GABRD promotes progression and predicts poor prognosis in colorectal cancer

AbstractLittle is known about the functional roles of gamma-aminobutyric acid type A receptor subunit delta (GABRD) in colorectal cancer (CRC). The expression of GABRD between CRCs and adjacent normal tissues (NTs), metastasis and primary tumors was compared using public transcriptomic datasets. A tissue microarray and immunohistochemical staining (IHC) were used to determine the clinical and prognostic significance of the GABRD in CRC. We used gain-of-function and loss-of-function experiments to investigate the in vitro roles of GABRD in cultured CRC cells. We characterized the potential mechanism of GABRD’s activities in CRC using a Gene Set Enrichment Analysis (GSEA) with The Cancer Genome Atlas Colon Adenocarcinoma (TCGA-COAD) dataset. We found that the GABRD expression was significantly increased in CRCs compared to that in NTs, but was similar between metastasis and primary tumors. Overexpression of GABRD was significantly associated with later pTNM stages and unfavorable patient survival. Overexpression of GABRD accelerated while knock-down of GABRD inhibited cell growth and migration. Mechanistically, the function of GABRD might be ascribed to its influence on major oncogenic events such as epithelial–mesenchymal transition (EMT), angiogenesis, and hedgehog signaling. Collectively, GABRD could be a novel prognostic predictor for CRC that deserves further investigation.

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RGL2 Drives the Metastatic Progression of Colorectal Cancer via Preventing the Protein Degradation of β-Catenin and KRAS

Cancers ◽

10.3390/cancers13081763 ◽

2021 ◽

Vol 13 (8) ◽

pp. 1763

Author(s):

Meng-Shun Sun ◽

Lan-Ting Yuan ◽

Chia-Hao Kuei ◽

Hui-Yu Lin ◽

Yen-Lin Chen ◽

...

Keyword(s):

Colorectal Cancer ◽

Protein Degradation ◽

Cancer Progression ◽

Epithelial Mesenchymal Transition ◽

Computational Simulation ◽

Gene Set Enrichment Analysis ◽

Metastatic Progression ◽

Primary Tumors ◽

Mesenchymal Transition

Colorectal cancer (CRC) is one of the most common cancers and results in high mortality worldwide, owing to cancer progression, i.e., metastasis. However, the molecular mechanism underlying the metastatic evolution of CRC remains largely unknown. Here, we find that the upregulation of Ral Guanine Nucleotide Dissociation Stimulator Like 2 (RGL2) is commonly detected in primary tumors compared normal tissues and is significantly associated with a poorer prognosis in CRC patients. Moreover, RGL2 expression appeared to positively correlate with the metastatic potentials of CRC cells. Whereas RGL2 knockdown dramatically suppresses the metastatic potentials of CRC cells in vitro and in vivo, RGL2 overexpression in the poorly metastatic CRC cells and reconstitution in the RGL2-silenced CRC cells enhanced and rescued the cellular metastatic ability, respectively. Computational simulation using Gene Set Enrichment Analysis program and cell-based assays demonstrated that RGL2 expression causally associated with the activity of Wnt/β-catenin signaling axis and Kirsten ras (KRAS)S, as well as the progression of epithelial-mesenchymal transition (EMT) in the detected CRC cells. Importantly, RGL2 upregulation was capable of preventing the protein degradation of β-catenin and KRAS in CRC cells. These findings suggest that RGL2 acts as a driver to promote the metastatic progression of CRC and also serves as a poor prognostic biomarker in CRC patients.

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Effect of ISM1 on the Immune Microenvironment and Epithelial-Mesenchymal Transition in Colorectal Cancer

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.681240 ◽

2021 ◽

Vol 9 ◽

Author(s):

Yuhui Wu ◽

Xiaojing Liang ◽

Junjie Ni ◽

Rongjie Zhao ◽

Shengpeng Shao ◽

...

Keyword(s):

