肠癌nmTOR/SAGE1信号通路异常活化调节转录的机制和功能研究

mTOR抑制剂Rapamycin已被用于治疗多种晚期恶性肿瘤，但目前尚无公认的可用于界定敏感人群的分子标签。我们曾经发现SAGE1在Rapamycin敏感肿瘤显著富集，随后的研究表明，在SAGE1阳性肿瘤可能存在独特的信号通路传递和转录调节机制：SAGE1招募mTOR入核并使之高度活化（nmTOR），nmTOR磷酸化SAGE1影响其功能；异常活化的nmTOR/SAGE1通过调节一组促癌因子的RNAPII转录释放而促进肿瘤生长，此过程可被Rapamycin完全阻断。我们据此提出科学问题：SAGE1招募mTOR入核形成高度活化的nmTOR/SAGE1信号通路；nmTOR/SAGE1上调促癌因子转录而促进肿瘤生长；SAGE1可作为Rapamycin敏感肿瘤的分子标签。本项目将在以往工作基础上进一步探讨肠癌SAGE1与nmTOR互相活化、共同调节转录的促癌机理，对于优化肿瘤靶向治疗具有重要意义。

Rapamycin, the mTOR inhibitor, has been approved by FDA and CFDA for treatment of advanced cancers for more than 10 years. However, it’s still unknown about the biomarker that could predict Rapamycin sensitivity. We have noticed that one of the cancer-testis antigen, SAGE1 (sarcoma antigen 1), was enriched in Rapamycin sensitive tumors in a PDX based preclinical study. Further molecular biology and structural biology analysis revealed that SAGE1 binds to the gene targets of the Integrator complex through an interaction with Integrator subunit INTS3, functioning as an RNAPII transcription pause-release regulatory switch to promote oncogenic genes transcription. SAGE1 recruits and interacts with mTOR in the nucleus (nmTOR), which dramatically augments mTOR (S2481) autokinase activity. mTOR phosphorylates SAGE1 at threonine residue(s) to regulate its structure and function. nmTOR/SAGE1 signaling promotes tumor growth by uplifting a group of oncogenic genes expression level, which confers Rapamycin sensitivity and can be blocked by Rapamycin treatment. Based on these previous findings, we hypothesize that the crosstalk mechanism between SAGE1 and nmTOR contributes to the oncogenic genes transcription, which further stimulates tumor growth. SAGE1 positive tumors are sensitive to Rapamycin because of the hyper-activated nmTOR/SAGE1 signaling. This study aimed at investigating the specific crosstalk mechanism between SAGE1 and nmTOR, and indentifying SAGE1 could be the biomarker of Rapamycin sensitive intestinal tumors. This project may provide fundamental evidence to elucidate the mechanism that nmTOR/SAGE1 promotes cancer progression. The results of this study will contribute to translate laboratory discoveries into important new clinical tools and applications that will improve the mTOR target therapy of human cancer.