The novel role and function of LINC01235 in metastasis of gastric cancer cells by inducing epithelial-mesenchymal transition

LncRNAs play a vital role in the tumorigenesis of gastric cancer (GC). This study determined that LINC01235 expression has greater fold changes by analyzing TCGA RNA-Seq data. The qRT-PCR assay confirmed that LINC01235 is significantly over-expressed in GC cells and tissues. Additionally, the overall survival analysis showed that patients with a higher LINC01235 expression had a poorer prognosis than those with a lower LINC01235 expression. Univariate Cox regression analysis indicated that high LINC01235 expression is positively correlated with poor prognosis. Moreover, LINC01235 was an independent poor prognostic marker for GC in multivariate Cox analysis. In vitro assays suggested that LINC01235 knockdown suppresses GC cell migration and invasion. GSEA revealed that high LINC01235 expression is strongly enriched in the EMT pathway. Western blotting results revealed that LINC01235 silencing decreases the expression of EMT-induced proteins. In conclusion, LINC01235 can promote GC cell metastasis via EMT and function as a prognostic biomarker.     

Cancer-associated fibroblast-derived SDF-1 induces epithelial-mesenchymal transition of lung adenocarcinoma via CXCR4/β-catenin/PPARδ signalling

Cancer-associated fibroblasts (CAFs) contribute to tumour epithelial-mesenchymal transition (EMT) via interaction with cancer cells. However, the molecular mechanisms underlying tumour-promoting EMT of CAFs in lung adenocarcinoma (ADC) remain unclear. Here, we observed that CAFs isolated from lung ADC promoted EMT via production of stromal cell-derived factor-1 (SDF-1) in conditioned medium (CM). CAF-derived SDF-1 enhanced invasiveness and EMT by upregulating CXCR4, β-catenin, and PPARδ, while downregulating these proteins reversed the effect. Furthermore, RNAi-mediated CXCR4 knockdown suppressed β-catenin and PPARδ expression, while β-catenin inhibition effectively downregulated PPARδ without affecting CXCR4; however, treatment with a PPARδ inhibitor did not inhibit CXCR4 or β-catenin expression. Additionally, pairwise analysis revealed that high expression of CXCR4, β-catenin, and PPARδ correlated positively with 75 human lung adenocarcinoma tissues, which was predictive of poor prognosis. Thus, targeting the CAF-derived, SDF-1-mediated CXCR4 β-catenin/ PPARδ cascade may serve as an effective targeted approach for lung cancer treatment.Subject terms: Cancer microenvironment, Non-small-cell lung cancer     

Sarcopenia and a 5-mRNA risk module as a combined factor to predict prognosis for patients with stomach adenocarcinoma

BackgroundSarcopenia is an important factor affecting the prognostic outcomes in adult cancer patients. Gastric cancer is considered an age-related disease and is one of the leading causes of global cancer mortality. We aimed to establish an effective age-related model at a molecular level to predict the prognosis of patients with gastric cancer.MethodsTCGA STAD (stomach adenocarcinoma) and NCBI GEO database were utilized in this study to explore the expression, clinical relevance and prognostic value of age-related mRNAs in stomach adenocarcinoma through an integrated bioinformatics analysis. WGCNA co-expression network, Univariate Cox regression analysis, LASSO regression and Multivariate Cox regression analysis were implemented to construct an age-related prognostic signature.ResultsAs a result, sarcopenia is not only an unfavorable factor for OS (overall survival) in patients with tumor of gastric (HR: 1.707, 95%CI: 1.437–2.026), but also increases the risk of postoperative complications in patients with gastric cancer (OR: 2.904, 95%CI: 2.150–3.922). A panel of 5 mRNAs (DCBLD1, DLC1, IGFBP1, RNASE1 and SPC24) were identified to dichotomize patients with significantly different OS and independently predicted the OS in TCGA STAD (HR = 3.044, 95%CI = 2.078–4.460, P < 0.001).ConclusionThe study provided novel insights to understand STAD at a molecular level and indicated that the 5 mRNAs might act as independent promising prognosis biomarkers for STAD. Sarcopenia and the 5-mRNA risk module as a combined factor to predict prognosis may play an important role in clinical diagnosis.     

