Potential Role of S-Palmitoylation in Cancer Stem Cells of Lung Adenocarcinoma

S-palmitoylation, catalyzed by a family of 23 zinc finger Asp-His-His-Cys (DHHC) domain-containing (ZDHHC) protein acyltransferases localized on the cell membrane. However, stemness genes modulated by ZDHHCs in lung adenocarcinoma (LUAD) remain to be defined. Previously, we have constructed a network of cancer stem cell genes, including INCENP, based on mRNA stemness indices (mRNAsi) of LUAD. INCENP has the function of a chromosomal passenger complex locating to centromeres, which is performed by the conserved region of its N-terminal domain. INCENP protein with a deletion of the first non-conserved 26 amino acid sequence failed to target centromeres. However, the exact function of the deleted sequence has not been elucidated. To identify novel cancer stem cell-relevant palmitoylated proteins and responsible ZDHHC enzymes in LUAD, we analyzed multi-omics data obtained from the database of The Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO), Clinical Proteomic Tumor Analysis Consortium (CPTAC), and the Human Protein Atlas (HPA). ZDHHC5 is distinguished from the ZDHHC family for being up-regulated in mRNA and protein levels and associated with malignant prognosis. ZDHHC5 was positively associated with INCENP, and the correlation score increased with LUAD stages. CSS-Palm results showed Cys15 was the S-palmitoylation site of INCENP. Interestingly, Cys15 locates in the 1–26 aa sequence of INCENP, and is a conserved site across species. As INCENP is a nuclear protein, we predicted that the nuclear localization signal of ZDHHC5 was specific to the importin αβ pathway, and the result of immunofluorescence proves that ZDHHC5 is located in the nucleoplasm, in addition to the plasma membrane. Therefore, our study indicates the S-palmitoylation of INCENP mediated by ZDHHC5 as a potential mechanism of S-palmitoylation to modulate CSCs in LUAD.

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DNASE1L3 as a Novel Diagnostic and Prognostic Biomarker for Lung Adenocarcinoma Based on Data Mining

Frontiers in Genetics ◽

10.3389/fgene.2021.699242 ◽

2021 ◽

Vol 12 ◽

Author(s):

Jianlin Chen ◽

Junping Ding ◽

Wenjie Huang ◽

Lin Sun ◽

Jinping Chen ◽

...

Keyword(s):

Lung Adenocarcinoma ◽

Prognostic Biomarker ◽

Function Analysis ◽

Mrna Level ◽

Gene Expression Omnibus ◽

The Cancer Genome Atlas ◽

Immune Checkpoints ◽

Diagnostic Efficiency ◽

Protein Levels ◽

Normal Tissues

Previous researches have highlighted that low-expressing deoxyribonuclease1-like 3 (DNASE1L3) may play a role as a potential prognostic biomarker in several cancers. However, the diagnosis and prognosis roles of DNASE1L3 gene in lung adenocarcinoma (LUAD) remain largely unknown. This research aimed to explore the diagnosis value, prognostic value, and potential oncogenic roles of DNASE1L3 in LUAD. We performed bioinformatics analysis on LUAD datasets downloaded from TCGA (The Cancer Genome Atlas) and GEO (Gene Expression Omnibus), and jointly analyzed with various online databases. We found that both the mRNA and protein levels of DNASE1L3 in patients with LUAD were noticeably lower than that in normal tissues. Low DNASE1L3 expression was significantly associated with higher pathological stages, T stages, and poor prognosis in LUAD cohorts. Multivariate analysis revealed that DNASE1L3 was an independent factor affecting overall survival (HR = 0.680, p = 0.027). Moreover, decreased DNASE1L3 showed strong diagnostic efficiency for LUAD. Results indicated that the mRNA level of DNASE1L3 was positively correlated with the infiltration of various immune cells, immune checkpoints in LUAD, especially with some m6A methylation regulators. In addition, enrichment function analysis revealed that the co-expressed genes may participate in the process of intercellular signal transduction and transmission. GSEA indicated that DNASE1L3 was positively related to G protein-coupled receptor ligand biding (NES = 1.738; P adjust = 0.044; FDR = 0.033) and G alpha (i) signaling events (NES = 1.635; P adjust = 0.044; FDR = 0.033). Our results demonstrated that decreased DNASE1L3 may serve as a novel diagnostic and prognostic biomarker associating with immune infiltrates in lung adenocarcinoma.

