Department of Oral and Maxillofacial Surgical Oncology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8549, Japan; Department of Biochemistry, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8549, Japan.
Department of Biochemistry, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8549, Japan; Institute of Industrial Science, The University of Tokyo, Fw704, 4-6-1 Komaba, Meguro-ku, Tokyo, 153-8505, Japan.
Biochem Biophys Res Commun. 2024 Jun 25;714:149965. doi: 10.1016/j.bbrc.2024.149965. Epub 2024 Apr 17.
At present, the molecular mechanisms driving the progression and metastasis of oral squamous cell carcinoma (OSCC) remain largely uncharacterized. The activation of transforming growth factor-β (TGF-β) signaling in the tumor microenvironment has been observed in various types of cancer and has been implicated their progression by enhancing the migration and invasion of epithelial cancer cells. However, its specific roles in the oral cancer progression remain unexplored. In this study, we examined the effects of TGF-β signaling on the murine squamous cell carcinoma, SCCVII cells in vitro and in vivo. The incubation of SCCVII cells with TGF-β induced the activation of TGF-β signals and epithelial-mesenchymal transition (EMT). Notably, the motility of SCCVII cells was increased upon the activation of the TGF-β signaling. RNA sequencing revealed upregulation of genes related to EMT and angiogenesis. Consistent with these in vitro results, the inhibition of TGF-β signals in SCCVII cell-derived primary tumors resulted in suppressed angiogenesis. Furthermore, we identified six candidate factors (ANKRD1, CCBE1, FSTL3, uPA, TSP-1 and integrin β3), whose expression was induced by TGF-β in SCCVII cells, and associated with poor prognosis for patients with head and neck squamous cell carcinoma. These results highlight the role of TGF-β signals in the progression of OSCC via multiple mechanisms, including EMT and angiogenesis, and suggest novel therapeutic targets for the treatment of OSCC.
目前，驱动口腔鳞状细胞癌（OSCC）进展和转移的分子机制在很大程度上仍未被阐明。在各种类型的癌症中都观察到肿瘤微环境中转化生长因子-β（TGF-β）信号的激活，并通过增强上皮癌细胞的迁移和侵袭而被牵连到其进展中。然而，其在口腔癌进展中的具体作用仍未被探索。在这项研究中，我们研究了 TGF-β 信号对体外和体内鼠鳞状细胞癌 SCCVII 细胞的影响。TGF-β 孵育诱导 SCCVII 细胞中 TGF-β 信号的激活和上皮-间充质转化（EMT）。值得注意的是，TGF-β 信号的激活增加了 SCCVII 细胞的迁移能力。RNA 测序揭示了与 EMT 和血管生成相关的基因上调。与这些体外结果一致，在 SCCVII 细胞衍生的原发性肿瘤中抑制 TGF-β 信号导致血管生成受到抑制。此外，我们鉴定了六个候选因子（ANKRD1、CCBE1、FSTL3、uPA、TSP-1 和整合素β3），它们在 SCCVII 细胞中受 TGF-β 诱导表达，并与头颈部鳞状细胞癌患者的预后不良相关。这些结果强调了 TGF-β 信号通过多种机制（包括 EMT 和血管生成）在 OSCC 进展中的作用，并为 OSCC 的治疗提供了新的治疗靶点。
