趋化素样因子1（CKLF1）在原发性肝细胞癌中的促炎症反应恶性转化研究

Hepatocellular carcinoma (HCC) is one of the most common and aggressive human cancers worldwide. HCC is an example of uncontrolled inflammation-related cancer and represents a paradigm of the relation occurring between tumor microenvironment and tumor development. In the microenvironment, chemokines, are involved in recruiting inflammatory cells, induce liver inflammation and promote angiogenesis and immunal evasion of tumor cells, which play an important role in tumor proliferation, metastasis and invasion. NF-κB signal pathway is also reported to be critical in inflammation-mediated malignant tumor transformation. Studies suggest chemokines of CC family interact with NF-κB, thus participate in heptocarcinogenesis. Chemokine-like factor 1 (CKLF1), selected from differential expression cDNA library of liver cancer, is a new member of CC family, which promotes proliferation and migration of multiple cells and involves in inflammatory response such as asthma by regulating NF-κB signal pathway. However, the functions of CKLF1 on HCC have not been reported yet. Our previous experiments showed that: 1) CKLF1 mRNA was up-regulated in 5 different HCC cell lines, especially in highly metastatic HCC cell lines; 2) CKLF1 was overexpressed in liver cancer tissues rather than non-tumorous liver tissues; 3) exogenous overexpression of CKLF1 promoted the proliferation and metastasis of Hep3B; 4) overexpression of CKLF1 upregulated the mRNA levels of p50 and p65 in Hep3B, and NF-κB downstream MMP-9. All the results imply that CKLF1 expression is involved in the development of HCC. Additionally, activation of NF-κB pathway is associated with the function of CKLF1 in HCC. However, the detailed mechanisms are still unclear. Therefore, this study aims to investigate the functions of CKLF1 in the development of HCC, and further illustrate the molecular mechanisms of CKLF1 promoting inflammation-mediated transformation in HCC, thus provide new therapeutic insight for HCC.

原发性肝细胞癌（HCC）是一种非可控性炎症相关的恶性肿瘤。趋化因子与NF-κB炎症信号通路的相互调节在HCC的炎癌转变过程中起重要作用。趋化素样因子1（CKLF1）是一个新发现的CC家族趋化因子，能促进细胞增殖和迁移，并能与NF-κB相互调控参与炎症反应。但CKLF1在HCC中的作用及具体机制未见报道。我们的预实验显示：CKLF1在HCC组织和细胞系中比癌旁显著过表达；CKLF1过表达促进Hep3B增殖和迁移；并能上调Hep3B中p50和p65及NF-κB下游靶基因MMP-9 mRNA水平。表明CKLF1与HCC相关，且NF-κB可能参与其在HCC中的作用。因此，本项目拟探讨CKLF1在HCC发生中的作用，并初步研究其通过NF-κB在HCC中促炎症反应恶性转化的分子机制，将为阐明HCC的分子机制提供科学的实验依据，也为探寻HCC分子治疗靶标提供新的思路。

原发性肝细胞癌（HCC）是一种非可控性炎症相关的恶性肿瘤。趋化因子与炎症信号通路的相互调节在HCC的炎癌转变过程中起重要作用。趋化素样因子1（CKLF1）是一个新发现的CC家族趋化因子，参与组织细胞炎症反应，并能促进细胞增殖和迁移。但CKLF1在HCC中的作用及具体机制未见报道。本项目研究发现CKLF1在HCC组织中过表达，CKLF1的表达与HCC分级，血管侵袭和患者生存率直接相关。功能分析发现CKLF1促进HCC肿瘤形成和侵袭潜能。进一步的研究发现CKLF1促肿瘤作用可能通过激活IL-6/STAT3等信号通路。该研究将为阐明HCC的分子机制提供科学的实验依据，也为探寻HCC分子治疗靶标提供新的思路。