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Abstract：
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 BRAFV600E mutations 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：
探讨LKB1表达缺失在非小细胞肺癌（NSCLC）中的发生率和预后相关性及协同作用。我们分析了来自188例转移性和60例非转移性可手术I-IIIA期NSCLC患者的手术标本,以评估其与各种过程相关的LKB1和pAMPK蛋白的表达.研究的因素包括抗肿瘤免疫反应调节剂STING和PD-L1;促血管生成，EMT和细胞周期目标，以及与转移相关的(VEGFC，PDGFRα,PDGFRβ,p53，p16，细胞周期蛋白D1，ZEB1，CD24）靶标；和细胞粘附（β-连环蛋白）分子。通过免疫组织化学评估蛋白质表达水平；通过PCR评估LKB1和NEDD9的RNA水平，而KRAS外显子2和BRAFV600E突变通过Sanger测序进行评估。总的来说,在21％（51/248）的患者中观察到LKB1蛋白表达丢失，并且与组织型显着相关（p<0.001），KRAS突变（p<0.001），KC状态（伴随KRAS突变和p16下调）（p<0.001），STING损失（p<0.001），和高CD24表达(p<0.001)。STING丢失也与转移背景下的LKB1表达丢失显著相关(p=0.014)和肺腺癌(LUACs)(p=0.005)。此外,LKB1缺失与仅在LUACs中缺乏或低β-catenin膜表达显著相关，与转移状态（p=0.019）和转移情况（p=0.007）无关。出现LKB1丢失和伴随不存在或低β-catenin膜表达的肿瘤患者的中位总生存期明显低于20.50。52.99个月;p<0.001以及显著更大的死亡风险(HR:3.32,95%c.i.:1.71-6.43;p<0.001)。我们的发现强调了LKB1与STING和β-catenin在NSCLC中的协同作用的影响。在预后方面。
