scholarly journals FAM64A: A Novel Oncogenic Target of Lung Adenocarcinoma Regulated by Both Strands of miR-99a (miR-99a-5p and miR-99a-3p)

Cells ◽  
2020 ◽  
Vol 9 (9) ◽  
pp. 2083
Author(s):  
Keiko Mizuno ◽  
Kengo Tanigawa ◽  
Nijiro Nohata ◽  
Shunsuke Misono ◽  
Reona Okada ◽  
...  
Keyword(s):  
Lung Adenocarcinoma ◽  
Cancer Progression ◽  
Target Genes ◽  
Ectopic Expression ◽  
Disease Free Survival ◽  
In Silico Analysis ◽  
The Cancer Genome Atlas ◽  
Aberrant Expression ◽  
Therapeutic Molecules ◽  
Cancer Tissues

Lung adenocarcinoma (LUAD) is the most aggressive cancer and the prognosis of these patients is unfavorable. We revealed that the expression levels of both strands of miR-99a (miR-99a-5p and miR-99a-3p) were significantly suppressed in several cancer tissues. Analyses of large The Cancer Genome Atlas (TCGA) datasets showed that reduced miR-99a-5p or miR-99a-3p expression is associated with worse prognoses in LUAD patients (disease-free survival (DFS): p = 0.1264 and 0.0316; overall survival (OS): p = 0.0176 and 0.0756, respectively). Ectopic expression of these miRNAs attenuated LUAD cell proliferation, suggesting their tumor-suppressive roles. Our in silico analysis revealed 23 putative target genes of pre-miR-99a in LUAD cells. Among these targets, high expressions of 19 genes were associated with worse prognoses in LUAD patients (OS: p < 0.05). Notably, FAM64A was regulated by both miR-99a-5p and miR-99a-3p in LUAD cells, and its aberrant expression was significantly associated with poor prognosis in LUAD patients (OS: p = 0.0175; DFS: p = 0.0276). FAM64A knockdown using siRNAs suggested that elevated FAM64A expression contributes to cancer progression. Aberrant FAM64A expression was detected in LUAD tissues by immunostaining. Taken together, our miRNA-based analysis might be effective for identifying prognostic and therapeutic molecules in LUAD.

scholarly journals Identification of hub driving genes and regulators of lung adenocarcinoma based on the gene Co-expression network

2020 ◽  
Vol 40 (4) ◽  
Author(s):  
Zihao Xu ◽  
Zilong Wu ◽  
Jiatang Xu ◽  
Jingtao Zhang ◽  
Bentong Yu
Keyword(s):  
Lung Adenocarcinoma ◽  
Target Genes ◽  
Characteristic Curve ◽  
Interaction Network ◽  
Mapk Signaling ◽  
The Cancer Genome Atlas ◽  
Circular Rnas ◽  
Node Degree ◽  
Protein Protein Interaction ◽  
Cancer Tissues

Abstract Lung adenocarcinoma (LUAD) remains the leading cause of cancer-related deaths worldwide. Increasing evidence suggests that circular RNAs (circRNAs) and long non-coding RNAs (lncRNAs) can regulate target gene expression and participate in tumor genesis and progression. However, hub driving genes and regulators playing a potential role in LUAD progression have not been fully elucidated yet. Based on data from The Cancer Genome Atlas database, 2837 differentially expressed genes, 741 DE-regulators were screened by comparing cancer tissues with paracancerous tissues. Then, 651 hub driving genes were selected by the topological relation of the protein–protein interaction network. Also, the target genes of DE-regulators were identified. Moreover, a key gene set containing 65 genes was obtained from the hub driving genes and target genes intersection. Subsequently, 183 hub regulators were selected based on the analysis of node degree in the ceRNA network. Next, a comprehensive analysis of the subgroups and Wnt, mTOR, and MAPK signaling pathways was conducted to understand enrichment of the subgroups. Survival analysis and a receiver operating characteristic curve analysis were further used to screen for the key genes and regulators. Furthermore, we verified key molecules based on external database, LRRK2, PECAM1, EPAS1, LDB2, and HOXA11-AS showed good results. LRRK2 was further identified as promising biomarker associated with CNV alteration and various immune cells’ infiltration levels in LUAD. Overall, the present study provided a novel perspective and insight into hub driving genes and regulators in LUAD, suggesting that the identified signature could serve as an independent prognostic biomarker.