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mRNAsi Index: Machine Learning in Mining Lung Adenocarcinoma Stem Cell Biomarkers

Genes ◽

10.3390/genes11030257 ◽

2020 ◽

Vol 11 (3) ◽

pp. 257 ◽

Cited By ~ 6

Author(s):

Yitong Zhang ◽

Joseph Ta-Chien Tseng ◽

I-Chia Lien ◽

Fenglan Li ◽

Wei Wu ◽

...

Keyword(s):

Gene Expression ◽

Stem Cell ◽

Lung Adenocarcinoma ◽

Tumor Necrosis Factor Receptor ◽

Enrichment Analysis ◽

Gene Expression Omnibus ◽

The Cancer Genome Atlas ◽

Clinical Stages ◽

Key Genes ◽

Geo Database

Cancer stem cells (CSCs), characterized by self-renewal and unlimited proliferation, lead to therapeutic resistance in lung cancer. In this study, we aimed to investigate the expressions of stem cell-related genes in lung adenocarcinoma (LUAD). The stemness index based on mRNA expression (mRNAsi) was utilized to analyze LUAD cases in the Cancer Genome Atlas (TCGA). First, mRNAsi was analyzed with differential expressions, survival analysis, clinical stages, and gender in LUADs. Then, the weighted gene co-expression network analysis was performed to discover modules of stemness and key genes. The interplay among the key genes was explored at the transcription and protein levels. The enrichment analysis was performed to annotate the function and pathways of the key genes. The expression levels of key genes were validated in a pan-cancer scale. The pathological stage associated gene expression level and survival probability were also validated. The Gene Expression Omnibus (GEO) database was additionally used for validation. The mRNAsi was significantly upregulated in cancer cases. In general, the mRNAsi score increases according to clinical stages and differs in gender significantly. Lower mRNAsi groups had a better overall survival in major LUADs, within five years. The distinguished modules and key genes were selected according to the correlations to the mRNAsi. Thirteen key genes (CCNB1, BUB1, BUB1B, CDC20, PLK1, TTK, CDC45, ESPL1, CCNA2, MCM6, ORC1, MCM2, and CHEK1) were enriched from the cell cycle Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway, relating to cell proliferation Gene Ontology (GO) terms, as well. Eight of the thirteen genes have been reported to be associated with the CSC characteristics. However, all of them have been previously ignored in LUADs. Their expression increased according to the pathological stages of LUAD, and these genes were clearly upregulated in pan-cancers. In the GEO database, only the tumor necrosis factor receptor associated factor-interacting protein (TRAIP) from the blue module was matched with the stemness microarray data. These key genes were found to have strong correlations as a whole, and could be used as therapeutic targets in the treatment of LUAD, by inhibiting the stemness features.

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Downregulated SPINK4 is associated with poor survival in colorectal cancer

BMC Cancer ◽

10.1186/s12885-019-6484-5 ◽

2019 ◽

Vol 19 (1) ◽

Author(s):

Xiaojie Wang ◽

Qian Yu ◽

Waleed M. Ghareeb ◽

Yiyi Zhang ◽

Xingrong Lu ◽

...

Keyword(s):

