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

2021 ◽  
Vol 12 ◽  
Author(s):  
Jianlin Chen ◽  
Junping Ding ◽  
Wenjie Huang ◽  
Lin Sun ◽  
Jinping Chen ◽  
...  

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.

BMC Cancer ◽  
2019 ◽  
Vol 19 (1) ◽  
Author(s):  
Xiaojie Wang ◽  
Qian Yu ◽  
Waleed M. Ghareeb ◽  
Yiyi Zhang ◽  
Xingrong Lu ◽  
...  

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.


Author(s):  
Yitong Zhang ◽  
Fenglan Li ◽  
Kexin Fu ◽  
Xiqing Liu ◽  
I-Chia Lien ◽  
...  

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.


2021 ◽  
Vol 12 ◽  
Author(s):  
Zhi Liu ◽  
Tiezheng Qi ◽  
Xiaowen Li ◽  
Yiyan Yao ◽  
Belaydi Othmane ◽  
...  

BackgroundThe TGF-β pathway plays critical roles in numerous malignancies. Nevertheless, its potential role in prognosis prediction and regulating tumour microenvironment (TME) characteristics require further elucidation in bladder cancer (BLCA).MethodsTGF-β-related genes were comprehensively summarized from several databases. The TCGA-BLCA cohort (training cohort) was downloaded from the Cancer Genome Atlas, and the independent validation cohorts were gathered from Xiangya Hospital (Xinagya cohort) and Gene Expression Omnibus. Initially, we identified differentially expressed TGF-β genes (DEGs) between cancer and normal tissues. Subsequently, univariate Cox analysis was applied to identify prognostic DEGs, which were further used to develop the TGF-β risk score by performing LASSO and multivariate Cox analyses. Then, we studied the role of the TGF-β risk score in predicting prognosis and the TME phenotypes. In addition, the role of the TGF-β risk score in guiding precision treatments for BLCA has also been assessed.ResultsWe successfully constructed a TGF-β risk score with an independent prognostic prediction value. A high TGF-β risk score indicated an inflamed TME, which was supported by the positive relationships between the risk score, enrichment scores of anticancer immunity steps, and the infiltration levels of tumour-infiltrating immune cells. In addition, the risk score positively correlated with the expression of several immune checkpoints and the T cell inflamed score. Consistently, the risk score was positively related to the enrichment scores of most immunotherapy-positive pathways. In addition, the sensitivities of six common chemotherapeutic drugs were positively associated with the risk score. Furthermore, higher risk score indicated higher sensitivity to radiotherapy and EGFR-targeted therapy. On the contrary, patients with low-risk scores were more sensitive to targeted therapies, including the blockade of FGFR3 and WNT-β-catenin networks.ConclusionsWe first constructed and validated a TGF-β signature that could predict the prognosis and TME phenotypes for BLCA. More importantly, the TGF-β risk score could aid in individual precision treatment for BLCA.


PeerJ ◽  
2021 ◽  
Vol 9 ◽  
pp. e12277
Author(s):  
Likui Fang ◽  
Guocan Yu ◽  
Wenfeng Yu ◽  
Gang Chen ◽  
Bo Ye

Background WD repeat domain 76 (WDR76) is a predicted member of the WD40-repeat-containing domain superfamily and possibly involves in various biological processes, but its function in cancers is poorly characterized. This study aimed to evaluate the role of WDR76 in the prognosis and immune infiltrates of lung adenocarcinoma (LUAD). Methods WDR76 expressions in LUAD tissues and normal tissues were primarily compared by The Cancer Genome Atlas (TCGA) database, and were validated in cohorts from Gene Expression Omnibus (GEO) database. The associations between WDR76 expression and clinicopathologic characteristics were analyzed. Kaplan–Meier and Cox regression analyses were performed to determine the impact of WDR76 expression on survival outcomes. The protein interaction network of WDR76 was built using STRING website. TIMER and GEPIA databases were used to investigate the correlation between WDR76 expression and immune infiltrates. Results WDR76 expression was elevated in LUAD (P < 0.001) and high WDR76 expression was associated with advanced N stage, M stage and pathologic stage. Expectedly, high WDR76 expression significantly correlated with poor survival outcomes and was the independent risk factor for overall survival (OS) (HR 1.468, 95% CI [1.031–2.089], P = 0.033) and disease specific survival (DSS) (HR 1.764, 95% CI [1.095–2.842], P = 0.020). DDB1 and LSH were the important proteins interacting with WDR76. WDR76 expression correlated with CD8+ T cells presence and was also positively associated with levels of inhibitory receptors. Conclusion WDR76 expression was involved in the regulation of immune infiltrates and had predictive value for prognosis in LUAD.


