SphK1对甲状腺癌细胞自噬的重要调控作用及分子机制研究

自噬在肿瘤细胞的化疗抵抗性中起重要作用。研究表明在甲状腺癌中抑制自噬活性导致细胞对化疗的敏感性降低，但调控机制尚不明确。前期我们证明鞘氨醇激酶1（SphK1）在甲状腺癌中高表达并促进细胞增殖。预实验显示，SphK1抑制甲状腺癌细胞自噬并增强甲状腺癌细胞的对化疗药物的抵抗性；同时发现SphK1抑制甲状腺癌细胞自噬不依赖于Akt活性而可能与Erk1/2活性相关；芯片提示miR-101是SphK1最为显著下调的microRNA，而miR-101下调mTOR及Erk1/2信号通路的正性调控因子Rap1b、Rac1及Pak2。基于以上基础，本项目将系统性研究SphK1具有抑制甲状腺癌细胞自噬的能力,从而增强甲状腺癌细胞的化疗抵抗性。在此过程中，SphK1下调miR-101的表达以促进mTOR、Rap1b、Rac1及Pak2的表达，因而激活Erk1/2-TSC1/2-Rheb-mTOR通路。

Accumulating evidence has demonstrated that autophagy play an imoportant role in chemoresistant of various cancers. It has been showed that inhibition of autophagy decrease the chemotherapy sensitivity of human thyroid cancer. However, the underlying precise mechanism is largely unkonwn. In our recent published paper, we found that SphK1 is overexpressed and promotes proliferation in human thyroid cancer. Moreover, our preliminary studies observed that: 1) SphK1 inhibited the autophagy of thyroid cancer cells, and thereby decrease the chemotherapy sensitivity of human thyroid cancer; 2）SphK1-induced inhibition of autophagy was Akt independent and maybe associated with Erk1/2 activation; 3）miR-101 was significantly down-regulated by ecotopic expression of SphK1and miR-101 could suppress the expression of mTOR, Rap1b, Rac1, and Pak2. Therefore, our aim in current project is to systematically explore the mechanism underlying SphK1-induced chemoresistance and inhibition of autophagy via activation of Erk1/2-TSC1/2-Rheb-mTOR signaling in thyroid cancer, which would provide new insights into the therapeutic strategies for thyroid cancer.