基于ox-LDL/LOX-1信号通路探讨脂质代谢紊乱促进肺癌进展中的机制

The mechanism of lipid metabolism disorders promoting progression of lung cancer based on the oxLDL/LOX⁃1 signaling pathway

目的基于氧化低密度脂蛋白(ox-LDL)/人凝集素样氧化低密度脂蛋白受体1(LOX-1)信号通路探讨脂质代谢紊乱促进肺癌进展的机制。方法收集81个已鉴定的具有成对相邻非癌组织(离肿瘤至少5 cm)的肺腺癌组织,使用免疫组织化学检测LOX-1表达。肺腺癌细胞系(A549、H1299细胞)中过表达LOX-1。用Transwell测定细胞侵袭能力。用不同浓度oxLDL处理细胞,并检测细胞中LOX-1表达情况。结果在包含原发性人肺癌和匹配的邻近非癌组织中,肿瘤中LOX-1染色比非癌组织样品明显增强(中值H分数99.4 vs.16.2,P<0.001)。高LOX-1表达与低生存显著相关(P<0.001)。与无淋巴结转移的患者相比,发生淋巴结转移患者的癌组织具有更高的LOX-1水平(中值H分数83.2 vs.121.1,P<0.01)。LOX-1过表达显著促进肺癌细胞的侵袭转移细胞数(P<0.01)。此外,LOX-1是ox-LDL诱导的肺癌细胞转移所必需的功能靶点。伊他替尼抑制LOX-1过表达的A549在体外的转移能力。结论LOX-1的表达随着oxLDL水平的升高而增加,并且LOX-1的表达上调促进了肺癌细胞的转移,其作用机制可能与激活Janus激酶/转录因子激活子(JAK1/STAT6)信号通路有关。

Objective To explore the mechanism of lipid metabolism disorder promoting the progress of lung cancer based on the oxidized low density lipoprotein(ox⁃LDL)/human lectin⁃like oxidized low density lipopro⁃tein receptor 1(LOX⁃1)signaling pathway.Methods Eighty⁃one identified lung adenocarcinoma tissues with paired adjacent non⁃cancerous tissues(at least 5 cm away from the tumor)were collected from our hospital,and the expression of LOX⁃1 was detected by immunohistochemistry.LOX⁃1 was overexpressed in lung adenocarcinoma cell lines(A549 and H1299 cells).Cell invasion ability was measured by Transwell.Cells were treated with different concentrations of oxLDL,and cellular LOX⁃1 expression was investigated.Results LOX⁃1 staining in the tumor was significantly stronger than that in the non⁃cancerous tissue samples(99.4 vs.16.2 for median H score,P<0.001).High LOX⁃1 expression was significantly correlated with low survival(P<0.001).As compared with the patients without lymph node metastasis,those with lymph node metastasis had higher LOX⁃1 level(83.2 vs.121.1 for median H score,P<0.01).Overexpression of LOX⁃1 in lung cancer cells significantly promoted the number of invasive and metastatic cells(P<0.01).In addition,LOX⁃1 was an essential functional target for oxLDL⁃induced metastasis of lung cancer cells.Itatinib inhibited the metastasis of LOX⁃1 overexpressed A549 in vitro.Conclusions With an increase in oxLDL level,the expression of LOX⁃1 increases.Up⁃regulation of LOX⁃1 promotes metastasis of lung cancer,and its mechanism may be related to activation of the JAK1/STAT6 signaling pathway.