HNRNPC可能成为肺腺癌独立的预后因子

为探讨RNA m⁶A甲基化调节因子在肺腺癌中的作用,从TCGA数据库下载肺腺癌患者的RNA表达数据和临床数据。通过limma软件包分析12种m⁶A调节剂的表达情况。使用Pheatmap、vioplot和corrplot软件包生成热图、小提琴图和表达相关图。采用Kaplan-Meier方法分别计算肺腺癌中12种RNA m⁶A调节因子的生存曲线。使用Cox回归和Kaplan-Meier方法分析TCGA肺腺癌患者的总体存活相关的临床病理学特征。最后用Kruskal(KS)检验和logistic回归分析临床病理学特征与HNRNPC表达的关系。 在肺腺癌的TCGA队列中,发现HNRNPC、WTAP、YTHDF3、FTO、ZC3H13、METTL14、METTL3、YTHDF1、YTHDF2这些基因是差异表达的。Kaplan-Meier生存分析显示,在这些差异表达的基因中仅仅HNRNPC和YTHDF2的表达与生存显著相关。然后,通过多因素Cox回归结果表明HNRNPC的表达在肺腺癌TCGA队列中是个独立危险因素。最后,HNRNPC在肺腺癌中的表达与临床分期(IV vs I, OR=3.692 308)和组织浸润(T2 vs T1, OR=1.776 471;T4 vs T1, OR=6.303 03)显著相关(所有p<0.05)。 结论认为HNRNPC可能作为肺腺癌的独立的预后因子。     

Low expression of ITIH5 in adenocarcinoma of the lung is associated with unfavorable patients' outcome

Inter-α-trypsin inhibitor heavy chain 5 (ITIH5) is supposed to be involved in extracellular matrix stability and thus may play a key role in the inhibition of tumor progression. The current study is the first to analyze in depth ITIH5 expression and DNA methylation, as well as its potential clinical impact in non-small-cell lung carcinoma (NSCLC). We examined ITIH5 mRNA expression in tumor and adjacent normal lung tissue specimens of NSCLC patients. In addition, methylation frequency of the ITIH5 promoter was investigated using methylation-specific PCR and pyrosequencing. Significance of our data was validated by independent data sets from The Cancer Genome Atlas and the Kaplan-Meier Plotter platform. Furthermore, ITIH5 protein expression was evaluated by immunohistochemistry utilizing a tissue microarray with 385 distinct lung tissue samples. Based on our tissue collections, ITIH5 mRNA expression was significantly decreased in NSCLC compared to normal lung tissue in line with an increased methylation frequency in lung cancer tissue. Independent TCGA data confirmed significant expression loss of ITIH5 in lung cancer concordant with ITIH5 promoter hypermethylation in NSCLC. Of interest, low ITIH5 mRNA expression was particularly found in the magnoid and squamoid ADC expression subtype, concordant with an unfavorable patients'' outcome in squamoid as well as tobacco smoking ADC patients. In conclusion, ITIH5 may be a novel putative tumor suppressor gene in NSCLC with a potential molecular significance in the squamoid ADC subtype and further clinical impact for risk stratification of adenocarcinoma patients. In addition, ITIH5 may serve as a novel biomarker for prognosis of tobacco smoking ADC patients.     

