FoxQ1通过激活Hedgehog通路聚集肿瘤相关巨噬细胞促进肝癌转移的机制研究

Tumor metastasis is the root cause of poor treatment result for hepatocellular carcinoma(HCC), current conclusions show that FoxO1 play an important role in cancer tumorigenesis and progression, but the key node and control mechanism of promoting invasion and metastasis by FoxQ1 still unclear; On the other hand, the tumor microenvironment has become the research focus of metastasis mechanisms of HCC. Recent preliminary experiments we found hepatocellular carcinoma cells with high expression of FoxQ1 can promote invasion and metastasis of HCC by recruiting tumor-associated macrophages(TAMs), this indicate that TAMs are the key node of FoxO1 promoting invasion and metastasis of HCC. Further bioinformatics and biology experiments showed CCL2 is the key cytokines of gathering TAMs and promoting HCC cells migration for FoxQ1，and then promote EMT in HCC cells; FoxO1 can upregulate expression of CCL2 by activating the hedgehog pathway and transcriptional activation of Gli2. The project will serve as a link between past and future, deeply analyze the molecular events and regulatory mechanism of FoxQ1 recruiting TAMs by activating hedgehog pathway of HCC and then promoting invasion and metastasis of HCC, provide new target site for the diagnosis and treatment of HCC.

肿瘤转移是肝癌治疗效果差的根本原因，已有结论表明FoxQ1在肿瘤发生发展过程中扮演重要角色，然而，FoxQ1促进肝癌侵袭转移的关键节点及调控机制，目前仍很不清楚；另一方面，肿瘤微环境在肝癌转移机制研究中备受关注。近期预实验我们发现：FoxQ1基因可诱导肝癌细胞聚集肿瘤相关巨噬细胞(TAMs)促进肝癌侵袭转移，这表明TAMs是FoxQ1促进肝癌侵袭转移的关键节点。进一步生物信息学及生物学实验结果显示：CCL2是FoxQ1聚集TAMs并促进肝癌细胞迁移的关键细胞因子，并可促进肝癌细胞发生上皮间质转化(EMT)；FoxQ1可通过激活Hedgehog通路上调CCL2表达。本项目将承前启后，深层次解析FoxQ1通过激活肝癌Hedgehog通路聚集TAMs，进而导致肝癌细胞发生侵袭转移的分子事件及其调控机制，为肝癌的诊断及治疗提供新的靶位点。

肿瘤相关巨噬细胞在肿瘤微环境中的作用近来备受关注，但其在肝癌发生发展中的作用及机制尚不明确。前期我们发现肝癌组织中有肿瘤相关巨噬细胞浸润，且M2型所占比例更高，本项目在肝癌HepG2及MHCC97H细胞系中发现M2型肿瘤相关巨噬细胞可促进肝癌细胞增殖及迁移侵袭，通过对M2型肿瘤相关巨噬细胞分泌的外泌体进行RNA测序，发现Circ_0020256是外泌体发挥促进肝癌细胞增殖及迁移侵袭的关键因子，进一步在临床标本及动物实验中证实Circ_0020256通过调控靶基因miR-432及下游转录因子E2F3发挥促进肝癌增殖及迁移侵袭的作用，提示Circ_0020256可能是潜在的肝癌转移治疗靶点。