SUN2通过抑制BDNF的表达抑制结直肠癌细胞的迁移和转移的研究

We have reported nuclear membrane protein SUN2 can inhibit cell migration in lung cancer, but the molecular mechanism of SUN2 inhibition of cell migration is not clear. Further pre experiment found that: 1) the expression of SUN2 is down regulated in colorectal cancer cells, and the patients with colorectal cancer who expressed the low level of SUN2 predict the poor over survival; 2) knocking down SUN2 significantly promoted cell migration in HCT116 cells; 3) using gene expression microarray technology, we found that knockdown of SUN2 significantly increased BDNF expression which is a cell migration promoting factor . Therefore, we propose the scientific hypothesis: SUN2 inhibits the migration and metastasis of colorectal cancer cells through negatively regulating BDNF expression. Next step, the lentiviral transduction experiments, transwell experiments and animal experiments will be uesed to obtain reliable evidence of SUN2 inhibiting cell migration and metastasis depending on the negative regulation of BDNF, at the same time the immunoprecipitation and mass spectrometry technology, chip technology clarify the molecular mechanism that SUN2 inhibiting the expression of BDNF. This project will reveal for the first time the molecular mechanism that SUN2 inhibit tumor cell migration and the new pathway of SUN2 / BDNF will provide the targets and strategies for the prevention and treatment of patients with colorectal metastasis.

我们已经报道核膜蛋白SUN2在肺癌中具有抑制细胞迁移的作用，但是SUN2抑制细胞迁移的分子机理不明确。进一步预实验发现：1）SUN2在结直肠癌细胞中表达下调，且低表达SUN2的结直肠癌病人总生存预后较差；2）在HCT116细胞中敲低SUN2显著性促进细胞迁移作用；3）通过全基因表达谱芯片技术，我们发现敲低SUN2显著性提升细胞迁移促进因子BDNF的表达。由此，我们提出科学假设：SUN2通过负调控BDNF的表达抑制结直肠细胞的迁移和转移。下一步本研究将通过慢病毒转导实验、transwell实验和动物实验以获取SUN2抑制细胞迁移和转移依赖于负调控BDNF表达的可靠证据，同时通过免疫共沉淀技术、质谱技术、ChIP技术阐明SUN2抑制BDNF表达的分子机理。本项目的开展将首次揭示SUN2抑制肿瘤细胞迁移的分子机理以及为基于SUN2/BDNF通路在结直肠转移病人防治中提供新的靶点和策略。

远处转移是结肠癌治疗失败的主要原因。SAD1/UNC84结构域蛋白-2（SUN2）是跨越核膜的核骨架和细胞骨架的连接体复合物的关键组成部分。本课题中，我们首先证实了SUN2在原发性结肠癌组织和远处转移瘤中的水平明显低于正常结肠组织，并且高表达SUN2表达预示着良好的总生存率（OS）。过表达或敲除SUN2分别抑制或促进肿瘤细胞迁移和侵袭。此外，沉默SUN2促进了裸鼠体内转移。在机制上，我们发现SUN2通过降低BDNF的表达来抑制BDNF/TrkB信号传导，从而发挥其肿瘤抑制功能。此外，SUN2与SIRT1相互作用并增加MeCP2的乙酰化以增加其与BDNF启动子的结合能力。我们的研究结果表明低表达SUN2是结肠癌进展的关键因素，并且新的SUN2-SIRT1-MeCP2-BDNF信号可能有助于开发治疗结肠癌患者的新策略。此外本项目还发现TRIM11在鼻咽癌耐药中其中重要的作用，同时发现、THAP7等在肺癌增殖和转移中起着重要作用。