scholarly journals MLH1 Deficiency Down-Regulates TLR4 Expression in Sporadic Colorectal Cancer

2021 ◽  
Vol 8 ◽  
Author(s):  
Melania Scarpa ◽  
Cesare Ruffolo ◽  
Andromachi Kotsafti ◽  
Fabio Canal ◽  
Francesca Erroi ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
The Cancer Genome Atlas ◽  
Sporadic Colorectal Cancer ◽  
Tlr4 Expression ◽  
Mmr Genes ◽  
Favorable Prognosis ◽  
Cancer Genome Atlas ◽  
Myd88 Signaling ◽  
Genome Atlas

Patients with mismatch repair (MMR)-deficient colorectal cancer (CRC) have a more favorable prognosis than patients with tumors with intact MMR. In order to obtain further insights on the reasons for this different outcome, we investigated the interplay between MMR genes and TLR4/MyD88 signaling. The cancer genome atlas (TCGA) databases were selected to predict the differential expression of TLR4 in colon cancer and its correlation with MMR genes. Moreover, the expression of MMR genes and TLR4 was evaluated by immunohistochemistry in 113 CRC samples and a cohort of 63 patients was used to assess TLR4 mRNA expression and MLH1 epigenetic silencing status. In vitro, the effect of MLH1 knockdown on TLR4 expression was quantified by Real Time PCR. TLR4 expression resulted dependent on MMR status and directly correlated to MLH1 expression. In vitro, MLH1 silencing decreased TLR4 expression. These observations may reflect the better prognosis and the chemoresistance of patients with CRC and MMR defects.

scholarly journals Exceptional Chemotherapy Response in Metastatic Colorectal Cancer Associated With Hyper-Indel–Hypermutated Cancer Genome and Comutation of POLD1 and MLH1

2017 ◽  
pp. 1-12
Author(s):  
Manish R. Sharma ◽  
James T. Auman ◽  
Nirali M. Patel ◽  
Juneko E. Grilley-Olson ◽  
Xiaobei Zhao ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Colon Cancer ◽  
Somatic Mutation ◽  
Mutation Rate ◽  
Germ Line ◽  
Cancer Genome ◽  
The Cancer Genome Atlas ◽  
Response To Chemotherapy ◽  
Cancer Genome Atlas ◽  
Genome Atlas

Purpose A 73-year-old woman with metastatic colon cancer experienced a complete response to chemotherapy with dose-intensified irinotecan that has been durable for 5 years. We sequenced her tumor and germ line DNA and looked for similar patterns in publicly available genomic data from patients with colorectal cancer. Patients and Methods Tumor DNA was obtained from a biopsy before therapy, and germ line DNA was obtained from blood. Tumor and germline DNA were sequenced using a commercial panel with approximately 250 genes. Whole-genome amplification and exome sequencing were performed for POLE and POLD1. A POLD1 mutation was confirmed by Sanger sequencing. The somatic mutation and clinical annotation data files from the colon (n = 461) and rectal (n = 171) adenocarcinoma data sets were downloaded from The Cancer Genome Atlas data portal and analyzed for patterns of mutations and clinical outcomes in patients with POLE- and/or POLD1-mutated tumors. Results The pattern of alterations included APC biallelic inactivation and microsatellite instability high (MSI-H) phenotype, with somatic inactivation of MLH1 and hypermutation (estimated mutation rate > 200 per megabase). The extremely high mutation rate led us to investigate additional mechanisms for hypermutation, including loss of function of POLE. POLE was unaltered, but a related gene not typically associated with somatic mutation in colon cancer, POLD1, had a somatic mutation c.2171G>A [p.Gly724Glu]. Additionally, we noted that the high mutation rate was largely composed of dinucleotide deletions. A similar pattern of hypermutation (dinucleotide deletions, POLD1 mutations, MSI-H) was found in tumors from The Cancer Genome Atlas. Conclusion POLD1 mutation with associated MSI-H and hyper-indel–hypermutated cancer genome characterizes a previously unrecognized variant of colon cancer that was found in this patient with an exceptional response to chemotherapy.

scholarly journals Role of INSL4 Signaling in Sustaining the Growth and Viability of LKB1-Inactivated Lung Cancer