scholarly journals TBX5-AS1, an enhancer RNA, is a potential novel prognostic biomarker for lung adenocarcinoma

2021 ◽  
Author(s):  
Lin Cheng ◽  
Tong Han ◽  
Bolin Chen ◽  
Kechao Nie ◽  
Weijun Peng
Keyword(s):  
Correlation Analysis ◽  
Lung Adenocarcinoma ◽  
Cancer Progression ◽  
Target Genes ◽  
Prognostic Biomarker ◽  
Lung Squamous Cell Carcinoma ◽  
The Cancer Genome Atlas ◽  
Pcr Analysis ◽  
Qrt Pcr ◽  
Pan Cancer

Abstract Background: Enhancer RNAs (eRNAs) are demonstrated to be closely associated with tumourigenesis and cancer progression. However, the role of eRNAs in lung adenocarcinoma (LUAD) remains largely unclear. Thus, a comprehensive analysis was constructed to identify the key eRNAs, and to explore the clinical utility of the identified eRNAs in LUAD.Methods: First, LUAD expression profile data from the Cancer Genome Atlas (TCGA) dataset and eRNA-relevant information were integrated for Kaplan-Meier survival analysis and Spearman’s correlation analysis to filtered the key candidate eRNAs that was associated with survival rate and their target genes in LUAD. Then, the key eRNA was selected for subsequent clinical correlation analysis. KEGG pathway enrichment analyses were undertaken to explore the potential signaling pathways of the key eRNA. Data from the human protein atlas (HPA) database were used to validate the outcomes and the quantitative real time-polymerase chain reaction (qRT-PCR) analysis was conducted to measure eRNA expression levels in tumour tissues and paired normal adjacent tissues from LUAD patients. Finally, the eRNAs were validated in pan-cancer.Results: As a result, TBX5-AS1 was identified as the key eRNA, which has T-box transcription factor 5 (TBX5) as its regulatory target. KEGG analysis indicated that TBX5-AS1 may exert a vital role via the PI3K/AKT pathway. Additionally, the qRT-PCR results and the HPA database indicated that TBX5-AS1 and TBX5 were significantly downregulated in tumour samples compared to matched-adjacent pairs. The pan-cancer validation results showed that TBX5-AS1 was associated with survival in four tumours, namely, adrenocortical carcinoma (ACC), LUAD, lung squamous cell carcinoma (LUSC), and uterine corpus endometrial carcinoma (UCEC). Correlations were found between TBX5-AS1 and its target gene, TBX5, in 26 tumour types.Conclusion: Collectively, we supposed that TBX5-AS1 is a tumor suppressor, and could be a new prognostic biomarker for LUAD patients and promote the targeted therapy of LUAD.

scholarly journals Molecular Pathogenesis of Gene Regulation by the miR-150 Duplex: miR-150-3p Regulates TNS4 in Lung Adenocarcinoma

Cancers ◽  
2019 ◽  
Vol 11 (5) ◽  
pp. 601 ◽  
Author(s):  
Shunsuke Misono ◽  
Naohiko Seki ◽  
Keiko Mizuno ◽  
Yasutaka Yamada ◽  
Akifumi Uchida ◽  
...  
Keyword(s):  
Lung Adenocarcinoma ◽  
Ectopic Expression ◽  
Disease Free Survival ◽  
Molecular Networks ◽  
In Vitro Assays ◽  
Aberrant Expression ◽  
Clinical Specimens ◽  
Passenger Strand ◽  
Genome Wide

