肿瘤相关成纤维细胞（CAF）在肿瘤恶性转化中扮演重要角色，有效逆转CAF促瘤表型，可以阻断其促肿瘤恶性转化作用，但CAF促瘤表型的维持机制目前尚不清楚。我们前期研究证实CAF可以促进肝癌生长（Plos One，2013）、免疫逃逸（Cancer Letters, 2012）及上皮间质转化等肿瘤恶性转化过程。进一步研究发现CD13低表达CAF亚群是其发挥促瘤作用的关键功能性亚群，而且CD13低表达与CAF促瘤表型维持有关（见工作基础）。本课题拟在此基础上，分选富集CD13低表达CAF亚群，以CD13分子为切入点，研究胞内CD13下游的结合蛋白（IQGAP1）和信号蛋白（FAK、ERK）通路对CAF表型活化信号（TGF-β、NF-κB、STAT3）的分子调控方式，以阐明CAF维持促瘤表型的机制。该机制的阐明，不但为靶向CAF抗肿瘤策略及药物开发提供依据，也将为肝癌预后评估提供一个新的预警因子。

Carcinoma associated fibroblast (CAF) plays a critical role in tumor malignant transformation and effective reversion of the CAF’s activated phenotype can impair its tumor promoting effect. However, the exact underlying mechanism of CAF’s tumor-promoting characteristic as well as the maintenance of its activated phenotype is still unclear. In our previous study, we proved that CAF participated in many processes of tumor malignant transformation such as promoting HCC cell proliferation, suppressing the activation of NK cells to create a favorable immunosuppressive shield for HCC cells and promoting epithelial to mesenchymal transition. Furthermore, we found that CD13 low-expression subpopulation of HCC-CAF are the key functional subsets to promote tumor progression, and the expression of CD13 was associated with tumor-promoting characteristics of CAFs. Based on our previous findings, we plan to isolate the CD13 low-expression subsets from CAFs, and then investigate the downstream intracellular binding protein of CD13 (IQGAP1) as well as the changes of relative pathways (FAK and ERK) that affect the phenotypic activation signaling pathways (TGF-β,NF-κB, STAT3) of CAF. Our present study try to elucidate the underlying mechanism of CAF to facilitate tumor progression, which will be helpful for developing novel molecular-targeted agents based on CAF and providing a new prognostic factor for HCC.