TGM2通过PTK7/SMAD通路调控CD44阳性胶质瘤细胞间质表型的分子机制研究

With the further development in neuro-oncology, molecular classification and targeted therapy of glioma has become the leading field of the research of brain tumor. CD44- positive glioma (“Mesenchymal” glioma) is an important molecular subtype of glioma. its malignant phenotype (Mesenchymal phenotype) has been described as strong capacity in cell migration, invasiveness, pro-angiogenesis, resistance to radiochemotherapy and association with poor prognosis. TGM2 and PTK7 are two potential targets identified in our previous studies for CD44-positive gliomas. In this study, we further investigate the biological function of TGM2 and PTK7 in CD44 -positive gliomas, and preliminarily understand the regulatory mechanism of TGM2 and PTK7 on the “Mesenchymal” phenotype of glioma cells. In addition, this study also explores the protein interaction between TGM2 and PTK7, which consequently enhances the TGF-β/SMAD2/3 pathway activity, and exerts effects on the maintenance of mesenchymal phenotype in CD44 positive glioma cells. We also investigate the usefulness of targeting TGM2 and PTK7 in order to sensitize CD44-positive glioma cells to temozolomide chemotherapy. This study may provide valuable ideas for searching for an effective treatment strategy for glioma.

随着神经肿瘤研究的进一步开展，胶质瘤分子分型和靶向治疗研究已经成为目前的前沿领域。CD44阳性胶质瘤（间质型胶质瘤）是一个重要的胶质瘤分子亚型，其恶性生物学表型（间质表型）主要体现为有较强的迁移、侵袭潜能和促血管生成能力，和胶质瘤放化疗耐受和预后不良相关。TGM2和PTK7是我们发现的两个CD44阳性胶质瘤的潜在靶点。本研究进一步探讨TGM2和PTK7在CD44阳性胶质瘤中的生物学功能，初步了解TGM2和PTK7对胶质瘤细胞间质表型的调控作用和分子机制。另外，本研究还深入研究CD44阳性胶质瘤细胞中TGM2和PTK7蛋白相互作用增强TGF-β/SMAD2/3通路活性，及其对CD44阳性胶质瘤细胞间质表型的影响；验证靶向TGM2和PTK7对CD44阳性胶质瘤细胞的替莫唑胺化疗增敏作用。本研究可能为寻找一种有效的胶质瘤治疗策略提供宝贵的思路。

胶质瘤分子分型和靶向治疗已经成为目前脑肿瘤研究的前沿领域。CD44阳性胶质瘤（间质型胶质瘤）是一个重要的胶质瘤分子亚型，和胶质瘤放化疗耐受和预后不良相关。TGM2和PTK7是我们发现的两个CD44阳性胶质瘤的潜在靶点。本研究发现TGM2 和PTK7 均在CD44阳性胶质瘤细胞中高表达。敲低TGM2或PTK7表达能够下调TGF-β/SMAD2/3 通路基因表达，抑制细胞增殖和侵袭。TGM2和PTK 7蛋白互作能够调控TGF-β/SMAD2/3 通路活性。靶向TGM2能够增强胶质瘤替莫唑胺化疗疗效。通过研究TGM2 和PTK7 相互作用增强TGF-β/SMAD2/3 通路活性的分子机制，可能为寻找一种有效的胶质瘤治疗策略提供宝贵的思路。