Based on our miRNA expression signatures, we focused on miR-150-5p (the guide strand) and miR-150-3p (the passenger strand) to investigate their functional significance in lung adenocarcinoma (LUAD). Downregulation of miR-150 duplex was confirmed in LUAD clinical specimens. In vitro assays revealed that ectopic expression of miR-150-5p and miR-150-3p inhibited cancer cell malignancy. We performed genome-wide gene expression analyses and in silico database searches to identify their oncogenic targets in LUAD cells. A total of 41 and 26 genes were identified as miR-150-5p and miR-150-3p targets, respectively, and they were closely involved in LUAD pathogenesis. Among the targets, we investigated the oncogenic roles of tensin 4 (TNS4) because high expression of TNS4 was strongly related to poorer prognosis of LUAD patients (disease-free survival: p = 0.0213 and overall survival: p = 0.0003). Expression of TNS4 was directly regulated by miR-150-3p in LUAD cells. Aberrant expression of TNS4 was detected in LUAD clinical specimens and its aberrant expression increased the aggressiveness of LUAD cells. Furthermore, we identified genes downstream from TNS4 that were associated with critical regulators of genomic stability. Our approach (discovery of anti-tumor miRNAs and their target RNAs for LUAD) will contribute to the elucidation of molecular networks involved in the malignant transformation of LUAD.

scholarly journals Involvement of Dual Strands of miR-143 (miR-143-5p and miR-143-3p) and Their Target Oncogenes in the Molecular Pathogenesis of Lung Adenocarcinoma

2019 ◽  
Vol 20 (18) ◽  
pp. 4482 ◽  
Author(s):  
Hiroki Sanada ◽  
Naohiko Seki ◽  
Keiko Mizuno ◽  
Shunsuke Misono ◽  
Akifumi Uchida ◽  
...  
Keyword(s):  
Lung Adenocarcinoma ◽  
Target Genes ◽  
Ectopic Expression ◽  
Molecular Pathogenesis ◽  
Molecular Networks ◽  
Migration And Invasion ◽  
Aberrant Expression ◽  
Clinical Specimens ◽  
Genome Wide ◽  
Tumor Suppressive Mirnas

Our analyses of tumor-suppressive microRNAs (miRNAs) and their target oncogenes have identified novel molecular networks in lung adenocarcinoma (LUAD). Moreover, our recent studies revealed that some passenger strands of miRNAs contribute to cancer cell malignant transformation. Downregulation of both strands of the miR-143 duplex was observed in LUAD clinical specimens. Ectopic expression of these miRNAs suppressed malignant phenotypes in cancer cells, suggesting that these miRNAs have tumor-suppressive activities in LUAD cells. Here, we evaluated miR-143-5p molecular networks in LUAD using genome-wide gene expression and miRNA database analyses. Twenty-two genes were identified as potential miR-143-5p-controlled genes in LUAD cells. Interestingly, the expression of 11 genes (MCM4, RAD51, FAM111B, CLGN, KRT80, GPC1, MTL5, NETO2, FANCA, MTFR1, and TTLL12) was a prognostic factor for the patients with LUAD. Furthermore, knockdown assays using siRNAs showed that downregulation of MCM4 suppressed cell growth, migration, and invasion in LUAD cells. Aberrant expression of MCM4 was confirmed in the clinical specimens of LUAD. Thus, we showed that miR-143-5p and its target genes were involved in the molecular pathogenesis of LUAD. Identification of tumor-suppressive miRNAs and their target oncogenes may be an effective strategy for elucidation of the molecular oncogenic networks of this disease.

scholarly journals Evaluation of the prognostic value of CBXs in gastric cancer patients