The Function of SARI in Modulating Epithelial-Mesenchymal Transition and Lung Adenocarcinoma Metastasis

The SARI (suppressor of AP-1, regulated by IFN) gene, which is also called BATF2, is associated with the risk of several kinds of cancer, and loss of SARI expression is frequently detected in aggressive and metastatic cancer. However, the functional role of SARI in lung adenocarcinoma remains unknown. We have shown that loss of SARI expression initiates epithelial-mesenchymal transition (EMT), which is visualized by repression of E-cadherin and up-regulation of vimentin in lung adenocarcinoma cell lines and in clinical lung adenocarcinoma specimens. Using a human lung xenograft-mouse model, we observed that knocking down endogenous SARI in human carcinoma cells leads to the development of multiple lymph node metastases. Moreover, we showed that SARI functions as a critical protein in regulating EMT by modulating the (GSK)-3β-β-catenin signaling pathway. These results demonstrate the mechanism of SARI function in EMT and suggest that assessment of SARI may serve as a prognostic biomarker and potential therapeutic target for lung adenocarcinoma metastasis.     

Overexpression of geranylgeranyl diphosphate synthase contributes to tumour metastasis and correlates with poor prognosis of lung adenocarcinoma

This study aimed to evaluate the biological role of geranylgeranyl diphosphate synthase (GGPPS) in the progression of lung adenocarcinoma. GGPPS expression was detected in lung adenocarcinoma tissues by qRT‐PCR, tissue microarray (TMA) and western blotting. The relationships between GGPPS expression and the clinicopathological characteristics and prognosis of lung adenocarcinoma patients were assessed. GGPPS was down‐regulated in SPCA‐1, PC9 and A549 cells using siRNA and up‐regulated in A549 cells using an adenoviral vector. The biological roles of GGPPS in cell proliferation, apoptosis, migration and invasion were determined by MTT and colony formation assays, flow cytometry, and transwell and wound‐healing assays, respectively. In addition, the regulatory roles of GGPPS on the expression of several epithelial‐mesenchymal transition (EMT) markers were determined. Furthermore, the Rac1/Cdc42 prenylation was detected after knockdown of GGPPS in SPCA‐1 and PC9 cells. GGPPS expression was significantly increased in lung adenocarcinoma tissues compared to that in adjacent normal tissues. Overexpression of GGPPS was correlated with large tumours, high TNM stage, lymph node metastasis and poor prognosis in patients. Knockdown of GGPPS inhibited the migration and invasion of lung adenocarcinoma cells, but did not affect cell proliferation and apoptosis. Meanwhile, GGPPS inhibition significantly increased the expression of E‐cadherin and reduced the expression of N‐cadherin and vimentin in lung adenocarcinoma cells. In addition, the Rac1/Cdc42 geranylgeranylation was reduced by GGPPS knockdown. Overexpression of GGPPS correlates with poor prognosis of lung adenocarcinoma and contributes to metastasis through regulating EMT.     

苹果酸-天冬氨酸穿梭关键酶和肺腺癌临床特征的相关性

目的:探讨苹果酸-天冬氨酸穿梭途径中的关键酶和肺腺癌临床特征的相关性。方法:首先从GEO数据库、TCGA平台中获取肺腺癌的转录组数据和相应的临床信息,通过非参数检验分析苹果酸脱氢酶1/2和天冬氨酸氨基转移酶1/2这四种关键酶在肿瘤组织和正常组织之间的表达差别,再进一步分析其和肺腺癌患者总生存期、人口学特征、TNM参数以及肿瘤恶性生物学标志物之间的关系。结果:肺腺癌中苹果酸脱氢酶1/2和天冬氨酸氨基转移酶1/2均呈高表达;天冬氨酸氨基转移酶2 (Glutamic-oxaloacetic transaminase 2,GOT2)和肺腺癌的生存概率有关,高表达GOT2的病人往往具有较短的总生存期;GOT2的表达和肺腺癌的人口学特征、TNM参数、临床分期均无明显统计学关联,与肿瘤恶性标志物PCNA呈显著正相关(r=0.2,P0.05)。结论:肺腺癌组织中苹果酸-天冬氨酸穿梭途径中关键酶GOT2呈高表达,并可能促进肺腺癌的发生和恶性进展。     

