lncRNA-TUG1调控细胞自噬介导肾癌舒尼替尼耐药的机制研究

Sunitinib resistance is the leading cause for the failure of molecular targeted therapy in renal cell carcinoma (RCC), but its mechanism remains unclear. Our preliminary experimental results show that lncRNA-TUG1 is the most highly expressed lncRNAs in sunitinib-resistant RCC cells. In addition, downregulation of TUG1 can inhibit autophagy in sunitinib-resistant RCC cells, and enhance RCC cell’s sensitivity to sunitinib. Further, our results also indicate that suppression of TUG1 level was associated with reduced the autophagy-related gene HMGB1 level in sunitinib-resistant RCC cells, and TUG1 level was positively correlated with HMGB1 level in RCC tissues. Based on this, we speculate that TUG1 contributes sunitinib resistance via regulating autophagy. To test this hypothesis, we initially performed in vitro and in vivo experiments to determine the role of TUG1 in promoting sunitinib resistance in RCC, to elucidate the mechanism of TUG1 in regulating autophagy of RCC cells. Then, we will clarify the mechanism through which TUG1 mediates sunitinib resistance in RCC by regulating HMGB1 to enhance autophagy. Finally, we analyzed the correlation between the expression of TUG1 and HMGB1, and the clinicopathological characteristics in RCC. This study will provide a new theoretical basis for reversing resistance to sunitinib in the molecular targeted therapy of RCC.

舒尼替尼耐药是导致肾癌分子靶向治疗失败的主要原因，但具体机制仍然不清楚。研究报道细胞自噬在肾癌舒尼替尼耐药中发挥关键作用。预实验结果显示：lncRNA-TUG1是舒尼替尼耐药肾癌细胞中表达升高最明显的lncRNAs；降低TUG1的表达可明显抑制肾癌耐药细胞自噬，并增强肾癌细胞对舒尼替尼的敏感性；下调TUG1可抑制肾癌耐药细胞中自噬相关基因HMGB1的表达，且肾癌组织中TUG1与HMGB1的表达呈正相关。据此我们假设：TUG1通过调控HMGB1增强细胞自噬，从而促进肾癌舒尼替尼耐药。本项目拟先利用体内外实验研究lncRNA-TUG1在肾癌舒尼替尼耐药中的作用，阐明TUG1调控细胞自噬的分子机制；然后明确TUG1调控HMGB1促进细胞自噬介导肾癌舒尼替尼耐药的机制，最后分析肾癌组织中TUG1及HMGB1的表达与患者临床病理特征的关系。本研究将为逆转肾癌舒尼替尼分子靶向治疗耐药提供新的理论依据。

舒尼替尼耐药是导致肾癌分子靶向治疗失败的主要原因，但具体机制仍然不清楚。研究报道细胞自噬在肾癌舒尼替尼耐药中发挥关键作用。在本研究中，我们研究发现：lncRNA-TUG1是舒尼替尼耐药肾癌细胞中表达显著的增加；降低lncRNA-TUG1的表达可明显抑制肾癌耐药细胞自噬，并增强肾癌细胞对舒尼替尼的敏感性；下调lncRNA-TUG1可抑制肾癌耐药细胞中自噬相关基因HMGB1的表达，且肾癌组织中TUG1与HMGB1的表达呈正相关；HMGB1是miR-144-3p下游的靶基因，且miR-144-3p是TUG1调控肾癌舒尼替尼耐药的关键分子；进一步机制探索发现：lncRNA-TUG1作为ceRNA通过竞争结合miR-144-3p，上调自噬相关基因HMGB1的表达，从而增强细胞自噬，最终导致肾癌舒尼替尼耐药。本课题的研究成果将为逆转肾癌舒尼替尼耐药提供理论依据，并为肾癌治疗提供新的特异性药物治疗靶点。