scholarly journals A Gene Signature Derived from the Loss of CDKN1A (p21) Is Associated with CMS4 Colorectal Cancer

Cancers ◽  
2021 ◽  
Vol 14 (1) ◽  
pp. 136
Author(s):  
Santiago Bueno-Fortes ◽  
Julienne K. Muenzner ◽  
Alberto Berral-Gonzalez ◽  
Chuanpit Hampel ◽  
Pablo Lindner ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Drug Resistance ◽  
Cell Line ◽  
Survival Data ◽  
Molecular Mechanisms ◽  
Cox Regression ◽  
Expression Profiles ◽  
Human Tumor ◽  
Gene Signature ◽  
Mesenchymal Transition

The epithelial–mesenchymal transition (EMT) is associated with tumor aggressiveness and increased invasion, migration, metastasis, angiogenesis, and drug resistance. Although the HCT116 p21-/- cell line is well known for its EMT-associated phenotype, with high Vimentin and low E-cadherin protein levels, the gene signature of this rather intermediate EMT-like cell line has not been determined so far. In this work, we present a robust molecular and bioinformatics analysis, to reveal the associated gene expression profile and its correlation with different types of colorectal cancer tumors. We compared the quantitative signature obtained with the NanoString platform with the expression profiles of colorectal cancer (CRC) Consensus Molecular Subtypes (CMS) as identified, and validated the results in a large independent cohort of human tumor samples. The expression signature derived from the p21-/- cells showed consistent and reliable numbers of upregulated and downregulated genes, as evaluated with two machine learning methods against the four CRC subtypes (i.e., CMS1, 2, 3, and 4). High concordance was found between the upregulated gene signature of HCT116 p21-/- cells and the signature of the CMS4 mesenchymal subtype. At the same time, the upregulated gene signature of the native HCT116 cells was similar to that of CMS1. Using a multivariate Cox regression model to analyze the survival data in the CRC tumor cohort, we selected genes that have a predictive risk power (with a significant gene risk incidence score). A set of genes of the mesenchymal signature was proven to be significantly associated with poor survival, specifically in the CMS4 CRC human cohort. We suggest that the gene signature of HCT116 p21-/- cells could be a suitable metric for mechanistic studies regarding the CMS4 signature and its functional consequences in CRC. Moreover, this model could help to discover the molecular mechanisms of intermediate EMT, which is known to be associated with extraordinarily high stemness and drug resistance.

scholarly journals Genomics and prognosis analysis of epithelial-mesenchymal transition in colorectal cancer patients

BMC Cancer ◽  
2020 ◽  
Vol 20 (1) ◽  
Author(s):  
Zizhen Zhang ◽  
Sheng Zheng ◽  
Yifeng Lin ◽  
Jiawei Sun ◽  
Ning Ding ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cox Regression ◽  
Epithelial Mesenchymal Transition ◽  
Enrichment Analysis ◽  
Gene Signature ◽  
The Cancer Genome Atlas ◽  
Differentially Expressed ◽  
Related Gene ◽  
Mesenchymal Transition ◽  
Cox Regression Analysis

Abstract Background The epithelial-mesenchymal transition (EMT) plays a pivotal role in various physiological processes, such as embryonic development, tissue morphogenesis, and wound healing. EMT also plays an important role in cancer invasion, metastasis, and chemoresistance. Additionally, EMT is partially responsible for chemoresistance in colorectal cancer (CRC). The aim of this research is to develop an EMT-based prognostic signature in CRC. Methods RNA-seq and microarray data, together with clinical information, were downloaded from The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) databases. A total of 244 differentially expressed EMT-related genes (ERGs) were obtained by comparing the expression between normal and tumor tissues. An EMT-related signature of 11 genes was identified as crucially related to the overall survival (OS) of patients through univariate Cox proportional hazard analysis, least absolute shrinkage and selection operator (LASSO), and Cox regression analysis. Finally, we established a clinical nomogram to predict the survival possibility of CRC patients by integrating clinical characteristics and the EMT-related gene signature. Results Two hundred and forty-four differentially expressed ERGs and their enriched pathways were confirmed. Significant enrichment analysis revealed that EMT-related signaling pathway genes were highly related to CRC. Kaplan-Meier analysis revealed that the 11-EMT signature could significantly distinguish high- and low-risk patients in both TCGA and GEO CRC cohorts. In addition, the calibration curves verified fine concordance between the nomogram prediction model and actual observation. Conclusion We developed a novel EMT-related gene signature for the prognosis prediction of CRC patients, which could improve the individualized outcome prediction in CRC.