2018 ◽  
Vol 111 (7) ◽  
pp. 664-674 ◽  
Author(s):  
Rongqiang Yang ◽  
Steven W Li ◽  
Zirong Chen ◽  
Xin Zhou ◽  
Wei Ni ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Transcriptome Profiling ◽  
Cancer Genome ◽  
The Cancer Genome Atlas ◽  
Growth And Survival ◽  
Cancer Genome Atlas ◽  
Lung Adenocarcinomas ◽  
Genome Atlas

Abstract Background The LKB1 tumor suppressor gene is commonly inactivated in non-small cell lung carcinomas (NSCLC), a major form of lung cancer. Targeted therapies for LKB1-inactivated lung cancer are currently unavailable. Identification of critical signaling components downstream of LKB1 inactivation has the potential to uncover rational therapeutic targets. Here we investigated the role of INSL4, a member of the insulin/IGF/relaxin superfamily, in LKB1-inactivated NSCLCs. Methods INSL4 expression was analyzed using global transcriptome profiling, quantitative reverse transcription PCR, western blotting, enzyme-linked immunosorbent assay, and RNA in situ hybridization in human NSCLC cell lines and tumor specimens. INSL4 gene expression and clinical data from The Cancer Genome Atlas lung adenocarcinomas (n = 515) were analyzed using log-rank and Fisher exact tests. INSL4 functions were studied using short hairpin RNA (shRNA) knockdown, overexpression, transcriptome profiling, cell growth, and survival assays in vitro and in vivo. All statistical tests were two-sided. Results INSL4 was identified as a novel downstream target of LKB1 deficiency and its expression was induced through aberrant CRTC-CREB activation. INSL4 was highly induced in LKB1-deficient NSCLC cells (up to 543-fold) and 9 of 41 primary tumors, although undetectable in all normal tissues except the placenta. Lung adenocarcinomas from The Cancer Genome Atlas with high and low INSL4 expression (with the top 10th percentile as cutoff) showed statistically significant differences for advanced tumor stage (P < .001), lymph node metastasis (P = .001), and tumor size (P = .01). The INSL4-high group showed worse survival than the INSL4-low group (P < .001). Sustained INSL4 expression was required for the growth and viability of LKB1-inactivated NSCLC cells in vitro and in a mouse xenograft model (n = 5 mice per group). Expression profiling revealed INSL4 as a critical regulator of cell cycle, growth, and survival. Conclusions LKB1 deficiency induces an autocrine INSL4 signaling that critically supports the growth and survival of lung cancer cells. Therefore, aberrant INSL4 signaling is a promising therapeutic target for LKB1-deficient lung cancers.

scholarly journals Evaluating the Prognostic Value of microRNA-203 in Solid Tumors Based on a Meta-Analysis and the Cancer Genome Atlas (TCGA) Datasets

2017 ◽  
Vol 41 (4) ◽  
pp. 1468-1480 ◽  
Author(s):  
Yingjie Shao ◽  
Wendong Gu ◽  
Zhonghua Ning ◽  
Xing Song ◽  
Honglei Pei ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Colorectal Cancer ◽  
Pancreatic Cancer ◽  
Esophageal Cancer ◽  
Solid Tumors ◽  
Prognostic Value ◽  
Meta Analysis ◽  
The Cancer Genome Atlas ◽  
Cancer Genome Atlas ◽  
Genome Atlas

Background: It has been reported that miR-203 expression was aberrant in various types of cancers, and it could be used as a prognostic biomarker. Therefore, in this study, we aimed to evaluate the prognostic value of miR-203 expression in solid tumors by using meta-analysis and The Cancer Genome Atlas (TCGA) datasets. Methods: By doing a literature research in PubMed, Embase and the Cochrane Library (last update by December 2016), we were able to identify the studies assessing the prognostic role of miR-203 in various tumors. We then used TCGA datasets to validate the results of meta-analysis. Results:33 studies from 26 articles were qualified and enrolled in this meta-analysis. Pooled analyses showed that higher expression of miR-203 in tissues couldn’t predict poor overall survival (OS) and progression-free survival (PFS) in solid tumors. However, the results of subgroup analyses revealed that the upregulation of tissue miR-203 expression was associated with poor OS in colorectal cancer (hazard ratio (HR)=1.81, 95% confidence intervals (CI) 1.31-2.49; P<0.001), pancreatic cancer (HR=1.19, 95% CI 1.09-1.31; P<0.001) and ovarian cancer (HR=1.85, 95% CI 1.45-2.37; P<0.001); but it had opposite association in liver cancer (HR=0.52, 95% CI 0.28-0.97; P=0.040) and esophageal cancer (HR=0.41, 95% CI 0.25-0.66; P<0.001). Based on TCGA datasets, we found the same results for pancreatic cancer and esophageal cancer, but not for colorectal cancer and liver cancer. Moreover, patients with high circulating miR-203 in blood had significantly poor OS and PFS in colorectal cancer and breast cancer. Conclusion: Our study showed that the prognostic values of tissue miR-203 varied in different tumor types. In addition, the upregulation of circulating miR-203 in blood was associated with poor prognosis in colorectal cancer and breast cancer.