Ginkgetin derived from Ginkgo biloba leaves enhances the therapeutic effect of cisplatin via ferroptosis-mediated disruption of the Nrf2/HO-1 axis in EGFR wild-type non-small-cell lung cancer

BackgroundCisplatin (DDP) is the first-in-class drug for advanced and non-targetable non-small-cell lung cancer (NSCLC). A recent study indicated that DDP could slightly induce non-apoptotic cell death ferroptosis, and the cytotoxicity was promoted by ferroptosis inducer. The agents enhancing the ferroptosis may therefore increase the anticancer effect of DDP. Several lines of evidence supporting the use of phytochemicals in NSCLC therapy. Ginkgetin, a bioflavonoid derived from Ginkgo biloba leaves, showed anticancer effects on NSCLC by triggering autophagy. Ferroptosis can be triggered by autophagy, which regulates redox homeostasis. Thus, we aimed to elucidate the possible role of ferroptosis involved in the synergistic effect of ginkgetin and DDP in cancer therapy.MethodsThe promotion of DDP-induced anticancer effects by ginkgetin was examined via a cytotoxicity assay and western blot. Ferroptosis triggered by ginkgetin in DDP-treated NSCLC was observed via a lipid peroxidation assay, a labile iron pool assay, western blot, and qPCR. With ferroptosis blocking, the contribution of ferroptosis to ginkgetin + DDP-induced cytotoxicity, the Nrf2/HO-1 axis, and apoptosis were determined via a luciferase assay, immunostaining, chromatin immunoprecipitation (CHIP), and flow cytometry. The role of ferroptosis in ginkgetin + DDP-treated NSCLC cells was illustrated by the application of ferroptosis inhibitors, which was further demonstrated in a xenograft nude mouse model.ResultsGinkgetin synergized with DDP to increase cytotoxicity in NSCLC cells, which was concomitant with increased labile iron pool and lipid peroxidation. Both these processes were key characteristics of ferroptosis. The induction of ferroptosis mediated by ginkgetin was further confirmed by the decreased expression of SLC7A11 and GPX4, and a decreased GSH/GSSG ratio. Simultaneously, ginkgetin disrupted redox hemostasis in DDP-treated cells, as demonstrated by the enhanced ROS formation and inactivation of the Nrf2/HO-1 axis. Ginkgetin also enhanced DDP-induced mitochondrial membrane potential (MMP) loss and apoptosis in cultured NSCLC cells. Furthermore, blocking ferroptosis reversed the ginkgetin-induced inactivation of Nrf2/HO-1 as well as the elevation of ROS formation, MMP loss, and apoptosis in DDP-treated NSCLC cells.ConclusionThis study is the first to report that ginkgetin derived from Ginkgo biloba leaves promotes DDP-induced anticancer effects, which can be due to the induction of ferroptosis.     

PKM2促进肿瘤发展的作用机制研究

为了分析丙酮酸激酶M2型（pyruvate kinase M2,PKM2）在不同肿瘤中的表达情况及其与肿瘤患者临床预后的关系,并探索PKM2对肿瘤细胞增殖和迁移的影响及其作用机制,用TCGA数据库和免疫印迹分析了33种肿瘤中PKM2的表达情况,探索了PKM2与不同肿瘤患者预后的关系。在肺癌细胞系中过表达PKM2,利用CCK8和Transwell方法分析PKM2对肺癌细胞增殖和迁移能力的影响。利用免疫印迹检测不同肿瘤细胞中过表达和敲低PKM2对热休克蛋白90α（Hsp90α）分泌的影响以及上皮-间质转化（epithelial-mesenchgmal transition,EMT）相关蛋白的变化。TCGA数据分析显示,PKM2在包括乳腺癌、肺癌等15种肿瘤中高表达,且9种肿瘤中PKM2的高表达与肿瘤的预后具有显著相关性。在肺癌细胞中过表达PKM2后,肺癌细胞的增殖和迁移能力显著增强。过表达PKM2能够显著增加乳腺癌和肺癌中Hsp90α的分泌。敲低PKM2能够抑制N-钙黏蛋白（N-cadhesion）和波形蛋白（Vimentin）的表达,促进E-钙黏蛋白（E-cadhesion）的表达。研究结果表明,PKM2在多种肿瘤中高表达且与肿瘤预后显著相关,能够通过影响Hsp90α的分泌以及上皮-间质转化相关蛋白的表达从而促进肿瘤的进展。PKM2有望成为潜在的广谱肿瘤标志物和治疗靶点。     