Identification and validation of gene expression subtypes in a large set of colorectal cancer samples.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 3511-3511 ◽  
Author(s):  
Eva Budinska ◽  
Vlad Calin Popovici ◽  
Katarzyna Otylia Sikora ◽  
Nicolas Lapique ◽  
Sabine Tejpar ◽  
...  
Keyword(s):  
Gene Expression ◽  
Colorectal Cancer ◽  
Molecular Markers ◽  
Molecular Mechanisms ◽  
Expression Profiles ◽  
Expression Patterns ◽  
Stage Ii ◽  
Large Set ◽  
Molecular Processes ◽  
Mesenchymal Transition

3511 Background: From a clinical perspective colorectal cancer (CRC) is a heterogeneous disease whose biological background is insufficiently understood. In order to adapt targeted treatment to biologically different categories of CRC patients, in depth understanding of the molecular mechanisms involved in CRC heterogeneity is urgently needed. Methods: Consensus cluster analysis of 1113 stage II-III CRC gene expression profiles from PETACC3 and 4 public datasets defined a set of subtypes which were confirmed in an independent set of 720 samples. The similarity between tumors was based on a set of 54 meta-genes. This approach improves the robustness to measurement noise and gives equal chances to each biological process to be accounted for in the subtype definition. We tested the association of the subtypes with clinical variables, molecular markers and patient survival. Results: We identified and validated 5 major subtypes A-E, with different levels of expression in 6 main molecular processes: epithelial-mesenchymal transition (EMT), immune response, colon crypt differentiation, proliferation, Wnt signaling and chromosome 20q. Significant differences in survival and an enrichment for markers such as MSI, BRAF mutation, site or p53 status were found between the subtypes. In addition, the new subtype classification uncovered heterogeneity within groups defined by these commonly used markers. Survival analysis showed significant prognostic value for meta-genes connected to EMT, proliferation and differentiation. Identical data processing and clustering applied to the validation set on the same meta-genes resulted in subtypes with almost identical expression patterns. Conclusions: We identified and validated robust molecular subtypes in the largest set of stage II-III CRC samples as a combination of multiple molecular processes, that complement current disease stratification based on clinico-pathological variables and molecular markers. The biological relevance of these subtypes was reflected in significant differences in survival. These insights open new perspectives for improving prognostic models and rationalize the prediction of tumor-specific drug sensitivity.

scholarly journals Circular RNA hsa_circ_0000277 sequesters miR-4766-5p to upregulate LAMA1 and promote esophageal carcinoma progression

2021 ◽  
Vol 12 (7) ◽  
Author(s):  
Peng Li Zhou ◽  
Zhengyang Wu ◽  
Wenguang Zhang ◽  
Miao Xu ◽  
Jianzhuang Ren ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Bioinformatics Analysis ◽  
Epithelial Mesenchymal Transition ◽  
Expression Profiles ◽  
Luciferase Reporter ◽  
Migration And Invasion ◽  
Circular Rnas ◽  
Mesenchymal Transition ◽  
Dismal Prognosis ◽  
Advanced Tumor

