长链非编码RNA ZXF1表达与肺腺癌预后的关系及相关分子机制

Correlation between expression of long non-coding RNA ZXF1 and prognosis of lung adenocarcinoma and its potential molecular mechanism

目的：探讨长链非编码RNA ZXF1的表达情况与肺腺癌临床病理特征和预后的关系以及相关分子机制。方法收集83例手术切除的肺腺癌组织标本，荧光实时定量PCR检测ZXF1 mRNA的表达，分析ZXF1表达水平与肺腺癌临床病理特征和预后的关系。建立肺腺癌A549细胞过表达ZXF1模型，利用蛋白质抗体芯片技术筛选与ZXF1功能上相关的靶蛋白。结果83例肺腺癌组织和癌旁组织中，ZXF1 mRNA的表达水平分别为8．32±3．05和1．05±0．47，差异有统计学意义（P＜0．05）。 ZXF1表达水平与肺腺癌患者的肿瘤分化程度和淋巴结转移有关（均P＜0．05），与患者性别、年龄和肿瘤大小无关（均P＞0．05）。 Kaplan？Meier分析显示，ZXF1 mRNA高表达组患者的无病生存时间（DFS）和总生存时间（OS）均低于ZXF1 mRNA低表达组（P＜0．05）。 Cox多因素分析显示，年龄、ZXF1表达水平、肿瘤大小和淋巴结转移为影响肺腺癌患者DFS的独立因素（均P＜0．05），年龄、ZXF1表达水平、肿瘤大小、淋巴结转移和肿瘤分化程度为影响肺腺癌患者OS的独立因素（均P＜0．05）。蛋白质抗体芯片检测显示，肺腺癌A549细胞过表达ZXF1后，骨形态发生蛋白5（ BMP？5）和干细胞因子受体（ SCFR）表达相应增加。结论 ZXF1在肺腺癌组织中高表达，并且与肿瘤分化程度及淋巴结转移有关，ZXF1高表达的肺腺癌患者预后较差。 ZXF1可能通过增强靶蛋白BMP？5和SCFR的表达而影响肺腺癌的进展。

Objective To investigate the correlation between expression of long non？coding RNA （ lncRNA） ZXF1 and clinicopathological characteristics, as well as prognosis of lung adenocarcinoma; and to explore its potential molecular mechanism. Methods A total of 83 lung adenocarcinoma tissue samples and 83 paracancerous lung tissue samples from lung adenocarcinoma patients were collected. The mRNA expression of ZXF1 in the tumors and the corresponding adjacent non？tumor tissues were determined by real？time fluorescence quantitative PCR. The correlation between ZXF1 level and clinicopathological characteristics such as age, gender, smoking history, tumor size, tumor differentiation and lymph node metastasis was evaluated. Survival analysis was performed using Kaplan？Meier and Cox multivariate regression, based on the data of a 12？56 months follow？up after surgery. In vitro ZXF1 was over？expressed in lung adenocarcinoma A549 cells, and then the proteins functionally related to ZXF1 were identified by protein array analysis. Results Of the 83 cases of lung adenocarcinoma, the ZXF1 mRNA levels in the tumor and adjacent non？tumor tissues were 8.32±3.05 and 1.05±0.47, respectively （P〈0.05）, and a high？level the high expression of ZXF1 in the tumor tissues was detected in 56 cases. The expression status of ZXF1 was closely correlated with the tumor differentiation and lymph node metastasis （ P〈0.05） , but was not significantly related to age, gender and tumor size. Based on a 12？56 months follow？up, the patients with high level ZXF1 expression had a shorter disease free survival （ DFS） and overall survival （ OS） than that of the group with low level ZXF1 （ all P〈0.05） . Multivariate analysis showed that ZXF1 expression, tumor sizenbsp;and lymph node metastasis were independent risk factors to DFS; and ZXF1 expression, tumor size, lymph node metastasis and tumor differentiation were independent risk factors to OS. The protein array data revealed that expressions of bone morphogenetic protein 5 （ BMP？5 ） and stem cell factor receptor （ SCFR ） were upregulated upon overexpression of the ZXF1 in A549 cells. Conclusions lncRNA ZXF1 is overexpressed in lung adenocarcinoma, and is closely correlated with tumor differentiation and lymph node metastasis. As an independent risk factor, a high expression of ZXF1 indicates a poor prognosis for the patients. ZXF1 may influence the biological behavior of lung adenocarcinoma by enhancing the protein expression of BMP？5 and SCFR.