Paracrine IL-6 signaling mediates the effects of pancreatic stellate cells on epithelial-mesenchymal transition via Stat3/Nrf2 pathway in pancreatic cancer cells

BackgroundWe previously showed that pancreatic stellate cells (PSC) secreted interleukin (IL)-6 and promoted pancreatic ductal adenocarcinoma (PDAC) cell proliferation via nuclear factor erythroid 2 (Nrf2)-mediated metabolic reprogramming. Epithelial-mesenchymal transition (EMT) is a key process for the metastatic cascade. To study the mechanism of PDAC progression to metastasis, we investigated the role of PSC-secreted IL-6 in activating EMT and the involvement of Nrf2 in this process.MethodsGene expression of IL-6 and IL-6Rα in PSC and PDAC cells was measured with qRT-PCR. The role of PSC-secreted IL-6, JAK/Stat3 signaling, and Nrf2 mediation on EMT-related genes expression was also examined with qRT-PCR. EMT phenotypes were assessed with morphological change, wound healing, migration, and invasion.ResultsPSC expressed higher mRNA levels of IL-6 but lower IL-6Rα compared to PDAC cells. Neutralizing IL-6 in PSC secretion reduced mesenchymal-like morphology, migration and invasion capacity, and mesenchymal-like gene expression of N-cadherin, vimentin, fibronectin, collagen I, Sip1, Snail, Slug, and Twist2. Inhibition of JAK/Stat3 signaling induced by IL-6 repressed EMT and Nrf2 gene expression. Induction of Nrf2 activity by tert-butylhydroquinone (tBHQ) increased both EMT phenotypes and gene expression (N-cadherin, fibronectin, Twist2, Snail, and Slug) repressed by IL-6 neutralizing antibody. Simultaneous inhibition of Nrf2 expression with siRNA and Stat3 signaling further repressed EMT gene expression, indicating that Stat3/Nrf2 pathway mediates EMT induced by IL-6.ConclusionsIL-6 from PSC promotes EMT in PDAC cells via Stat3/Nrf2 pathway.General significanceTargeting Stat3/Nrf2 pathway activated by PSC-secreted IL-6 may provide a novel therapeutic option to improve the prognosis of PDAC.     

A comprehensive study of construction and analysis of competitive endogenous RNA networks in lung adenocarcinoma

BackgroundLong noncoding RNAs (lncRNAs) have gain increasing attention in lung adenocarcinoma. In this study, we aimed at constructing and analyzing the lncRNAs and the related proteins based competitive endogenous RNA (ceRNA) network.MethodsRNA expression data of lung adenocarcinoma were extracted from the TCGA database. Differentially expressed (DE) lncRNAs, messenger RNAs (mRNAs) and microRNAs (miRNAs) were identified and then a DElncRNA-DEmiRNA-DEmRNA ceRNA network was constructed for lung adenocarcinoma. We also analyzed the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment of the DEgenes. Kaplan-Meier survival curves were also been further utilized for exploring the prognostic factors.ResultsAfter compared and calculated lncRNA, mRNA and miRNA expression profiles between lung adenocarcinoma and normal samples, 1709 differential expressed lncRNAs, 2554 differential expressed mRNAs and 116 differential expressed miRNAs were finally identified. Afterwards, a lncRNA mediated ceRNA network was constructed, according to the interactions among 544 pairs of DElncRNA-DEmiRNA relationships and 47 pairs of DEmiRNA-DEmRNA relationships. As for the survival analyses, we found 10 DElncRNAs, 25 DEmRNAs and 7 miRNAs have statistically prognostic significance for overall survival, respectively.ConclusionsThis study provides meaningful information for deeper understanding the underlying molecular mechanism of lung adenocarcinoma and for evaluating prognosis, which could monitor recurrence, guide clinical treatment drugs and subsequent related researches.     