scholarly journals METTL3-Mediated m6A mRNA Modification of FBXW7 Suppresses Lung Adenocarcinoma

2020 ◽  
Author(s):  
Yingtong Wu ◽  
Ning Chang ◽  
Yong Zhang ◽  
Xinxin Zhang ◽  
Leidi Xu ◽  
...  
Keyword(s):  
Lung Adenocarcinoma ◽  
Cell Model ◽  
Biological Effects ◽  
Cancer Genome ◽  
The Cancer Genome Atlas ◽  
Luciferase Reporter ◽  
Rna Immunoprecipitation ◽  
Cancer Genome Atlas ◽  
Genome Atlas

Abstract BackgroundFBXW7 m6A modification plays an important role in lung adenocarcinoma (LUAD) progression; however, the underlying mechanisms remain unclear.MethodsThe correlation between FBXW7 and various genes related to m6A modification was analyzed using The Cancer Genome Atlas database. The regulatory effects of METTL3 on FBXW7 mRNA m6A modification were examined in a cell model, and the underlying mechanism was determined by methylated RNA immunoprecipitation, RNA immunoprecipitation, luciferase reporter, and mutagenesis assays. In vitro experiments were performed to further explore the biological effects of METTL3-mediated FBXW7 m6A modification on LUAD development.ResultsDecreased FBXW7 expression was accompanied by downregulated METTL3 expression in human LUAD tissues and was associated with a worse prognosis for LUAD in The Cancer Genome Atlas database. m6A was highly enriched in METTL3-mediated FBXW7 transcripts, and increased m6A modification in the coding sequence region increased its translation. Functionally, METTL3 overexpression or knockdown affected the apoptosis and proliferation phenotype of LUAD cells by regulating FBXW7 m6A modification and expression. Furthermore, FBXW7 overexpression in METTL3-depleted cells partially restored the suppression of LUAD cells in vitro and in vivo.ConclusionsOur findings reveal that METTL3 positively regulates FBXW7 expression and confirm the tumor-suppressive role of m6A-modified FBXW7, thus providing insight into its epigenetic regulatory mechanisms in LUAD initiation and development.

scholarly journals Local Delivery of Minocycline and Vorinostat Act Synergistically to Inhibit Recurrence of Gliomas

2020 ◽  
Author(s):  
Gang Zhao ◽  
Jun Jia ◽  
Lansheng Wang ◽  
Yongkang Zhang ◽  
Han Yang ◽  
...  
Keyword(s):  
High Performance ◽  
Postoperative Recurrence ◽  
The Cancer Genome Atlas ◽  
The Public ◽  
Continuous Release ◽  
Clinical Consequences ◽  
Cancer Genome Atlas ◽  
Genome Atlas

Abstract Background:Postoperative recurrence is the main reason of poor clinical consequences in glioma patients, so preventing recurrence of tumors is crucial in management of gliomas. Methods:In this study, the expression of matrix metalloproteinases (MMPs)in tissues from normal were detected by using RNA-seq analysis.Glioma cases from the public databases (The Cancer Genome Atlas (TCGA), The Chinese Glioma Genome Atlas(CGGA), Betastasis) were included in this study.The hydrogelcontains minocycline (Mino) and vorinostat (Vor)(G/Mino + Vor) was formed under 365 nm when photoinitiator was added in. High Performance Liquid Chromatography (HPLC) assay was used to assessed the release of drugs in G/Mino + Vor hydrogel. MTT assay was used to explore the biosecurity of GelMA. Immunohistochemistry assay, ELISA assay, Tunel assay were used to demonstrate the antitumor effect of G/Mino + Vor hydrogel.Results:We developed G/Mino + Vor hydrogel successfully. Thenthe experiment in vitro and in vivo confirmed MMPs-responsive delivery of minocycline and vorinostat in hydrogel and the anti-glioma effect on incomplete tumor operation model, which indicated that G/Mino + Vor hydrogel effectively inhibited the recurrence of glioma after surgery.Conclusions: In summary, G/Mino + Vor hydrogel could continuous release minocycline and vorinostat in surgical cavity for inhibiting local recurrence of glioma after operation.