Colorectal Cancer ◽

Gene Expression Omnibus ◽

The Cancer Genome Atlas ◽

Expression Data ◽

Poor Survival ◽

Protein Levels ◽

Normal Tissues ◽

Human Protein Atlas ◽

Cancer Genome Atlas ◽

Independent Indicator

Abstract Background SPINK4 is known as a gastrointestinal peptide in the gastrointestinal tract and is abundantly expressed in human goblet cells. The clinical significance of SPINK4 in colorectal cancer (CRC) is largely unknown. Methods We retrieved the expression data of 1168 CRC patients from 3 Gene Expression Omnibus (GEO) datasets (GSE24551, GSE39582, GSE32323) and The Cancer Genome Atlas (TCGA) to compare the expression level of SPINK4 between CRC tissues and normal colorectal tissues and to evaluate its value in predicting the survival of CRC patients. At the protein level, these results were further confirmed by data mining in the Human Protein Atlas and by immunohistochemical staining of samples from 81 CRC cases in our own center. Results SPINK4 expression was downregulated in CRC compared with that in normal tissues, and decreased SPINK4 expression at both the mRNA and protein levels was associated with poor prognosis in CRC patients from all 3 GEO datasets, the TCGA database and our cohort. Additionally, lower SPINK4 expression was significantly related to higher TNM stage. Moreover, in multivariate regression, SPINK4 was confirmed as an independent indicator of poor survival in CRC patients in all databases and in our own cohort. Conclusions We concluded that reduced expression of SPINK4 relates to poor survival in CRC, functioning as a novel indicator.

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Effects of Salinomycin on Cancer Stem Cell in Human Lung Adenocarcinoma A549 Cells

Medicinal Chemistry ◽

10.2174/157340611794859307 ◽

2011 ◽

Vol 7 (2) ◽

pp. 106-111 ◽

Cited By ~ 56

Author(s):

Yi Wang

Keyword(s):

Stem Cell ◽

Cancer Stem Cell ◽

Lung Adenocarcinoma ◽

Human Lung ◽

A549 Cells ◽

Human Lung Adenocarcinoma ◽

Lung Adenocarcinoma A549

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Functions and clinical significance of KLRG1 in the development of lung adenocarcinoma and immunotherapy

BMC Cancer ◽

10.1186/s12885-021-08510-3 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Xiaodong Yang ◽

Yuexin Zheng ◽

Zhihai Han ◽

Xiliang Zhang

Keyword(s):

Gene Expression ◽

Overall Survival ◽

Lung Adenocarcinoma ◽

Molecular Mechanisms ◽

Killer Cell ◽

Gene Expression Omnibus ◽

The Cancer Genome Atlas ◽

Normal Lung ◽

Using Data ◽

Low Expression

Abstract Background As a marker of differentiation, Killer cell lectin like receptor G1 (KLRG1) plays an inhibitory role in human NK cells and T cells. However, its clinical role remains inexplicit. This work intended to investigate the predictive ability of KLRG1 on the efficacy of immune-checkpoint inhibitor in the treatment of lung adenocarcinoma (LUAD), as well as contribute to the possible molecular mechanisms of KLRG1 on LUAD development. Methods Using data from the Gene Expression Omnibus, the Cancer Genome Atlas and the Genotype-Tissue Expression, we compared the expression of KLRG1 and its related genes Bruton tyrosine kinase (BTK), C-C motif chemokine receptor 2 (CCR2), Scm polycomb group protein like 4 (SCML4) in LUAD and normal lung tissues. We also established stable LUAD cell lines with KLRG1 gene knockdown and investigated the effect of KLRG1 knockdown on tumor cell proliferation. We further studied the prognostic value of the four factors in terms of overall survival (OS) in LUAD. Using data from the Gene Expression Omnibus, we further investigated the expression of KLRG1 in the patients with different responses after immunotherapy. Results The expression of KLRG1, BTK, CCR2 and SCML4 was significantly downregulated in LUAD tissues compared to normal controls. Knockdown of KLRG1 promoted the proliferation of A549 and H1299 tumor cells. And low expression of these four factors was associated with unfavorable overall survival in patients with LUAD. Furthermore, low expression of KLRG1 also correlated with poor responses to immunotherapy in LUAD patients. Conclusion Based on these findings, we inferred that KLRG1 had significant correlation with immunotherapy response. Meanwhile, KLRG1, BTK, CCR2 and SCML4 might serve as valuable prognostic biomarkers in LUAD.

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Development and validation of a 13-m6a related lncRNA prognostic signature for lung adenocarcinoma

10.21203/rs.3.rs-771653/v1 ◽

2021 ◽

Author(s):

Pingfan Wu ◽

Xiaowen Zhao ◽

Ling Xue ◽

Xiaojing Yang ◽

Yuxiang Shi ◽

...

