【作者】 林莉；

【导师】 欧阳高亮；

【作者基本信息】 厦门大学 ， 生物学， 2021， 硕士

【摘要】 结直肠癌患者绝大多数死于复发和远端转移。肝转移是结直肠癌患者最主要的死亡原因之一。TGFBI 蛋白(Transforming growth factor-beta induced protein,TGFBI)是一种细胞外基质蛋白,其异常表达与许多肿瘤的发生发展密切相关。目前,TGFBI在结直肠癌肝转移中的功能尚不清楚。在本研究中,我们发现TGFBI在AOM/DSS诱导的小鼠肠炎相关结直肠癌模型和ApcMin/+小鼠肠腺瘤肿瘤组织中高表达,而且TGFBI在脾内注射结直肠癌细胞形成的小鼠结直肠癌肝转移肿瘤组织中高表达,且TGFBI主要分布在肿瘤间质区域,并与肝星形细胞有很好的共定位现象。我们进一步利用TGFBI基因敲除小鼠模型研究TGFBI在结直肠癌肝转移中发挥的作用。我们研究发现,相较于野生型小鼠,结直肠癌细胞在形成肝转移灶的过程中,TGFBI基因敲除小鼠形成肝转移灶的能力显著减弱;敲除TGFBI可显著抑制结直肠癌肝转移小鼠肝脏纤维化微环境、炎症微环境的形成。体外实验TGFBI重组蛋白处理结直肠癌细胞可促进其细胞迁移和侵袭。此外,我们还发现TGFBI在临床结直肠原位癌组织和肝转移组织中高表达。以上研究结果表明,TGFBI促进了结直肠癌肝转移的发生发展,在结直肠癌肝转移发生发展进程中的肝脏纤维化微环境、炎症微环境起重要作用。该研究将有助于进一步阐明TGFBI在结直肠癌肝转移中的功能,也将有助于进一步阐明TGFBI是如何参与调控并重塑肝脏组织微环境从而促进结直肠癌肝转移的发生发展。更多还原

【Abstract】 The majority of colorectal cancer patients die from recurrence and distant metastasis.Liver metastasis is the leading cause of death in patients with colorectal cancer.Transforming growth factor-beta induced protein(TGFBI)is an extracellular matrix protein that has been reported to be associated with tumorigenesis and the development of tumors.At present,the functions of TGFBI in colorectal cancer liver metastasis is unclear.In this study,we find that TGFBI is highly expressed in AOM/DSS-induced colitis-associated colorectal cancer(CAC)and spontaneous intestinal tumor of ApcMin/+ mice.Moreover,TGFBI is up-regulated in mice colorectal cancer liver metastasis formed by injecting colorectal cancer cells into the spleen.TGFBI is mainly distributed in the interstitial area of liver metastasis and has a good co-localization phenomenon with hepatic stellate cells.We further use the TGFB1 knockout mice to study the role of TGFBI in colorectal cancer liver metastasis.We find that compared to wild-type mice,TGFBI knockout mice with colorectal cancer liver metastasis form less metastatic lesions;knockout of TGFBI significantly inhibits the formation of liver fibrosis and inflammation microenvironment in mice colorectal cancer liver metastasis.In vitro,recombinant TGFBI promotes the migration and invasion of colorectal cancer cells.In addition,we find that TGFBI is highly expressed in the clinical samples of patient with the primary colorectal cancer and liver metastasis.These results suggest that TGFBI promotes the tumorigenesis and development of colorectal cancer liver metastasis,and plays important roles in the liver fibrosis microenvironment and inflammation microenvironment of the progress.This study will help us to further clarify the functions of TGFBI in colorectal cancer liver metastasis and how TGFBI regulates liver tissue microenvironment to promote the development of colorectal cancer liver metastasis.更多还原