AbstractGrowing evidence has indicated that circular RNAs (circRNAs) play a pivotal role as functional RNAs in diverse cancers. However, most circRNAs involved in esophageal squamous cell carcinoma (ESCC) remain undefined, and the underlying molecular mechanisms mediated by circRNAs are largely unclear. Here, we screened human circRNA expression profiles in ESCC tissues and found significantly increased expression of hsa_circ_0000277 (termed circPDE3B) in ESCC tissues and cell lines compared to the normal controls. Moreover, higher circPDE3B expression in patients with ESCC was correlated with advanced tumor-node-metastasis (TNM) stage and dismal prognosis. Functional experiments demonstrated that circPDE3B promoted the tumorigenesis and metastasis of ESCC cells in vitro and in vivo. Mechanistically, bioinformatics analysis, a dual-luciferase reporter assay, and anti-AGO2 RNA immunoprecipitation showed that circPDE3B could act as a competing endogenous RNA (ceRNA) by harboring miR-4766-5p to eliminate the inhibitory effect on the target gene laminin α1 (LAMA1). In addition, LAMA1 was significantly upregulated in ESCC tissues and was positively associated with the aggressive oncogenic phenotype. More importantly, rescue experiments revealed that the oncogenic role of circPDE3B in ESCC is partly dependent on the miR-4766-5p/LAMA1 axis. Furthermore, bioinformatics analysis combined with validation experiments showed that epithelial-mesenchymal transition (EMT) activation was involved in the oncogenic functions of the circPDE3B–miR-4766-5p/LAMA1 axis in ESCC. Taken together, we demonstrate for the first time that the circPDE3B/miR-4766-5p/LAMA1 axis functions as an oncogenic factor in promoting ESCC cell proliferation, migration, and invasion by inducing EMT, implying its potential prognostic and therapeutic significance in ESCC.

scholarly journals A novel ferroptosis related gene signature is associated with prognosis in patients with ovarian serous cystadenocarcinoma

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Zhixiang Yu ◽  
Haiyan He ◽  
Yanan Chen ◽  
Qiuhe Ji ◽  
Min Sun
Keyword(s):  
Cox Regression ◽  
Expression Profiles ◽  
Critical Role ◽  
Gene Signature ◽  
Cancer Genome ◽  
Training Data ◽  
Hub Genes ◽  
Validation Data ◽  
Data Set ◽  
Cox Regression Analysis

AbstractOvarian cancer (OV) is a common type of carcinoma in females. Many studies have reported that ferroptosis is associated with the prognosis of OV patients. However, the mechanism by which this occurs is not well understood. We utilized Genotype-Tissue Expression (GTEx) and The Cancer Genome Atlas (TCGA) to identify ferroptosis-related genes in OV. In the present study, we applied Cox regression analysis to select hub genes and used the least absolute shrinkage and selection operator to construct a prognosis prediction model with mRNA expression profiles and clinical data from TCGA. A series of analyses for this signature was performed in TCGA. We then verified the identified signature using International Cancer Genome Consortium (ICGC) data. After a series of analyses, we identified six hub genes (DNAJB6, RB1, VIMP/ SELENOS, STEAP3, BACH1, and ALOX12) that were then used to construct a model using a training data set. The model was then tested using a validation data set and was found to have high sensitivity and specificity. The identified ferroptosis-related hub genes might play a critical role in the mechanism of OV development. The gene signature we identified may be useful for future clinical applications.

scholarly journals A Novel Multidrug-Resistant Cell Line from an Italian Intrahepatic Cholangiocarcinoma Patient

Cancers ◽  
2021 ◽  
Vol 13 (9) ◽  
pp. 2051
Author(s):  
Caterina Peraldo-Neia ◽  
Annamaria Massa ◽  
Francesca Vita ◽  
Marco Basiricò ◽  
Chiara Raggi ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Cell Line ◽  
Intrahepatic Cholangiocarcinoma ◽  
Biological Behavior ◽  
Population Doubling ◽  
Sequencing Analysis ◽  
Tumor Type ◽  
Clinical Issue ◽  
Mesenchymal Transition