2021 ◽  
Vol 2021 ◽  
pp. 1-22
Author(s):  
Jie Li ◽  
Ye Tong ◽  
Zhi Wang ◽  
Yi Liu ◽  
Xiaobo Dai ◽  
...  

Recently, it was reported that ubiquilin 4 (UBQLN4) alteration was associated with genomic instability in some cancers. However, whether UBQLN4 is a valuable biomarker for the prognosis of immunotherapy in pan-cancer was not identified. We evaluated the biologic and oncologic significance of UBQLN4 in pan-cancer at multiomics level, such as expression, mutation, copy number variation (CNV), methylation, and N6-methyladenosine (m6A) methylation. These omics data were obtained from several public databases, including Oncomine, The Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO), the Genotype-Tissue Expression (GTEx), the Human Protein Atlas (HPA), Gene Set Cancer Analysis (GSCA), m6A-Atlas, CancerSEA, and RNAactDrug. We found that UBQLN4 mRNA and protein were overexpressed in most cancer types, and the expression, mutation, CNV, and methylation of UBQLN4 were associated with the prognosis of some cancers. Mechanistically, UBQLN4 was involved in angiogenesis, DNA damage, apoptosis, and the pathway of PI3K/AKT and TSC/mTOR. Moreover, UBQLN4 mRNA was significantly correlated with immune checkpoints, tumor mutational burden (TMB), microsatellite instability (MSI), and mismatch repair (MMR). And, the correlation among UBQLN4 mRNA, CNV, and methylation and immune microenvironment was also identified. Furthermore, UBQLN4 was associated with the sensitivity of chemotherapy and targeted drugs at multiomics level. In conclusion, UBQLN4 was a promising prognostic biomarker of immune-related therapy in pan-cancer.


2021 ◽  
Vol 11 ◽  
Author(s):  
Yi He ◽  
Ruijie Liu ◽  
Mei Yang ◽  
Wu Bi ◽  
Liuyin Zhou ◽  
...  

Lung adenocarcinoma (LUAD) is one of the most malignant tumors with high morbidity and mortality worldwide due to the lack of reliable methods for early diagnosis and effective treatment. It’s imperative to study the mechanism of its development and explore new biomarkers for early detection of LUAD. In this study, the Gene Expression Omnibus (GEO) dataset GSE43458 and The Cancer Genome Atlas (TCGA) were used to explore the differential co-expressed genes between LUAD and normal samples. Three hundred sixity-six co-expressed genes were identified by differential gene expression analysis and Weighted Gene Co-expression Network Analysis (WGCNA) method. Those genes were mainly enriched in ameboidal-type cell migration (biological process), collagen-containing extracellular matrix (cell component), and extracellular matrix structure constituent (molecular function). The protein-protein network (PPI) was constructed and 10 hub genes were identified, including IL6, VWF, CDH5, PECAM1, EDN1, BDNF, CAV1, SPP1, TEK, and SELE. The expression level of hub genes was validated in the GEPIA database, compared with normal tissues, VWF is lowly expressed and SPP1 is upregulated in LUAD tissues. The survival analysis showed increased expression of SPP1 indicated unfavorable prognosis whereas high expression of VWF suggested favorable prognosis in LUAD (p &lt; 0.05). Based on the immune infiltration analysis, the relationship between SPP1 and VWF expression and macrophage, neutrophil, and dendritic cell infiltration was weak in LUAD. Quantitative real-time PCR (qRT-PCR) and western blotting were used to validate the expression of VWF and SPP1 in normal human bronchial epithelial (HBE) cell and three LUAD cell lines, H1299, H1975, and A549. Immunohistochemistry (IHC) was further performed to detect the expression of VWF in 10 cases LUAD samples and matched normal tissues. In summary, the data suggest that VWF is a potential novel biomarker for prognosis of LUAD.