scholarly journals Multi-omics analysis to identify driving factors in colorectal cancer

Epigenomics ◽  
2020 ◽  
Vol 12 (18) ◽  
pp. 1633-1650
Author(s):  
Xi Xu ◽  
Chaoju Gong ◽  
Yunfeng Wang ◽  
Yanyan Hu ◽  
Hong Liu ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Molecular Mechanisms ◽  
Copy Number Variations ◽  
The Cancer Genome Atlas ◽  
Single Nucleotide Variants ◽  
Single Nucleotide ◽  
Omics Analysis ◽  
Competing Endogenous Rna Network ◽  
Cancer Genome Atlas

Aim: We aim to identify driving genes of colorectal cancer (CRC) through multi-omics analysis. Materials & methods: We downloaded multi-omics data of CRC from The Cancer Genome Atlas dataset. Integrative analysis of single-nucleotide variants, copy number variations, DNA methylation and differentially expressed genes identified candidate genes that carry CRC risk. Kernal genes were extracted from the weighted gene co-expression network analysis. A competing endogenous RNA network composed of CRC-related genes was constructed. Biological roles of genes were further investigated in vitro. Results: We identified LRRC26 and REP15 as novel prognosis-related driving genes for CRC. LRRC26 hindered tumorigenesis of CRC in vitro. Conclusion: Our study identified novel driving genes and may provide new insights into the molecular mechanisms of CRC.

scholarly journals TP53 hot spot mutations in ovarian cancer: Selective resistance to microtubule stabilizers in vitro and differential survival outcomes from The Cancer Genome Atlas

2015 ◽  
Vol 138 (1) ◽  
pp. 159-164 ◽  
Author(s):  
Brandon-Luke L. Seagle ◽  
Chia-Ping Huang Yang ◽  
Kevin H. Eng ◽  
Monica Dandapani ◽  
Oluwatosin Odunsi-Akanji ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Hot Spot ◽  
Cancer Genome ◽  
The Cancer Genome Atlas ◽  
Survival Outcomes ◽  
Differential Survival ◽  
Cancer Genome Atlas ◽  
Genome Atlas

scholarly journals Identification of intestinal flora-related key genes and therapeutic drugs in colorectal cancer

2020 ◽  
Author(s):  
Jiayu Zhang ◽  
Huaiyu Zhang ◽  
Faping Li ◽  
Zheyu Song ◽  
Yezhou Li ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Intestinal Flora ◽  
Interaction Network ◽  
Gene Interaction ◽  
The Cancer Genome Atlas ◽  
Interaction Database ◽  
Therapeutic Drugs ◽  
Cancer Genome Atlas ◽  
Key Genes ◽  
Genome Atlas

Abstract Background: Colorectal cancer (CRC) is a multifactorial tumor and a leading cause of cancer-specific deaths worldwide. Recent research has shown that the alteration of intestinal flora contributes to the development of CRC. However, the molecular mechanism by which intestinal flora influences the pathogenesis of CRC remains unclear. This study aims to explore the key genes underlying the effect of intestinal flora on CRC and therapeutic drugs for CRC.Methods: Intestinal flora-related genes were determined using text mining. Based on The Cancer Genome Atlas database, differentially expressed genes (DEGs) between CRC and normal samples were identified with the limma package of the R software. Then, the intersection of the two gene sets was selected for enrichment analyses using the tool Database for Annotation, Visualization and Integrated Discovery. Protein interaction network analysis was performed for identifying the key genes using STRING and Cytoscape. The correlation of the key genes with overall survival of CRC patients was analyzed. Finally, the key genes were queried against the Drug-Gene Interaction database to find drug candidates for treating CRC.Results: 518 genes associated with intestinal flora were determined by text mining. Based on The Cancer Genome Atlas database, we identified 48 DEGs associated with intestinal flora, including 25 up-regulated and 23 down-regulated DEGs in CRC. The enrichment analyses indicated that the selected genes were mainly involved in cell-cell signaling, immune response, cytokine-cytokine receptor interaction, and JAK-STAT signaling pathway. The protein-protein interaction network was constructed with 13 nodes and 35 edges. Moreover, 8 genes in the significant cluster were considered as the key genes and chemokine (C-X-C motif) ligand 8 (CXCL8) correlated positively with the overall survival of CRC patients. Finally, a total of 24 drugs were predicted as possible drugs for CRC treatment using the Drug-Gene Interaction database.Conclusions: These findings of this study may provide new insights into CRC pathogenesis and treatments. The prediction of drug-gene interaction is of great practical significance for exploring new drugs or novel targets for existing drugs.

