乳腺癌中4E-BP1反馈激活mTORC1促进肿瘤进展新机制

Eukaryotic translation initiation factor 4E–binding protein 1 (4E-BP1) is a key downstream effector of mTOR complex 1 (mTORC1) that represses cap-dependent mRNA translation initiation by sequestering the translation initiation factor eIF4E. The level of 4E-BP1 often appears upregulated in breast tumors. 4E-BP1 are amplified and overexpressed in breast cancer, associated with a poor outcome. However, the mechanism underlying this process is unclear. Our previous study showed that 4E-BP1 triggers the activation of mTORC1 through release of the feedback loop and inhibit activity of autophagy with enhanced expression of 4E-BP1 in breast cancer. Based on these observations, we will further investigate the molecular mechanism of 4E-BP1 feedback activation of mTORC1. We will determine how 4E-BP1 alters autophagy through mTORC1. We will examine the effect of 4E-BP1 on breast cancer cell growth in vitro and in vivo. Using breast cancer specimens, we will define the correlation between 4E-BP1 expression and the phosphorylation of mTORC1 and autophagy as well as its clinical significance. This study will lay a solid foundation for elucidation of molecular mechanisms of tumorigenesis and identification of novel targets of breast cancer diagnosis and therapy.

4E-BP1是mTORC1下游关键分子，通过与支架蛋白eIF4G竞争性结合翻译起始因子eIF4E，抑制帽子依赖的蛋白质翻译。目前，发现4E-BP1在多数乳腺肿瘤中的表达水平升高，并且4E-BP1高表达的肿瘤患者临床表现预后较差，提示其在肿瘤的发生发展中发挥重要作用。然而，4E-BP1促进肿瘤进展的分子机制有待阐明。我们的前期研究发现，4E-BP1能够反馈激活mTORC1，抑制细胞自噬，促进肿瘤细胞生长。本申请拟在此基础上，进一步确定4E-BP1反馈激活mTORC1的分子机制；探索4E-BP1对细胞自噬的调节方式；体内外检测4E-BP1对乳腺癌细胞生长的影响；利用乳腺癌标本，确定4E-BP1和mTORC1及自噬的相关性及临床意义，为阐明肿瘤发生的分子机制及发现新的诊断和治疗靶标打下坚实基础。

肿瘤是危害人类健康的重大疾病，它的发生发展与癌基因的激活和抑癌基因的失活密切相关。mTOR信号通路在调节细胞的生长、增殖、存活及自噬等方面发挥重要作用。在乳腺癌等多种肿瘤中发现mTOR信号通路被异常激活而促进肿瘤的恶性进展，但是其相关肿瘤发生、发展的具体调控机制仍不是完全清楚。对mTOR信号通路深入研究，不但有助于揭示肿瘤发生发展的分子机制，而且将为肿瘤的临床诊断和治疗的提供重要的理论依据和分子靶标。4E-BP1是mTORC1下游重要分子，通过本课题研究发现4E-BP1能够通过蛋白质翻译调控细胞线粒体功能，影响细胞能量代谢及ATP的产生，细胞能量水平变化激活LKB1/AMPK/mTORC1信号通路，进而抑制细胞自噬促进乳腺癌细胞增殖。我们的工作证实了4E-BP1确是癌基因并阐明了其分子机制，确定其在肿瘤发生进展中的重要地位。基于这些研究发现，4E-BP1可能成为有效的肿瘤药物治疗靶标，将为4E-BP1过量表达而引发的恶性肿瘤患者提高治疗疗效和改善预后，为研制新抗肿瘤药物以及制定有效的个体化的治疗方案提供理论依据。