癌代谢物R-2HG上调TGF-β1/p-Smad3信号通路促进前列腺癌迁移、侵袭及其诱导前列腺癌神经内分泌分化转移的机制研究

Prostate cancer with IDH1 mutation is one of the special molecular types of prostate cancer with increase of intracellular oncometabolite R-2HG level. However, little is known and fully discovered about this type of prostate cancer as well as the role of R-2HG in prostate cancer. We previously first verified the existence of IDH1 mutation in prostate cancer among Chinese population with increase of R-2HG level. We further found that both exogenous and endogenous R-2HG could induce prostate cancer migration and invasion via upregulating TGF-β 1/p-Smad3 signal pathway. Besides, in silico data showed that copy number amplification of ADHFE1, which could produce R-2HG, was more frequent in neuroendocrine prostate cancer than that it in prostate adenocarcinoma. And we also found that R-2HG could increase neuroendocrine markers expression and neuroendocrine transdifferentiation of prostate cancer. It’s suggested that R-2HG played an important role in prostate cancer based our preliminary data. We plan to further dissect the mechanism of how R-2HG upregulate TGF-β 1/p-Smad3 pathway to clarify its role in inducing prostate cancer migration and invasion, as well as to further illustrate the mechanism of how R-2HG promote prostate cancer neuroendocrine transdifferentiation. Our research will provide novel theoretical basis for the biological characteristics of prostate cancer with IDH1 mutation, as well as for future drug development targeting this special molecular type of prostate cancer.

IDH1突变型前列腺癌为一类特殊分子类型前列腺癌，伴有癌代谢物R-2HG水平显著升高，而其生物学特点及R-2HG在前列腺癌中的生物学作用均无深入研究。本课题组首次在中国人群中证实了IDH1突变型前列腺癌的存在，并进一步发现增加R-2HG水平均能通过上调TGF-β1/p-Smad3信号通路促进前列腺癌迁移与侵袭；同时，生物信息学数据提示编码产生R-2HG关键酶ADHFE1的基因在前列腺神经内分泌癌中基因拷贝数扩增频率明显增高，而我们也发现R-2HG能诱导前列腺癌发生神经内分泌分化转移。因此，我们认为R-2HG在前列腺癌中具有重要生物学作用，我们将进一步揭示其上调TGF-β1/p-Smad3信号通路而促进前列腺癌迁移与侵袭的分子机制，以及揭示R-2HG诱导前列腺癌神经内分泌分化转移的原理，为阐明IDH1突变类型前列腺癌的生物学特点提供依据，并为开发治疗此类特殊突变类型前列腺癌相关药物奠定基础。

IDH1突变型前列腺癌为一类特殊分子类型前列腺癌，伴有癌代谢物R-2HG水平显著升高，而其生物学特点及R-2HG在前列腺癌中的生物学作用均无深入研究。本课题组首次在中国人群中证实了IDH1突变型前列腺癌的存在，并进一步发现增加R-2HG水平均能通过上调TGFβ1/p-Smad3信号通路促进前列腺癌迁移与侵袭。本项目拟进一步揭示癌代谢物R-2HG在前列腺癌中的分子生物学机制。通过体外细胞实验，我们发现R-2HG可以通过影响TGFβ1前体mRNA中m6A修饰水平，进而促进其自身circRNA产生，从而通过Sponge作用结合更多的microRNA来上调TGFβ1 mRNA的翻译，最终激活TGFβ1/p-Smad2/3信号通路而促进前列腺癌侵袭。动物实验也进一步验证了具有IDH1突变的前列腺癌更易发生远处转移。本项目的研究结果初步阐明了IDH1突变类型前列腺癌的生物学特点及癌代谢物R-2HG的分子生物学机制，为开发治疗此类特殊突变类型前列腺癌相关药物奠定基础。