蛋白表达反映）以及S期细胞周期阻滞，但抑制细胞凋亡和铁死亡（通过二价金属离子转运体1、溶质载体家族7成员11、铁蛋白1和谷胱甘肽过氧化物酶4表达反映）；而敲低KRT15则表现出相反的效果。重要的是，通过细胞增殖、迁移、侵袭、集落形成、细胞周期和细胞凋亡检测发现，KRT15过表达增强了MCF-7细胞的放射抗性。此外，无论有无放射处理，KRT15过表达均增加了MCF-7细胞的EMT并激活了Wnt/β-连环蛋白信号通路（通过β-连环蛋白、T细胞因子1、c-Myc、细胞周期蛋白D1、基质金属蛋白酶7表达反映）。体内实验进一步证实，KRT15过表达促进肿瘤生长、EMT、Wnt/β-连环蛋白信号通路及放射抗性，但抑制铁死亡。总体而言，KRT15可能通过与Wnt/β-连环蛋白信号相关的方式促进肿瘤生长、侵袭、EMT和放射抗性，但抑制铁死亡，提示其作为乳腺癌治疗靶点的潜力。