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Mengya He ◽  
Limin Yue ◽  
Haiyan Wang ◽  
Feiyan Yu ◽  
Mingyang Yu ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Target Genes ◽  
Prognostic Significance ◽  
Disease Free Survival ◽  
Genetic Alterations ◽  
Genetic Mutation ◽  
The Cancer Genome Atlas ◽  
Normal Tissues ◽  
Interactive Analysis ◽  
Gastric Cancer Patients

AbstractChromobox (CBX) proteins were suggested to exert epigenetic regulatory and transcriptionally repressing effects on target genes and might play key roles in the carcinogenesis of a variety of carcinomas. Nevertheless, the functions and prognostic significance of CBXs in gastric cancer (GC) remain unclear. The current study investigated the roles of CBXs in the prognosis of GC using the Oncomine, The Gene Expression Profiling Interactive Analysis (GEPIA), UALCAN, The Cancer Genome Atlas (TCGA), and cBioPortal databases. CBX1/2/3/4/5 were significantly upregulated in GC tissues compared with normal tissues, and CBX7 was downregulated. Multivariate analysis showed that high mRNA expression levels of CBX3/8 were independent prognostic factors for prolonged OS in GC patients. In addition, the genetic mutation rate of CBXs was 37% in GC patients, and genetic alterations in CBXs showed no association with OS or disease-free survival (DFS) in GC patients. These results indicated that CBX3/8 can be prognostic biomarkers for the survival of GC patients.

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

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.

scholarly journals Prognostic implications of programmed death ligand 1 expression in resected lung adenocarcinoma: a systematic review and meta-analysis

2020 ◽  
Vol 58 (5) ◽  
pp. 888-898
Author(s):  
Donglai Chen ◽  
Yiming Mao ◽  
Qifeng Ding ◽  
Wei Wang ◽  
Feng Zhu ◽  
...  
Keyword(s):  
Gene Expression ◽  
Protein Expression ◽  
Lung Adenocarcinoma ◽  
Messenger Rna ◽  
Disease Free Survival ◽  
Pooled Analysis ◽  
The Cancer Genome Atlas ◽  
Free Survival ◽  
L1 Protein ◽  
Disease Free

Abstract OBJECTIVES Conflicting results have been reported about the prognostic value of programmed death ligand 1 (PD-L1) protein and gene expression in lung adenocarcinoma. METHODS We performed a comprehensive online search to explore the association between PD-L1 expression (protein and messenger RNA) and overall survival (OS) or disease-free survival. Outcomes also included pooled rates of high PD-L1 protein expression in different cell types, per threshold used and per antibody used. A pooled gene expression analysis was also performed on 3 transcriptomic data sets that were obtained from The Cancer Genome Atlas database and the Gene Expression Omnibus database. RESULTS A total of 6488 patients from 25 studies were included. The pooled results suggested that high PD-L1 expression was associated with shorter OS [hazard ratio (HR) 1.57; P &lt; 0.001] and disease-free survival (HR 1.341; P = 0.037) in the overall population. The overall pooled rate of high PD-L1 protein expression was 29% (95% confidence interval 23–34%) in tumour cells. In subgroup analysis, high PD-L1 protein expression in tumour cells predicted worse OS and disease-free survival. A pooled analysis of The Cancer Genome Atlas and Gene Expression Omnibus data sets revealed that higher levels of PD-L1 messenger RNA predicted poorer OS in the entire population. CONCLUSIONS This study is, to our knowledge, the largest pooled analysis on the subject to shed light on the high expression rate of PD-L1 and the prognostic value of high PD-L1 expression in resected lung adenocarcinomas. PD-L1 gene expression is a promising prognostic factor for patients with surgically resected lung adenocarcinoma. Standardization of staining should be underscored prior to routine implementation.

scholarly journals Mitochondrial Deoxyguanosine Kinase Regulates NAD+ Biogenesis Independent of Mitochondria Complex I Activity