Chemotherapy resistance is a relevant clinical issue in tumor treatment, in particular in biliary tract carcinoma (BTC), for which there are no effective therapies, neither in the first nor in the second line. The development of chemoresistant cell lines as experimental models to investigate the mechanisms of resistance and identify alternative druggable pathways is mandatory. In BTC, in which genetics and biological behavior depend on the etiology, ethnicity, and anatomical site of origin, the creation of models that better recapitulate these characteristics is even more crucial. Here we have established and characterized an intrahepatic cholangiocarcinoma (iCCA) cell line derived from an Italian patient, called 82.3. Cells were isolated from a patient-derived xenograft (PDX) and, after establishment, immunophenotypic, biological, genetic, molecular characteristics, and tumorigenicity in vivo in NOD/SCID mice were investigated. 82.3 cells exhibited epithelial morphology and cell markers (EPCAM, CK7, and CK19); they also expressed different cancer stem markers (CD44, CD133, CD49b, CD24, Stro1, PAX6, FOXA2, OCT3/4), α–fetoprotein and under anchorage-independent and serum-free conditions were capable of originating cholangiospheres. The population doubling time was approximately 53 h. In vitro, they demonstrated a poor ability to migrate; in vivo, 82.3 cells retained their tumorigenicity, with a long latency period (16 weeks). Genetic identity using DNA fingerprinting analysis revealed 16 different loci, and the cell line was characterized by a complex hyperdiploid karyotype. Furthermore, 82.3 cells showed cross-resistance to gemcitabine, 5-fluorouracil, carboplatin, and oxaliplatin; in fact, their genetic profile showed that 60% of genes (n = 168), specific for drug resistance and related to the epithelial-mesenchymal transition, were deregulated in 82.3 cells compared to a control iCCA cell line sensitive to chemotherapeutics. RNA sequencing analysis revealed the enrichment for genes associated with epithelial to mesenchymal transition (EMT), vasculature development, and extracellular matrix (ECM) remodeling, underlining an aggressive phenotype. In conclusion, we have created a new iCCA cell line of Caucasian origin: this could be exploited as a preclinical model to study drug resistance mechanisms and to identify alternative therapies to improve the prognosis of this tumor type.

Evaluation of MACF1-regulatory non-coding RNA as a potential therapeutic target in Colorectal Cancer

QJM ◽  
2021 ◽  
Vol 114 (Supplement_1) ◽  
Author(s):  
Rowaida Mohammed Reda M. M Aboushahba ◽  
Fayda Ibrahim Abdel Motaleb ◽  
Ahmed Abdel Aziz Abou-Zeid ◽  
Enas Samir Nabil ◽  
Dalia Abdel-Wahab Mohamed ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cell Proliferation ◽  
Wnt Signaling ◽  
Cell Line ◽  
Signaling Pathway ◽  
Therapeutic Target ◽  
Molecular Mechanisms ◽  
Wnt Signaling Pathway ◽  
Control Group ◽  
Potential Therapeutic Target

ABSTRACT Colorectal cancer (CRC) is one of the leading causes of cancer-related deaths world-wide. There is an increasing need for the identification of novel biomarkers/targets for early diagnosis and for the development of novel chemopreventive and therapeutic agents for CRC. Recently, MACF1 gene has emerged as a potential therapeutic target in cancer as it involved in processes critical for tumor cell proliferation, invasion and metastasis. It is suggested that MACF1 may function in cancers through Wnt signaling. MiR-34a is a well-known tumor suppressor miRNA.miR-34a targets MACF1 gene as a part of the wnt signaling pathway. In this study, 40 colonic tissues were collected from CRC patients (20) and control subjects (20). miR-34a-5p was assessed by real time PCR in all study groups. The results showed highly significant decrease (P < 0.01) in miR-34a relative expression in the CRC group (median RQ 0.13) when compared to the benign group (median RQ 5.3) and the healthy control group (median RQ 19.63). miR-34a mimic and inhibitor were transfected in CaCo-2 cell line and proliferation was assessed. The transfection of the cell line with miR-34a mimic decreased cell proliferation. Our study suggests that miR-34a-5p targets MACF1 gene as a part of the wnt signaling pathway leading to the involvement in the molecular mechanisms of CRC development and progression.

