Lagoudaki Eleni D, Koutsopoulos Anastasios V, Sfakianaki Maria, Papadaki Chara, Manikis Georgios C, Voutsina Alexandra, Trypaki Maria, Tsakalaki Eleftheria, Fiolitaki Georgia, Hatzidaki Dora, Yiachnakis Emmanuel, Koumaki Dimitra, Mavroudis Dimitrios, Tzardi Maria, Stathopoulos Efstathios N, Marias Kostas, Georgoulias Vassilis, Souglakos John
Department of Pathology, University General Hospital of Heraklion, 71500 Heraklion, Greece.
School of Medicine, University of Crete, 70013 Heraklion, Greece.
Cancers (Basel). 2024 May 10;16(10):1818. doi: 10.3390/cancers16101818.
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 BRAF mutations were evaluated by Sanger sequencing. Overall, loss of LKB1 protein expression was observed in 21% (51/248) patients and correlated significantly with histotype ( < 0.001), KRAS mutations ( < 0.001), KC status (concomitant KRAS mutation and p16 downregulation) ( < 0.001), STING loss ( < 0.001), and high CD24 expression ( < 0.001). STING loss also correlated significantly with loss of LKB1 expression in the metastatic setting both overall ( = 0.014) and in lung adenocarcinomas (LUACs) ( = 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 ( = 0.019) and in the metastatic setting ( = 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; < 0.001 as well as significantly greater risk of death (HR: 3.32, 95% c.i.: 1.71-6.43; <0.001). Our findings underscore the impact of the synergy of LKB1 with STING and β-catenin in NSCLC, in prognosis.
为了研究非小细胞肺癌（NSCLC）中LKB1表达缺失的发生率及其与预后相关的显著相关性和协同作用，我们分析了188例转移性和60例非转移性可手术的I-IIIA期NSCLC患者的手术标本，以评估LKB1和pAMPK蛋白在各种过程中的表达情况。研究因素包括抗肿瘤免疫反应调节因子STING和PD-L1；促血管生成、上皮-间质转化（EMT）和细胞周期靶点，以及与转移相关的（VEGFC、PDGFRα、PDGFRβ、p53、p16、细胞周期蛋白D1、ZEB1、CD24）靶点；以及细胞黏附（β-连环蛋白）分子。通过免疫组织化学评估蛋白表达水平；通过PCR评估LKB1和NEDD9的RNA水平，而通过桑格测序评估KRAS外显子2和BRAF突变。总体而言，21%（51/248）的患者存在LKB1蛋白表达缺失，且与组织学类型（<0.001）、KRAS突变（<0.001）、KC状态（KRAS突变与p16下调同时存在）（<0.001）、STING缺失（<0.001）以及高CD24表达（<0.001）显著相关。STING缺失在总体转移情况下（=0.014）以及在肺腺癌（LUACs）中（=0.005）也与LKB1表达缺失显著相关。此外，仅在LUACs中，LKB1缺失与β-连环蛋白膜表达缺乏或低表达显著相关，无论是否存在转移状态（=0.019）还是在转移情况下（=0.007）。LKB1缺失且β-连环蛋白膜表达不存在或低表达的肿瘤患者的中位总生存期显著较差，分别为20.50个月和52.99个月；<0.001，且死亡风险显著更高（HR：3.32，95%置信区间：1.71-6.43；<0.001）。我们的研究结果强调了LKB1与STING和β-连环蛋白的协同作用在NSCLC预后中的影响。
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