文章：

LKB1缺失与STING缺失相关，并与β-连环蛋白膜性缺失协同作用，预示可手术非小细胞肺癌患者的不良预后。

LKB1 Loss Correlates with STING Loss and, in Cooperation with β-Catenin Membranous Loss, Indicates Poor Prognosis in Patients with Operable Non-Small Cell Lung Cancer

原文发布日期：10 May 2024

DOI: 10.3390/cancers16101818

类型: Article

开放获取: 是

英文摘要：

To investigate the incidence and prognostically significant correlations and cooperations of LKB1 loss of expression in non-small cell lung cancer (NSCLC), surgical specimens from 188 metastatic and 60 non-metastatic operable stage I-IIIA NSCLC patients were analyzed to evaluate their expression of LKB1 and pAMPK proteins in relation to various processes. The investigated factors included antitumor immunity response regulators STING and PD-L1; pro-angiogenic, EMT and cell cycle targets, as well as metastasis-related (VEGFC, PDGFRα, PDGFRβ, p53, p16, Cyclin D1, ZEB1, CD24) targets; and cell adhesion (β-catenin) molecules. The protein expression levels were evaluated via immunohistochemistry; the RNA levels of LKB1 and NEDD9 were evaluated via PCR, while KRAS exon 2 and BRAFV600Emutations were evaluated by Sanger sequencing. Overall, loss of LKB1 protein expression was observed in 21% (51/248) patients and correlated significantly with histotype (p< 0.001), KRAS mutations (p< 0.001), KC status (concomitant KRAS mutation and p16 downregulation) (p< 0.001), STING loss (p< 0.001), and high CD24 expression (p< 0.001). STING loss also correlated significantly with loss of LKB1 expression in the metastatic setting both overall (p= 0.014) and in lung adenocarcinomas (LUACs) (p= 0.005). Additionally, LKB1 loss correlated significantly with a lack of or low β-catenin membranous expression exclusively in LUACs, both independently of the metastatic status (p= 0.019) and in the metastatic setting (p= 0.007). Patients with tumors yielding LKB1 loss and concomitant nonexistent or low β-catenin membrane expression experienced significantly inferior median overall survival of 20.50 vs. 52.99 months;p< 0.001 as well as significantly greater risk of death (HR: 3.32, 95% c.i.: 1.71–6.43;p<0.001). Our findings underscore the impact of the synergy of LKB1 with STING and β-catenin in NSCLC, in prognosis.

摘要翻译： 

为探究非小细胞肺癌（NSCLC）中LKB1表达缺失的发生率及其预后相关性，本研究对188例转移性与60例非转移性可手术I-IIIA期NSCLC患者的手术标本进行分析，评估LKB1及pAMPK蛋白表达与多种生物学过程的关系。研究指标包括：抗肿瘤免疫应答调控因子STING与PD-L1；促血管生成、上皮间质转化及细胞周期相关靶点，以及转移相关靶点（VEGFC、PDGFRα、PDGFRβ、p53、p16、Cyclin D1、ZEB1、CD24）；细胞黏附分子（β-连环蛋白）。蛋白表达水平通过免疫组织化学法检测；LKB1与NEDD9的RNA水平通过PCR检测；KRAS外显子2及BRAFV600E突变通过桑格测序评估。总体而言，21%（51/248）的患者出现LKB1蛋白表达缺失，该现象与组织学亚型（p<0.001）、KRAS突变（p<0.001）、KC状态（KRAS突变伴p16下调）（p<0.001）、STING缺失（p<0.001）及高CD24表达（p<0.001）显著相关。在转移病例中，STING缺失与LKB1表达缺失呈显著相关性，总体（p=0.014）及肺腺癌（LUAC）亚组（p=0.005）均具统计学意义。此外，LKB1缺失与β-连环蛋白膜表达缺失或低表达显著相关，该相关性在LUAC中独立于转移状态存在（p=0.019），且在转移背景下尤为显著（p=0.007）。同时存在LKB1缺失与β-连环蛋白膜表达缺失/低表达的患者中位总生存期显著缩短（20.50个月 vs. 52.99个月，p<0.001），死亡风险显著增高（风险比：3.32，95%置信区间：1.71–6.43，p<0.001）。本研究结果揭示了LKB1与STING、β-连环蛋白的协同作用在NSCLC预后中的重要意义。

原文链接：

LKB1 Loss Correlates with STING Loss and, in Cooperation with β-Catenin Membranous Loss, Indicates Poor Prognosis in Patients with Operable Non-Small Cell Lung Cancer