2020 ◽  
Vol 10 ◽  
Author(s):  
Lei Sang ◽  
Ying-Jie He ◽  
Jiaxin Kang ◽  
Hongyi Ye ◽  
Weiyu Bai ◽  
...  
Keyword(s):  
Lung Adenocarcinoma ◽  
Cancer Progression ◽  
Complex I ◽  
Ectopic Expression ◽  
Dependent Manner ◽  
Potential Therapeutic Target ◽  
Protein Levels ◽  
Deoxyguanosine Kinase ◽  
Complex I Activity ◽  
Mitochondria Complex I

Overexpression of DGUOK promotes mitochondria oxidative phosphorylation and lung adenocarcinoma progression. However, the role and mechanism of DGUOK in regulation of mitochondria function and lung cancer progression still poorly understood. Here we demonstrated that DGUOK regulated NAD+ biogenesis. Depletion of the DGUOK significantly decreased NAD+ level. Furthermore, knockout of the DGUOK considerably reduced expression of the NMNAT2, a key molecule controlling NAD+ synthesis, at both mRNA and protein levels. Ectopic expression of the NMNAT2 abrogated the effect of knockdown of DGUOK on NAD+. Notably, this regulation is independent of DGUOK -mediated mitochondria complex I activity. We also showed that NMNAT2 was highly expressed in lung adenocarcinoma and negatively correlated with the patient overall survival. Our study suggested that DGUOK regulates NAD+ in a NMNAT2 dependent manner and DGUOK-NMNAT2-NAD+ axis could be a potential therapeutic target in lung adenocarcinoma.

scholarly journals Elevated Glutathione Peroxidase 2 Expression Promotes Cisplatin Resistance in Lung Adenocarcinoma

2020 ◽  
Vol 2020 ◽  
pp. 1-14
Author(s):  
He Du ◽  
Bi Chen ◽  
Nan-Lin Jiao ◽  
Yan-Hua Liu ◽  
San-Yuan Sun ◽  
...  
Keyword(s):  
Energy Metabolism ◽  
Glutathione Peroxidase ◽  
Lung Adenocarcinoma ◽  
Cell Line ◽  
A549 Cells ◽  
Disease Free Survival ◽  
Gene Set Enrichment Analysis ◽  
The Cancer Genome Atlas ◽  
Normal Lung

The aim of this study was to explore the roles of GPX2, a member of the glutathione peroxidase family (GPXs, GSH-Px), in cisplatin (DDP) resistance in lung adenocarcinoma (LUAD). GPX2 was found to be the most significantly upregulated gene in a DDP-resistant A549/DDP cell line compared with the parental A549 cell line by RNA sequencing. The knockdown of GPX2 expression in A549/DDP cells inhibited cell proliferation in vitro and in vivo, decreased the IC50 values of DDP, induced apoptosis, inhibited the activities of GSH-Px and superoxide dismutase (SOD), inhibited ATP production and glucose uptake, and increased malondialdehyde (MDA) and reactive oxygen species (ROS) production; while GPX2 overexpression in A549 cells resulted in the opposite effects. Using gene set enrichment analysis (GSEA), we found that GPX2 may be involved in DDP resistance through mediating drug metabolism, the cell cycle, DNA repair and energy metabolism, and the regulation of an ATP-binding cassette (ABC) transporters member ABCB6, which is one of the hallmark genes in glycolysis. Moreover, immunohistochemistry revealed that GPX2 was upregulated in 58.6% (89/152) of LUAD cases, and elevated GPX2 expression was correlated with high expression of ABCB6, high 18-fluorodeoxyglucose (18F-FDG) uptake, and adverse disease-free survival (DFS) in our cohort. The Cancer Genome Atlas (TCGA) data also indicated that GPX2 expression was higher in LUAD than it was in normal lung tissues, and the mRNA expression levels of GPX2 and ABCB6 were positively correlated. In conclusion, our study demonstrates that GPX2 acts as oncogene in LUAD and promotes DDP resistance by regulating oxidative stress and energy metabolism.

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