scholarly journals Identification of intestinal flora-related key genes and therapeutic drugs in colorectal cancer

2020 ◽  
Author(s):  
Jiayu Zhang ◽  
Huaiyu Zhang ◽  
Faping Li ◽  
Zheyu Song ◽  
Yezhou Li ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Intestinal Flora ◽  
Interaction Network ◽  
Gene Interaction ◽  
The Cancer Genome Atlas ◽  
Interaction Database ◽  
Therapeutic Drugs ◽  
Cancer Genome Atlas ◽  
Key Genes ◽  
Genome Atlas

Abstract Background: Colorectal cancer (CRC) is a multifactorial tumor and a leading cause of cancer-specific deaths worldwide. Recent research has shown that the alteration of intestinal flora contributes to the development of CRC. However, the molecular mechanism by which intestinal flora influences the pathogenesis of CRC remains unclear. This study aims to explore the key genes underlying the effect of intestinal flora on CRC and therapeutic drugs for CRC.Methods: Intestinal flora-related genes were determined using text mining. Based on The Cancer Genome Atlas database, differentially expressed genes (DEGs) between CRC and normal samples were identified with the limma package of the R software. Then, the intersection of the two gene sets was selected for enrichment analyses using the tool Database for Annotation, Visualization and Integrated Discovery. Protein interaction network analysis was performed for identifying the key genes using STRING and Cytoscape. The correlation of the key genes with overall survival of CRC patients was analyzed. Finally, the key genes were queried against the Drug-Gene Interaction database to find drug candidates for treating CRC.Results: 518 genes associated with intestinal flora were determined by text mining. Based on The Cancer Genome Atlas database, we identified 48 DEGs associated with intestinal flora, including 25 up-regulated and 23 down-regulated DEGs in CRC. The enrichment analyses indicated that the selected genes were mainly involved in cell-cell signaling, immune response, cytokine-cytokine receptor interaction, and JAK-STAT signaling pathway. The protein-protein interaction network was constructed with 13 nodes and 35 edges. Moreover, 8 genes in the significant cluster were considered as the key genes and chemokine (C-X-C motif) ligand 8 (CXCL8) correlated positively with the overall survival of CRC patients. Finally, a total of 24 drugs were predicted as possible drugs for CRC treatment using the Drug-Gene Interaction database.Conclusions: These findings of this study may provide new insights into CRC pathogenesis and treatments. The prediction of drug-gene interaction is of great practical significance for exploring new drugs or novel targets for existing drugs.

scholarly journals CpG-methylation-based risk score predicts progression in colorectal cancer

Epigenomics ◽  
2020 ◽  
Vol 12 (7) ◽  
pp. 605-615 ◽  
Author(s):  
Yao Deng ◽  
Hao Wan ◽  
Jianbo Tian ◽  
Xiang Cheng ◽  
Meilin Rao ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Risk Score ◽  
Area Under The Curve ◽  
The Cancer Genome Atlas ◽  
Free Interval ◽  
Future Clinical Practice ◽  
Risk Of Progression ◽  
Precision Therapy ◽  
Cancer Genome Atlas ◽  
Genome Atlas

Aim: To identify patients with colorectal cancer (CRC) who are at a truly higher risk of progression, which is key for individualized approaches to precision therapy. Materials & methods: We developed a predictor associated with progression-free interval (PFI) using The Cancer Genome Atlas CRC methylation data. Results: The risk score was associated with PFI in the whole cohort (p < 0.001). A nomogram consisting of the risk score and other significant clinical features was generated to predict the 3- and 5-year PFI in the whole set (area under the curve: 0.79 and 0.71, respectively). Conclusion: The risk score based on 23 DNA-methylation sites may serve as the basis for improved prediction of progression in patients with CRC in future clinical practice.

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