The calcium pump PMCA4 prevents epithelial-mesenchymal transition by inhibiting NFATc1-ZEB1 pathway in gastric cancer

Epithelial-mesenchymal transition (EMT) is considered as the key mechanism involved in cancer metastasis. Several studies showed that various cell membrane calcium channels play different roles in cancer metastasis. In the present study, the potential role of ATPase plasma membrane Ca²⁺ transporting 4 (PMCA4) in regulating EMT in gastric cancer (GC) was investigated. GC patients who underwent radical surgery were enrolled in this study. In vitro human GC cell lines MKN45 and NCI-N87 were used, and MKN45 cells were injected in nude mice to evaluate tumor development. Our results showed that low PMCA4 expression was associated with advanced TNM stage and poor prognosis in GC patients. Knockdown of PMCA4 suppressed E-cadherin, grainyhead like 2 (GRHL2) and ovo-like 1 (OVOL1) expression, up-regulated vimentin expression, increased migration and invasion ability, and promoted the resistance to cytotoxic drug. Furthermore, GC cells displayed an elongated fibroblastoid morphology when PMCA4 was knockdown. PMCA4 overexpression resulted in an up-regulated E-cadherin expression and decreased migration and invasion ability. In vivo metastasis assay showed that PMCA4 overexpression resulted in a decreased incidence of lung metastasis. PMCA4 inhibition increased ZEB1 expression and nuclear accumulation of nuclear factor of activated T-cell isoform c1 (NFATc1). EMT induced by PMCA4 inhibition could be prevented by the knockdown of NFATc1 or ZEB1. In addition, cyclosporine A prevented EMT induced by PMCA4 inhibition by suppressing the NFATc1-ZEB1 pathway. Our data identified a novel mechanism in the regulation of EMT in GC, and provided a novel target in the treatment of EMT subtype in GC.     

The high expression of miR-31 in lung adenocarcinoma inhibits the malignancy of lung adenocarcinoma tumor stem cells

Therapies for lung adenocarcinoma (LUAD) are mainly limited by drug resistance, metastasis or recurrence related to cancer stem cells (CSCs) with high proliferation and self-renewing. This research validated that miR-31 was over-expressed in LUAD by the analysis of generous clinical samples data. And the results of clinical data analysis showed that high expression of miR-31 was more common in patients with worse prognosis. The genes differentially expressed in LUAD tissues compared with normal tissues and A549CD133⁺ cells (LUAD CSCs) compared with A549 cells were separately screened from Gene Expression Profiling Interactive Analysis and GEO datasets. The target genes that may play a role in the regulation of lung adenocarcinoma was screened by comparison between the differential genes and the target genes of miR-31. The functional enrichment analysis of GO Biological Processes showed that the expression of target genes related to cell proliferation was increased, while the expression of target genes related to cell invasion and metastasis was decreased in LUAD tissues and A549CD133⁺ cells. The results suggested that miR-31 may have a significant inhibitory effect on the differentiation, invasion, metastasis and adhesion of LUAD CSCs, which was verified in vivo and in vitro experiments. Knock down of miR-31 accelerated xenograft tumor growth and liver metastasis in vivo. Likewise, the carcinogenicity, invasion and metastasis of A549CD133⁺ CSCs were promoted after miR-31 knockdown. The study validated that miR-31 was up regulated in LUAD and its expression may affect the survival time of patients with lung adenocarcinoma, which indicated that miR-31 may have potential value for diagnosis and prognosis of LUAD. However, the inhibitory effect of miR-31 on tumorigenesis, invasion and metastasis of lung adenocarcinoma CSCs suggested its complexity in the regulation of lung adenocarcinoma, which may be related to its extensive regulation of various target genes.     

