甾醇调节素结合蛋白1（SREBP1）受突变K-ras基因调控参与大肠癌发生及恶性转化过程的研究

About 95% of fatty acids de novo synthesizes in tumor tissue to meet their requirements for proliferation and invasion.Sterol-regulatory element-binding protein-1(SREBP1) paly important role in maintaining malignant activity of tumor. However the mechnism of SREBP1 in colorectal cancer(CRC) remains largely unclear. Our preliminary study have revealed that metabolic disturbance is one important trait of CRC. The expression level of SREBP1 were related to grade malignancy of adenoma and CRC,and SREBP1 especially high expressed in invasion nestes. Combined with reported data and results, and our results as well, high expression level of SREBP1 and K-ras mutation were appeared together in same stage in both mice and human CRC,accompanied with E2F，MMP7，MMP9 up regulated. Therefore, We speculated”SREBP1 regulated by mutation K-ras,then influenced E2F，MMP7，MMP9 to participate in carcinogenesis and vicious transformation of CRC”.To verify this mechanism, we will use human and mice adenoma and CRC cells ,gene transfection, gene interference，nude mouse plant in vivo，cytobiology,western-blot,real-timePCR,Chip，etc. to investigate the function of SREBP1 in CRC carcinogenesis and vicious transformation,and clear out the regulated mechanism of between K-ras and SREBP1. Our study will lay the foundation of uncovering CRC carcinogenesis and vicious transformation.

肿瘤中95%的脂类靠自身合成满足增殖、侵袭需要。脂类合成关键调控因子甾醇调节素结合蛋白1（SREBP1）对肿瘤恶性行为有重要作用。但目前SREBP1在大肠癌（CRC）中的作用机制尚不清楚。前期研究示脂类代谢异常是CRC的重要特征，SREBP1表达与腺瘤、CRC恶性度相关，且侵润癌巢中呈显著核内表达；结合文献，在人和小鼠CRC中，SREBP1高表达与K-ras突变在同时期，且伴E2F与MMP7、9表达升高。提示SREBP1可能受突变K-ras调控，影响E2F与MMP7、9表达参与CRC发生、恶性转化。为验证该机制，我们将对人和小鼠腺瘤、CRC细胞进行基因转染与干扰、裸鼠体内种植等手段，采用细胞生物学、PCR、CHip等检测方法，从分子、细胞、动物水平探讨SREBP1促进CRC发生及恶性转化的重要作用，明确突变K-ras对SREBP1调控机制。本研究将为揭示CRC发生、发展机制奠定基础。

SREBP1是位于内质网中的细胞内胆固醇传感器通过Insig-Srebp-Scap途径调节细胞内胆固醇。 srebp1的过度表达可引起血脂异常。srebp1可以改变肿瘤细胞的代谢途径，进而促进肿瘤细胞的增殖，但是在结肠癌领域并没有深入的相关研究，我们在临床样本中发现，结肠癌组织中1的表达明显高于癌旁组织，尤其在侵出浆膜层的肿瘤组织中高表达。在肠癌细胞中分别上调下调了1的表达后，我们发现，高表达SREBP1的肠癌细胞可以增加对5-fu诱导凋亡的抵抗，增加细胞的侵袭能力、促进血管上皮细胞血管生成能力，进一步研究发现SREBP1可以分别通过降低caspase7表达和抑制PARP-1剪切来抑制凋亡，通过增加NFKB-p65磷酸化而导致MMP7的表达上调的途径促进肠癌细胞转移。我们的实验证明，SREBP1可以提高肠癌细胞的抗凋亡能力和侵袭能力，并且初步阐明机制，为肠癌的凋亡和侵袭找到一个潜在的靶点。