Qi Jin, Liu Sihang, Wu Baomin, Xue Gang
Department of Orthopedics, The First Affiliated Hospital of Wannan Medical College (Yijishan Hospital of Wannan Medical College), Wuhu 241001, Anhui Province, China.
Key Laboratory of Non-coding RNA Transformation Research of Anhui Higher Education Institution (Wannan Medical College), No. 2, Zhe Shan Xi Road, Wuhu, China.
J Bone Oncol. 2025 Feb 10;51:100662. doi: 10.1016/j.jbo.2025.100662. eCollection 2025 Apr.
Osteosarcoma, a prevalent and aggressive skeletal malignancy, significantly impacts the prognosis of individuals, particularly young patients. Current treatments, including surgery and chemotherapy, often prove inadequate for advanced osteosarcoma with metastasis. This study investigates the role of the METTL3/TGF-β1 signaling axis in promoting osteosarcoma progression by inducing mesenchymal stem cells (MSCs) to differentiate into cancer-associated fibroblasts (CAFs). Utilizing co-culture technology, we demonstrated that osteosarcoma cells secrete TGF-β1, which is crucial for MSC differentiation into CAFs, as evidenced by the increased expression of CAF markers α-SMA, FSP-1, and FAP. Additionally, METTL3 was found to enhance the stability and expression of TGF-β1 mRNA through mA modification, thereby facilitating the differentiation process of MSCs. xenograft experiments further confirmed that the METTL3/TGF-β1 axis significantly promotes tumor growth in osteosarcoma by mediating the differentiation of MSCs into CAFs. These findings provide new insights into the molecular mechanisms underlying osteosarcoma progression and highlight potential therapeutic targets for treating advanced stages of this malignancy.
骨肉瘤是一种常见且侵袭性强的骨骼恶性肿瘤，对个体尤其是年轻患者的预后有重大影响。目前的治疗方法，包括手术和化疗，对于伴有转移的晚期骨肉瘤往往效果不佳。本研究调查了METTL3/TGF-β1信号轴通过诱导间充质干细胞（MSC）分化为癌相关成纤维细胞（CAF）在促进骨肉瘤进展中的作用。利用共培养技术，我们证明骨肉瘤细胞分泌TGF-β1，这对MSC分化为CAF至关重要，CAF标志物α-SMA、FSP-1和FAP的表达增加证明了这一点。此外，发现METTL3通过mA修饰增强TGF-β1 mRNA的稳定性和表达，从而促进MSC的分化过程。异种移植实验进一步证实，METTL3/TGF-β1轴通过介导MSC分化为CAF显著促进骨肉瘤的肿瘤生长。这些发现为骨肉瘤进展的分子机制提供了新的见解，并突出了治疗这种恶性肿瘤晚期的潜在治疗靶点。