结合自噬相关基因表达谱和临床因素的肺腺癌预后预测模型

对肺腺癌自噬相关基因进行生物信息学分析,结合多基因预后标志和临床参数构建能够预测肺腺癌患者预后的模型。首先,对TCGA肺腺癌数据中的938个自噬相关基因进行差异分析,获得了82个差异自噬相关基因,使用单因素Cox比例风险回归模型从差异自噬相关基因中筛选出候选基因,通过 lasso回归进一步筛选出预后相关基因,分别是ARNTL2、NAPSA、ATG9B、CAPN12、MAP1LC3C和KRT81。通过多因素Cox回归分析以构建风险评分模型,根据最优cutoff值将患者分为高低风险组,生存曲线显示高低风险组之间生存差异显著,ROC曲线显示风险评分的预测能力良好,并在内、外验证集中得到验证。同时对传统的临床因素进行单因素和多因素Cox回归分析,结果显示Stage、复发和风险评分能够独立预测预后,结合这三个独立的预后参数以构建列线图模型,使用一致性指数、校准曲线评估列线图的预测能力,结果显示预测结果与实际结果之间具有良好的一致性。通过与Stage和风险评分的比较发现,列线图的预测能力表现最佳。基于肺腺癌相关的自噬基因和临床参数构建了一个列线图模型来预测肺腺癌患者的预后生存,这可能为临床医生提供了一种可靠的预后评估工具。     

Clinical significance of ALDH1A1 expression and its association with E-cadherin and N-cadherin in resected large cell neuroendocrine carcinoma

BackgroundThe roles of cancer stem cells (CSCs) and epithelial-mesenchymal transition (EMT) in solid tumors are well established. However, the interaction between CSCs and EMT in pulmonary large cell neuroendocrine carcinoma (LCNEC) remains unknown. The aim of this study was to investigate the expression and clinical significance of a CSC marker (ALDH1A1) and its correlation with Epithelial-like phenotype marker (E-cadherin) and Mesenchymal-like phenotype marker (N-cadherin) in LCNEC patients.MethodsImmunohistochemistry (IHC) for ALDH1A1, E-cadherin and N-cadherin expression was conducted on tissue microarrays made from 79 resected LCNEC patient samples. ALDH1A1 protein expression was evaluated by the IHC score, and its correlations with the expression of E-cadherin, N-cadherin and clinicopathological features were determined based on IHC data. Survival analyses were also performed.ResultsALDH1A1 was positively expressed in 75.9% (60/79 cases) of LCNEC patients. No significant difference in clinicopathological variables was observed between the ALDH1A1-negative and ALDH1A1-positive groups. However, ALDH1A1 expression was positively correlated with E-cadherin (Spearman's rho = 0.229, p-value = 0.007), which represents the epithelial-like phenotype, but not with N-cadherin. Patients with expression of ALDH1A1 had significantly longer disease-free survival (DFS) and overall survival (OS) than those who were ALDH1A1 negative (median DFS: 52 vs 12 months, p = 0.028; median OS: not reached; p = 0.027). Multivariate analysis showed that ALDH1A1 was an independent favorable prognostic factor for DFS (p = 0.032, HR: 0.438, 95% CI: 0.206–0.932) and OS (p = 0.025, HR: 0.279, 95% CI: 0.091–0.852) in LCNEC patients.ConclusionThis study suggests that ALDH1A1 can act as a favorable independent prognostic factor for LCNEC, which related to the epithelioid phenotype in EMT, and its internal mechanism needs further study.