2021 ◽  
Vol 12 ◽  
Author(s):  
Tao Fan ◽  
Shize Pan ◽  
Shuo Yang ◽  
Bo Hao ◽  
Lin Zhang ◽  
...  

Interleukins (ILs) and interleukin receptors (ILRs) play important role in the antitumor immune response. However, the expression signature and clinical characteristics of the IL(R) family in lung adenocarcinoma (LUAD) remains unclear. The main purpose of this study was to explore the expression profile of IL(R) family genes and construct an IL(R)-based prognostic signature in LUAD. Five public datasets of 1,312 patients with LUAD were enrolled in this study. Samples from The Cancer Genome Atlas (TCGA) were used as the training set, and samples from the other four cohorts extracted from Gene Expression Omnibus (GEO) database were used as the validation set. Additionally, the profile of IL(R) family signature was explored, and the association between this signature and immunotherapy response was also analyzed. Meanwhile, the prognostic value was compared between this IL(R)-based signature and different immunotherapy markers. A signature based on five identified IL(R)s (IL7R, IL5RA, IL20RB, IL11, IL22RA1) was constructed using the TCGA dataset through univariate/multivariable Cox proportional hazards regression and least absolute shrinkage and selection operator (LASSO) Cox analysis. These cases with LUAD were stratified into high- and low-risk group according to the risk score. This signature showed a strong prognostic ability, which was verified by the five independent cohorts and clinical subtypes. The IL(R)-based models presented unique characteristics in terms of immune cell infiltration and immune inflammation profile in tumor microenvironment (TME). Biological pathway analysis confirmed that high-risk patients showed significant T- and B-cell immunosuppression and rapid tumor cell proliferation. More importantly, we researched the relationship between this IL(R)-based signature and immune checkpoints, tumor mutation burden (TMB), tumor purity and ploidy, and tumor immune dysfunction and exclusion (TIDE) score, which confirmed that this signature gave the best prognostic value. We first provided a robust prognostic IL(R)-based signature, which had the potential as a predictor for immunotherapy response to realize individualized treatment of LUAD.


BMC Cancer ◽  
2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Xiaodong Yang ◽  
Yuexin Zheng ◽  
Zhihai Han ◽  
Xiliang Zhang

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.


2018 ◽  
Vol 2018 ◽  
pp. 1-7 ◽  
Author(s):  
Yuan He ◽  
Li-Yue Sun ◽  
Jing Wang ◽  
Rui Gong ◽  
Qiong Shao ◽  
...  

Objective. To investigate methylation of the adenomatosis polyposis coli homologue (APC2) promoter and its correlation with prognostic implications in Chinese colorectal cancer (CRC). Methods. The mRNA expression of APC2 in colorectal tissues was evaluated using the database of The Cancer Genome Atlas (TCGA). Methylation analysis of APC2 in tumor (n=66) and corresponding adjacent formalin-fixed and paraffin-embedded (FFPE) tissues (n=44) was performed by Sequenom EpiTYPER® and verified by cloning-based bisulfite sequencing analysis. Demethylation and retrieval of APC2 expression in cell lines HT29, HCT116, and SW480 were treated with 5-aza-2′-deoxycytidine (5-AZC). Results. Analysis of TCGA showed that APC2 mRNA was significantly downregulated in primary tumors when compared to normal tissues (p<0.05). APC2 methylation was upregulated (43.93% vs 7.31%, p<0.05) in tumors compared to adjacent FFPE tissues. In vitro experiments demonstrated that 5-AZC downregulated the methylation of APC2 and retrieved its expression of mRNA and protein levels (p<0.05). Multivariate Cox regression indicated that APC2_CPG_14 was an independent risk factor for overall survival (HR = 6.38, 95% CI: 1.59–25.64, p<0.05). Conclusion. This study indicates that APC2 is hypermethylated and may be a tumorigenesis biomarker for Chinese CRC patients.


2021 ◽  
Author(s):  
Pingfan Wu ◽  
Xiaowen Zhao ◽  
Ling Xue ◽  
Xiaojing Yang ◽  
Yuxiang Shi ◽  
...  

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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