转录因子HOXB9调控IFITM3表达在肝癌细胞侵袭转移中的作用及机制

Our team confirmed that the transcription factor HOXB9 promotes invasion and metastasis of hepatocellular carcinoma (Cancer Research), but the specific mechanisms are not clear.In recent years,our early studies have found that miR-29a/IFITM3 plays an important role in the invasion and metastasis of hepatocellular carcinoma.The preliminary experiments revealed that HOXB9 and IFITM3 are highly expressed in HCC tissues and are positively correlated; the silence of HOXB9 can reduce IFITM3 expression, but HOXB9 can not directly regulate the transcription levels of IFITM3.In addition, studies confirmed that the TUG1/miR-29a axis plays a key role in tumor progression. Combined some relevant literature with the result of Chip-seq, it was found that HOXB9 binds to the promoter of TUG1 to regulate the expression of IFITM3 that is the target gene of miR-29a.Accordingly, we speculated that HOXB9 may increase the expression of IFITM3 through regulating the TUG1/miR-29a axis to promote the invasion and metastasis of hepatocellular carcinoma.To provide the new basis of treatment of hepatocellular carcinoma,this study intends to confirm how HOXB9 regulates IFITM3 to promote invasion and metastasis of hepatocellular carcinoma and its specific mechanism by a series of molecular biotechnologies,such as luciferase reporter gene in cell, tissue, and animal experiments.

本团队证实转录因子HOXB9促进肝癌侵袭转移(Cancer Research)，但机制不详。近年来，我们前期研究发现miR-29a/IFITM3通路在肝癌侵袭转移中起重要作用。预实验发现：HOXB9和IFITM3在肝癌组织中均高表达，且呈正相关；沉默HOXB9可降低IFITM3表达，但HOXB9不能直接调控IFITM3转录水平。另外，研究证实TUG1/miR-29a轴在肿瘤进展中起关键作用，结合相关文献并通过Chip-seq等实验发现HOXB9结合TUG1启动子调控miR-29a靶基因IFITM3的表达。据此，我们推测HOXB9通过调控TUG1/miR-29a轴导致IFITM3表达增加，促进肝癌侵袭转移。本研究拟在细胞、组织、动物实验等多层面采用荧光素酶报告基因等实验方法明确HOXB9调控IFITM3促进肝癌侵袭转移，并探讨HOXB9调控IFITM3表达的具体机制，为肝癌治疗提供新的依据。

肝癌是我国最常见恶性肿瘤之一，但是肝癌复发转移的分子机制不完全清楚，这导致临床治疗过程中对于肝癌复发转移能够采取的干预措施有限，效果欠佳。本团队证实转录因子HOXB9和IFITM3在肝癌组织中均高表达，且呈正相关，并预示不良预后。此外，HOXB9可通过调控IFITM3促进肝癌细胞侵袭转移。我们还通过体内和体外实验发现TUG1作为ceRNA竞争性地结合miR-29a来调节IFITM3的表达。由于HOXB9可发挥转录因子作用，因此我们猜想HOXB9可能通过调控TUG1/miR-29a轴导致IFITM3表达。为了验证这一猜想，我们通过双荧光素酶报告基因实验证实HOXB9通过直接与TUG1的启动子区域结合而增强其表达。最后我们得出结论，转录因子HOXB9通过调控TUG1/miR-29a 轴导致IFITM3表达增加，进而促进肝癌细胞的侵袭和转移。本研究阐释了转录因子HOXB9调控IFITM3表达在肝癌细胞侵袭转移中的作用及机制，将为为肝癌治疗提供新的依据。