Keyword(s):

Gene Expression ◽

Lung Adenocarcinoma ◽

Treatment Strategies ◽

Risk Groups ◽

Gene Expression Omnibus ◽

High Risk Group ◽

The Cancer Genome Atlas ◽

Prognostic Signature ◽

P53 Signaling ◽

Selection Operator

Abstract Considerable evidence suggests that N6-methyladenosine (m6A) is involved in the regulation of long non-coding RNA (lncRNA), whichparticipates in the occurrence, development and prognosis of tumorscancerBut the relationship between m6A regulators-related lncRNA (mRlncRNA) and lung adenocarcinoma (LUAD) remains unclear. This study aims to determine a feature based on mRlncRNA for prognostic evaluation of LUAD patients. By integrating the gene expression data of LUAD and normal samples from the Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) database, the m6A gene and mRlncRNA with imbalanced expression were screened out. Then we used the least absolute shrinkage and selection operator (LASSO) to obtain the 13-lncRNA prognostic signature in the TCGA training cohort. Patients were divided into two risk groups based on the risk score of lncRNAs characteristics, and their overall survival (OS) was significantly different. The predictive power of this signature was verified in TCGA testing cohort and entire TCGA cohort. These landmark lncRNAs were involved in several biologiocal processes and pathways related to cell cycle, DNA replication, P53 signaling pathway and mismatch repair. Besides, the high-risk group was low-response to cisplatin, while high-response to mitomycin, docetaxel and immunotherapy. In conclusion, we identified a 13-mRlncRNA model associated with prognosis and treatment sensitivity in LUAD, which may provide clues about the influence of m6A on lncRNA in LUAD and promote the further improvement of LUAD individualized treatment strategies.

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Increased GOLM1 Expression Independently Predicts Unfavorable Overall Survival and Recurrence-Free Survival in Lung Adenocarcinoma

Cancer Control ◽

10.1177/1073274818778001 ◽

2018 ◽

Vol 25 (1) ◽

pp. 107327481877800 ◽

Cited By ~ 4

Author(s):

Xi Liu ◽

Lei Chen ◽

Tao Zhang

Keyword(s):

Overall Survival ◽

Lung Adenocarcinoma ◽

Survival Data ◽

Methylation Status ◽

Lung Squamous Cell Carcinoma ◽

Prognostic Indicator ◽

Gene Expression Omnibus ◽

The Cancer Genome Atlas ◽

Recurrence Free Survival ◽

Free Survival

Golgi membrane protein 1 (GOLM1) is a transmembrane glycoprotein of the Golgi cisternae, which is implicated in carcinogenesis of multiple types of cancer. In this study, using data from the Gene Expression Omnibus and The Cancer Genome Atlas, we compared the expression of GOLM1 in lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC) and studied its prognostic value in terms of overall survival (OS) and recurrence-free survival (RFS) in these 2 subtypes of non-small cell lung cancer (NSCLC). Results showed that GOLM1 was significantly upregulated in both LUAD and LUSC tissues compared to the normal controls. However, GOLM1 expression was higher in LUAD tissues than in LUSC tissues. More importantly, using over 10 years’ survival data from 502 patients with LUAD and 494 patients with LUSC, we found that high GOLM1 expression was associated with unfavorable OS and RFS in patients with LUAD, but not in patients with LUSC. The following univariate and multivariate analyses confirmed that increased GOLM1 expression was an independent prognostic indicator of poor OS (hazard ratio [HR]: 1.30, 95% confidence interval [CI]: 1.11-1.54, P = .002) and RFS (HR: 1.37, 95% CI: 1.14-1.64, P = .001) in patients with LUAD. Of 511 cases with LUAD, 248 (48.5%) had heterozygous loss (−1), while 28 (5.5%) of 511 cases with LUAD had low-level copy gain (+1). In addition, we also found that the methylation status of 1 CpG site (chr9: 88,694,942-88,694,944) showed a weak negative correlation with GOLM1 expression (Pearson r = −0.25). Based on these findings, we infer that GOLM1 might serve as a valuable prognostic biomarker in LUAD, but not in LUSC. In addition, DNA copy number alterations and methylation might be 2 important mechanisms of dysregulated GOLM1 in LUAD.

