Xu Jiaojiao, Dong Keting, Bai Xue, Zhang Miao, Du Qian, Chen Lei, Yang Jianhong
Medical School, University of Chinese Academy of Sciences, Beijing, 101400, China.
Cancer Cell Int. 2024 Jul 25;24(1):263. doi: 10.1186/s12935-024-03445-8.
Triple negative breast cancer (TNBC) is a type of breast cancer that is negative for oestrogen receptor, progesterone receptor and human epidermal growth factor receptor 2, is highly malignant and aggressive, lacks of corresponding targeted therapy, and has a relatively poor prognosis. Therefore, understanding the mechanism of TNBC development and formulating effective treatment strategies for inducing cell death are still urgent tasks in the treatment of TNBC. Research has shown that uncarboxylated osteocalcin can promote the proliferation of prostate cancer, lung adenocarcinoma and TNBC cells, but the mechanism by which GluOC affects TNBC growth and metastasis needs further study.
MDA-MB-231 breast cancer cells were used for in vitro cell analysis. Key target molecules or pathways were identified by RNA sequencing, and migration ability was detected by scratch assays, Transwell assays, cell adhesion assays and western blot analysis. Fluorescence staining, colony detection, qRT‒PCR and flow cytometry were used to detect apoptosis, oxidative stress, the cell cycle and the stemness of cancer cells, and a xenotransplantation model in BALB/C nude mice was used for in vivo analysis.
This study demonstrated that GluOC facilitates the migration of MDA-MB-231 breast cancer cells through the ROCK1/MYPT1/MLC2 signalling pathway and promotes the proliferation of TNBC cells via the ROCK1/JAK2/PIK3CA/AKT signalling pathway. Experiments in nude mice demonstrated that GluOC promoted tumour cell proliferation and metastasis in tumour-bearing mice, which further clarified the molecular mechanism of TNBC growth and invasion.
Our findings highlight the importance of GluOC in driving TNBC progression and its association with poor patient outcomes. This study clarifies the functional effects of GluOC on TNBC growth, providing insight into the molecular basis of TNBC and potentially providing new ideas for developing targeted therapies to improve patient outcomes.
三阴性乳腺癌（TNBC）是一种雌激素受体、孕激素受体及人表皮生长因子受体2均为阴性的乳腺癌，具有高度恶性和侵袭性，缺乏相应的靶向治疗，预后相对较差。因此，了解TNBC的发生机制并制定有效的诱导细胞死亡的治疗策略仍是TNBC治疗中的紧迫任务。研究表明，未羧化骨钙素可促进前列腺癌、肺腺癌和TNBC细胞的增殖，但谷氨酸化骨钙素（GluOC）影响TNBC生长和转移的机制尚需进一步研究。
采用MDA-MB-231乳腺癌细胞进行体外细胞分析。通过RNA测序鉴定关键靶分子或信号通路，采用划痕试验、Transwell试验、细胞黏附试验及蛋白质免疫印迹分析检测迁移能力。利用荧光染色、集落检测、qRT-PCR及流式细胞术检测癌细胞的凋亡、氧化应激、细胞周期及干性，并采用BALB/C裸鼠异种移植模型进行体内分析。
本研究表明，GluOC通过ROCK1/MYPT1/MLC2信号通路促进MDA-MB-231乳腺癌细胞的迁移，并通过ROCK1/JAK2/PIK3CA/AKT信号通路促进TNBC细胞的增殖。裸鼠实验表明，GluOC促进荷瘤小鼠肿瘤细胞的增殖和转移，进一步阐明了TNBC生长和侵袭的分子机制。
我们的研究结果突出了GluOC在驱动TNBC进展中的重要性及其与患者不良预后的关联。本研究阐明了GluOC对TNBC生长的功能作用，为TNBC的分子基础提供了见解，并可能为开发改善患者预后的靶向治疗提供新思路。