scholarly journals Proton-irradiated breast cells: molecular points of view

2019 ◽  
Vol 60 (4) ◽  
pp. 451-465 ◽  
Author(s):  
Valentina Bravatà ◽  
Francesco P Cammarata ◽  
Luigi Minafra ◽  
Pietro Pisciotta ◽  
Concetta Scazzone ◽  
...  
Keyword(s):  
Cell Line ◽  
Cell Fate ◽  
Cell Lines ◽  
Molecular Mechanisms ◽  
Proton Irradiation ◽  
Expression Profiles ◽  
Treatment Plan ◽  
Mcf10a Cell ◽  
Specific Cell ◽  
Dose Dependent

Abstract Breast cancer (BC) is the most common cancer in women, highly heterogeneous at both the clinical and molecular level. Radiation therapy (RT) represents an efficient modality to treat localized tumor in BC care, although the choice of a unique treatment plan for all BC patients, including RT, may not be the best option. Technological advances in RT are evolving with the use of charged particle beams (i.e. protons) which, due to a more localized delivery of the radiation dose, reduce the dose administered to the heart compared with conventional RT. However, few data regarding proton-induced molecular changes are currently available. The aim of this study was to investigate and describe the production of immunological molecules and gene expression profiles induced by proton irradiation. We performed Luminex assay and cDNA microarray analyses to study the biological processes activated following irradiation with proton beams, both in the non-tumorigenic MCF10A cell line and in two tumorigenic BC cell lines, MCF7 and MDA-MB-231. The immunological signatures were dose dependent in MCF10A and MCF7 cell lines, whereas MDA-MB-231 cells show a strong pro-inflammatory profile regardless of the dose delivered. Clonogenic assay revealed different surviving fractions according to the breast cell lines analyzed. We found the involvement of genes related to cell response to proton irradiation and reported specific cell line- and dose-dependent gene signatures, able to drive cell fate after radiation exposure. Our data could represent a useful tool to better understand the molecular mechanisms elicited by proton irradiation and to predict treatment outcome

scholarly journals miR-942-5p Inhibits Proliferation, Metastasis, and Epithelial-Mesenchymal Transition in Colorectal Cancer by Targeting CCBE1

2021 ◽  
Vol 2021 ◽  
pp. 1-13
Author(s):  
Lin Zhou ◽  
Qing Chen ◽  
Jie Wu ◽  
Jian Yang ◽  
Huancai Yin ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Molecular Mechanisms ◽  
Opposite Effect ◽  
Epithelial Mesenchymal Transition ◽  
Cell Counting ◽  
Proliferative Potential ◽  
Mesenchymal Transition ◽  
Downstream Target ◽  
Clinical Biomarker

Although colorectal cancer (CRC) is common, there is a paucity of information regarding its molecular pathogenesis. Studies have shown that miRNAs play pivotal roles in the development and progression of CRC. There is a need to further investigate the biological functions of miRNAs in CRC. In particular, it has been reported that miR-942-5p exhibits tumor-suppressive properties. Thus, we analyzed the functional significance of miR-942-5p in CRC and the underlying molecular mechanisms. We found that miR-942-5p was downregulated in CRC tissues and cells. Cell Counting Kit-8, EdU, and colony formation assays revealed that the overexpression of miR-942-5p by mimics inhibited the proliferation of CRC cells. Use of the miR-942-5p inhibitor effectively enhanced the proliferative potential of CRC cells. Further, in vivo xenograft experiments confirmed these results. Increased expression of miR-942-5p suppressed the invasion, migration, and epithelial-mesenchymal transition of CRC cell lines, while decreased miR-942-5p expression had the opposite effect. CCBE1, a secretory molecule for lymphangiogenesis, was established as a downstream target of miR-942-5p, and its expression was inversely correlated with the expression of miR-942-5p in CRC cells. Additionally, cotransfection of the miR-942-5p inhibitor with si-CCBE1 into CRC cells reversed the effects induced by miR-942-5p overexpression. In conclusion, we confirmed that miR-942-5p exerts oncogenic actions in CRC by targeting CCBE1 and identified miR-942-5p as a potential clinical biomarker for CRC diagnosis and therapy.

scholarly journals Identification of a Glycolysis-Related Gene Signature for Survival Prediction of Ovarian Cancer Patients