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Elevated expression of ASF1B correlates with poor prognosis in human lung adenocarcinoma

Personalized Medicine ◽

10.2217/pme-2020-0112 ◽

2021 ◽

Vol 18 (2) ◽

pp. 115-127

Author(s):

Zhenxing Feng ◽

Jiao Zhang ◽

Yafang Zheng ◽

Qingzhang Wang ◽

Xiaochuan Min ◽

...

Keyword(s):

Overall Survival ◽

Lung Adenocarcinoma ◽

Tumor Development ◽

Tumor Stage ◽

Gene Expression Omnibus ◽

The Cancer Genome Atlas ◽

Advanced Tumor Stage ◽

Aberrant Expression ◽

Free Survival ◽

Advanced Tumor

Aim: ASF1 is involved in tumorigenesis. However, its possible role in lung adenocarcinoma (LUAD) is unclear. This study thus explored the role of ASF1A and ASF1B in LUAD. Materials & methods: Data from The Cancer Genome Atlas and Gene Expression Omnibus were employed to investigate ASF1A and ASF1B expression and its roles in LUAD prognosis. Immunohistochemistry was applied to determine the protein expression of ASF1B of 30 LUAD patients. Results: The upregulation of ASF1B in tumor tissues is associated with worse overall survival and progress-free survival and is correlated with advanced tumor stage and tumor development. However, aberrant expression of ASF1A was not found in LUAD and ASF1A was not related to patients’ overall survival and progress-free survival. Conclusion: ASF1B could be a promising prognostic and therapeutic biomarker in LUAD.

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Deciphering N6-Methyladenosine-Related Genes Signature to Predict Survival in Lung Adenocarcinoma

BioMed Research International ◽

10.1155/2020/2514230 ◽

2020 ◽

Vol 2020 ◽

pp. 1-13

Author(s):

Jie Zhu ◽

Min Wang ◽

Daixing Hu

Keyword(s):

Lung Adenocarcinoma ◽

Gene Expression Omnibus ◽

The Cancer Genome Atlas ◽

Consensus Clustering ◽

Lasso Regression ◽

Gene Expressions ◽

Tumor Tissues ◽

Cancer Genome Atlas ◽

Selection Operator ◽

Cox Analysis

Lung cancer is the most commonly diagnosed cancer and the leading cause of cancer-related death. Among these, lung adenocarcinoma (LUAD) accounts for most cases. Due to the improvement of precision medicine based on molecular characterization, the treatment of LUAD underwent significant changes. With these changes, the prognosis of LUAD becomes diverse. N6-methyladenosine (m6A) is the most predominant modification in mRNAs, which has been a research hotspot in the field of oncology. Nevertheless, little has been studied to reveal the correlations between the m6A-related genes and prognosis in LUAD. Thus, we conducted a comprehensive analysis of m6A-related gene expressions in LUAD patients based on The Cancer Genome Atlas (TCGA) database by revealing their relationship with prognosis. Different expressions of the m6A-related genes in tumor tissues and non-tumor tissues were confirmed. Furthermore, their relationship with prognosis was studied via Consensus Clustering Analysis, Principal Components Analysis (PCA), and Least Absolute Shrinkage and Selection Operator (LASSO) Regression. Based on the above analyses, a m6A-based signature to predict the overall survival (OS) in LUAD was successfully established. Among the 479 cases, we found that most of the m6A-related genes were differentially expressed between tumor and non-tumor tissues. Six genes, HNRNPC, METTL3, YTHDC2, KIAA1429, ALKBH5, and YTHDF1 were screened to build a risk scoring signature, which is strongly related to the clinical features pathological stages (p<0.05), M stages (p<0.05), T stages (p < 0.05), gender (p=0.04), and survival outcome (p=0.02). Multivariate Cox analysis indicated that risk value could be used as an independent prognostic factor, revealing that the m6A-related genes signature has great predictive value. Its efficacy was also validated by data from the Gene Expression Omnibus (GEO) database.

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