ITLN-1通过HGF/c-Met信号通路抑制肝癌侵袭转移的机制研究

Hepatocellular carcinoma is one of the most common malignant tumors in China. Using gene chip, we previously screen all molecules that expressed differentially between HCC and its corresponding noncancerous liver tissues in three HCC patients, and ITLN-1 was found down-regulated significantly in HCC tissues. Our preliminary results indicated that the down-regulation ofITLN-1 was closely correlated with tumor size, differentiation, microvascular invasion and tumor recurrence and metastasis in patients who underwent liverresection, suggesting that ITLN-1 plays as an anti-oncogene in HCC. Several studies suggested that ITLN-1 could inhibit tumor progression in neuroblastoma and gastrointestinal tumors, however, the function and detailed molecular mechanism of ITLN-1 in hepatocarcinogenesis and progression remains unclear. We found that ectopic expression of ITLN-1 suppressed the growth of HCC cells in vitro and in vivo, meanwhile, we further found that ITLN-1 decreased the levels of HGF and c-Met. These results demonstrated that ITLN-1 might repressing tumor invasion and migration in HCC cells through inactivating the HGF/c-Met signaling pathway. Our study aims to reveal the molecular mechanism of ITLN-1 in regulating the invasion and metastasis of HCC and perfect the function of HGF/c-Met signaling pathway in hepatocarcinogenesis and progression. This study is of great importance in searching for new therapeutic targets and improving the outcomes of HCC treatment.

肝癌是我国最常见的恶性肿瘤之一。申请人前期利用基因芯片技术检测了肝癌组织和其对应的癌周肝组织中差异表达的基因，发现ITLN-1在肝癌组织中的表达明显低于其对应的癌周肝组织，且其表达与肿瘤大小、分化程度、血管侵犯及术后肿瘤复发转移等因素密切相关，这提示ITLN-1在肝癌中发挥抑癌基因的作用。虽然有研究表明ITLN-1可抑制神经母细胞瘤和胃肠道肿瘤的生长，但是其在肝癌发生发展中的作用及分子机制尚不清楚。我们发现上调肝癌细胞中ITLN-1的表达后，肝癌细胞在体内外增殖能力明显下降，同时HGF和c-Met的mRNA表达水平明显下降，这提示ITLN-1可能通过HGF/c-Met信号通路抑制肝癌的侵袭转移。本项目旨在揭示ITLN-1调控肝癌侵袭转移的具体分子机制，进一步完善HGF/c-Met信号传导通路在肝癌发生发展过程中的作用，该研究对肝癌开辟新的治疗靶点、提高肝癌治疗效果具有重要意义。

内凝集素1 (ITLN1)，也被称为网膜素 1，是一种新发现的分泌性脂肪因子，在先天免疫系统、炎症和葡萄糖摄取中发挥着关键作用。然而，它在肝细胞癌（HCC）中的确切作用仍未被完全阐明。在此，我们发现ITLN1在HCC组织中的表达低于相邻的非肿瘤组织，其表达与肿瘤大小、肝硬化、血管侵犯等因素密切相关，而且ITLN1的表达降低预示着较差的总体生存。在功能上，ITLN1通过激活ERK1/2信号，以细胞周期停止的方式减弱了HCC的增殖。我们还通过生物信息学分析确定了干扰素调节因子1（IRF1）是ITLN1的一个转录因子，并确认了IRF1在ITLN1启动子区域的结合位点。此外，干扰素γ（IFNγ）是IRF1的经典上游细胞因子，可以通过IRF1促进ITLN1的表达。随后，IFNγ-IRF1-ITLN1轴被确定，并发现其能抑制HCC细胞增殖和细胞周期进展。总之，我们的研究发现，受IRF1调控的ITLN1通过持续激活ERK1/2信号来抑制HCC的增殖，可能是一个有价值的预后生物标志物和HCC的潜在治疗目标。