2020 ◽  
Author(s):  
Dai Zhang ◽  
Si Yang ◽  
Yiche Li ◽  
Meng Wang ◽  
Jia Yao ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Risk Model ◽  
Cox Regression ◽  
Expression Profiles ◽  
Gynecological Cancer ◽  
Predictive Ability ◽  
Gene Signature ◽  
The Cancer Genome Atlas ◽  
Survival Prediction ◽  
Test Sets

Abstract Background: Ovarian cancer (OV) is deemed as the most lethal gynecological cancer in women. The aim of this study was construct an effective gene prognostic model for OV patients.Methods: The expression profiles of glycolysis-related genes (GRGs) and clinical data of patients with OV were extracted from The Cancer Genome Atlas (TCGA) database. Univariate, multivariate, and least absolute shrinkage and selection operator Cox regression analyses were conducted, and a prognostic signature based on GRGs was constructed. The predictive ability of the signature was analyzed in training and test sets.Results: Based on nine GRGs (ISG20, CITED2, PYGB, IRS2, ANGPTL4, TGFBI, LHX9, PC, and DDIT4), a gene risk signature was identified to predict the outcome of patients with OV. The signature showed a good prognostic ability for OV, particularly high-grade OV, in the TCGA dataset, with areas under the curve of 0.709, 0.762, and 0.808 for 3-, 5- and 10-year survival, respectively. Similar results were found in the test sets, and the signature was also an independent prognostic factor. Moreover, a nomogram combining the prediction model and clinical factors was constructed.Conclusion: Our study established a nine-GRG risk model and a nomogram to better perform on OV patients’ survival prediction. The risk model represents a promising and independent prognostic predictor for OV patients. Moreover, our study of GRGs could offer guidances for underlying mechanisms explorations in the future.

scholarly journals Combination the Gene Expression of Adjacent Normal and Tumor Makes more Robust Gene Signature as Cancer Prognosis Biomarker

2020 ◽  
Author(s):  
Wei Ma ◽  
Dandan Li ◽  
Changjian Zhang ◽  
Ming Xiong ◽  
Yuanyuan Qiao
Keyword(s):  
Expression Profile ◽  
Normal Tissue ◽  
Cox Regression ◽  
Expression Profiles ◽  
Lung Squamous Cell Carcinoma ◽  
Enrichment Analysis ◽  
Gene Signature ◽  
The Cancer Genome Atlas ◽  
Cancer Prognosis ◽  
Adjacent Normal Tissue

Abstract Purpose: We tried to explore new gene signature via the combination of tumor-derived expression profile and the adjacent normal-derived expression profile to find more robust cancer biomarker. Methods: Log2 transformed ratio of tumor tissue and the adjacent normal tissue (Log2TN) expression, tumor-derived expression, and normal-derived expression were used to do univariate Cox regression in The Cancer Genome Atlas (TCGA) lung squamous cell carcinoma (LUSC) respectively. Then, we used factor analysis and least absolute shrinkage and selection operator Cox (LASSO-Cox) to select gene signature in TCGA LUSC for Log2TN, tumor, and adjacent normal respectively.Results: By comparing Log2TN with tumor and adjacent normal in LUSC, we found that genes derived from Log2TN show more robust (p = 0.006 and p = 0.001) and have lower p-values (p < 0.001). Gene signature selected from Log2TN shows the best generalization in the three GEO datasets even though only tumor-derived expression profiles were available in the three datasets. Enrichment analysis showed that the tumor cells mainly focus on proliferation with losing functional of metabolism.Conclusions: These results indicate that (1) Log2TN could get more robust genes and gene signature than tumor-derived expression profiles used traditionally; (2) the adjacent-normal tissue may also play an important role in the progress and outcome of the tumor.Implications for Cancer Survivors: By combined of tumor-derived expression profile and the adjacent normal-derived expression profile, we could find more robust gene signature than traditionally method. Using these robust gene signatures, robust cancer biomarkers could be constructed and will do great help to improve cancer prognosis.

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