分泌型Galectin-3在细胞衰老诱导肝癌干细胞恶性转化中的作用及机制

Primary hepatocellular carcinoma is an age-related malignant tumor with a high mortality rate, which is a serious threat to the health of the elderly. Senescence is a double-edged sword that can inhibit the appearance of precancerous lesions. However, senescence-associated reprogramming can change the metabolic and the stemness of tumor cells and promote tumor progression. Explaining the key aging-related proteins and their functions is the key link to reveal the phenomenon of aging related diseases. Our previous study found that secretory galectin-3 is a senescence-related protein and is associated with the stemness of liver cancer cells. In view of this, this study focuses on the regulation and mechanism of senescence-associated galectin-3 protein in the malignant transformation of cancer stem cells. In this project, we intend to clarify the interaction ant its function and regulation of galectin-3 and cancer stem cell marker CD133, explain the molecular mechanism of senescent microenvironment regulating the malignant transformation of cancer stem cells. Furthermore, we intend to find more senescence-associated secreted proteins in cancer.

原发性肝细胞肝癌是增龄相关恶性肿瘤，死亡率高，严重威胁老年健康。衰老早期可抑制癌前病变的出现，然而衰老相关的重编程又可改变肿瘤细胞的代谢和干性特征，促进肿瘤进展。因此阐释主要衰老-肿瘤相关蛋白及功能是揭示老年患者高发肝癌现象的关键。我们前期研究发现Galectin-3是衰老相关分泌蛋白，和肝癌细胞“干性”特征相关。鉴于此，本课题拟深入研究衰老相关分泌型Galectin-3蛋白在肿瘤干细胞恶性转化中的调控作用及机制。拟寻找衰老和肝癌重叠的差异表达基因，发现和验证肝癌中衰老相关Galectin-3蛋白，解析肝癌干细胞与Galectin-3互作的分子基础——糖链结构，证实分泌型Galectin-3和肿瘤干细胞标志蛋白CD133相互作用的规律和功能，阐释衰老微环境调控肿瘤干细胞恶性转化的分子机制，完善肿瘤中衰老相关分泌表型的研究，以期发现老年人肝癌检测标志物。

原发性肝细胞肝癌是增龄相关恶性肿瘤，死亡率高，严重威胁老年健康。衰老早期可抑制癌前病变的出现，然而衰老相关的重编程又可改变肿瘤细胞的代谢和干性特征，促进肿瘤进展。因此阐释主要衰老-肿瘤相关蛋白及功能是揭示老年患者高发肝癌现象的关键。在本项目中，我们发现Galectin-3在老年人肝细胞肝癌以及老年小鼠自发性肝癌中表达上调，并与老年患者寿命呈负相关；通过地塞米松诱导的肝脏衰老模型我们发现Galectin-3可能来源于巨噬细胞、衰老细胞等多种细胞；体外实验证实外源分泌型Galectin-3蛋白参与肿瘤干细胞球的形成和生长；同时还证实分泌型Galectin-3与干细胞标志物CD133等糖蛋白相互作用依赖于糖链结构的分子互作机制。此外，我们还发现分泌型Galectin-3通过 PPARγ/CD36 信号通路促进肝脏脂肪变性，研究报道CD36调节的脂质代谢参与肿瘤侵袭等特性。我们的研究提示了糖链受体/蛋白质糖基化在老年肝癌发生发展中的重要作用，并为老年肝癌的临床治疗提供新的线索。