Colorectal Cancer ◽

Signaling Pathways ◽

Cox Regression ◽

Epithelial Mesenchymal Transition ◽

Enrichment Analysis ◽

Gene Set Enrichment Analysis ◽

The Cancer Genome Atlas ◽

Mesenchymal Transition ◽

Normal Tissues

Background: An increasing number of studies have shown that Isthmin 1 (ISM1), a secreted protein, is important in tumorigenesis and invasion, including in colorectal cancer (CRC). However, the mechanisms are still unclear. This study aims to explore the function and prognosis capacity of ISM1 in CRC.Methods: We investigated the expression of ISM1 in 18 CRC tissues vs. adjacent normal tissues from GSE50760, 473 CRC tissues vs. 41 normal tissues from The Cancer Genome Atlas (TCGA), and across gastrointestinal cancer types. Differences were further confirmed in CRC tissues via quantitative real-time polymerase chain reaction (qRT-PCR). Then, we analyzed correlations between clinicopathologic features and ISM1 expression, including prognostic prediction value, using the Kaplan–Meier method and multivariate Cox regression. Gene set enrichment analysis (GSEA) was performed to identify ISM1-related pathways. In vitro experiments were performed to verify the role of ISM1 in epithelial-mesenchymal transition (EMT) and CRC progression.Results: Multiple datasets showed that ISM1 is upregulated in CRC tissues, which was validated. Patients with higher ISM1 expression had shorter overall survival (OS), and ISM1 expression served as an independent prognostic factor. Enrichment analysis showed that ISM1 upregulation was positively correlated with cancer-related pathways, such as EMT, hypoxia, and the Notch and KRAS signaling pathways. We were exclusively interested in the connection between ISM1 and EMT because 71% of genes in this pathway were significantly positively co-expressed with ISM1, which may account for why patients with higher ISM1 expression are prone to regional lymph node involvement and progression to advanced stages. In addition, we found that ISM1 was positively correlated with multiple immunosuppressive pathways such as IL2/STAT5, TNF-α/NF-κB, and TGF-β, and immune checkpoints, including PD-L1, PD-1, CTLA-4, and LAG3, which may account for upregulation of ISM1 in immunotherapy-resistant patients. Notably, through in vitro experiments, we found that ISM1 promoted EMT and colon cancer cell migration and proliferation.Conclusion: ISM1 is critical for CRC development and progression, which enhances our understanding of the low response rate of CRC to immunotherapy via immunosuppressive signaling pathways.

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RGL2 Drives the Metastatic Progression of Colorectal Cancer via Preventing the Protein Degradation of β-catenin and KRAS

10.21203/rs.3.rs-229914/v1 ◽

2021 ◽

Author(s):

Meng-Shun Sun ◽

Lan-Ting Yuan ◽

Chia-Hao Kuei ◽

Hui-Yu Lin ◽

Yen-Lin Chen ◽

...

Keyword(s):

Colorectal Cancer ◽

Protein Degradation ◽

Prognostic Significance ◽

Metastatic Potential ◽

Gene Set Enrichment Analysis ◽

Cellular Migration ◽

Metastatic Progression ◽

Primary Tumors ◽

Mesenchymal Transition ◽

Normal Tissues

Abstract Background: Colorectal cancer (CRC) is a common cancer and results in high mortality worldwide, owing to cancer progression, e.g., metastasis. However, the molecular mechanism underlying the metastatic evolution of CRC remains largely unknown. In this study, we investigated the clinical relevance and oncogenic function of RGL2 in CRC.Methods: Cellular migration ability was assessed by transwell cultivation. The metastatic potential was estimated by lung colony-forming assay. DNA-binding activity of transcription factors was determined by luciferase-based reporter assay. RGL2 expression was analyzed by immunohistochemistry in human CRC specimens. RGL2 mRNA expression from the Cancer Genome Atlas (TCGA) CRC database was compared between the primary tumors and normal tissues.Results: The upregulation of Ral Guanine Nucleotide Dissociation Stimulator Like 2 (RGL2) was commonly detected in primary tumors compared with normal tissues and is significantly associated with a poorer prognosis in CRC patients. Moreover, RGL2 expression appeared to positively correlate with the metastatic potential of CRC cells. Whereas RGL2 knockdown dramatically suppressed the metastatic potential of CRC cells in vitro and in vivo, RGL2 overexpression in poorly metastatic CRC cells and reconstitution in RGL2-silenced CRC cells enhanced and rescued the cellular metastatic ability, respectively. Computational simulation using the Gene Set Enrichment Analysis program and cell-based assays demonstrated that RGL2 expression was causally associated with the activity of the Wnt/β-catenin signaling axis and KRAS, as well as the progression of epithelial-mesenchymal transition (EMT) in the detected CRC cells. Importantly, RGL2 upregulation was capable of preventing the protein degradation of β-catenin and KRAS in CRC cells. Conclusion: RGL2 has metastasis-promoting effects via stabilizing β-catenin and KRAS in CRC cells and prognostic significance in CRC patients. These findings suggest that RGL2 acts as a driver to promote the metastatic progression of CRC and serves as a poor prognostic biomarker in CRC patients.

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Identification of a Novel Epithelial-Mesenchymal Transition Gene Signature Regulated by KEAP1-NRF2 Pathway in Esophageal Carcinoma

10.21203/rs.3.rs-77379/v1 ◽

2020 ◽

Author(s):

Mohamed Elshaer ◽

Ahmed Hammad ◽

Xiu Jun Wang ◽

Xiuwen Tang

Keyword(s):

Cell Lines ◽

Epithelial Mesenchymal Transition ◽

Cancer Cell Line ◽

Enrichment Analysis ◽

Gene Signature ◽

Gene Set Enrichment Analysis ◽

The Cancer Genome Atlas ◽

Mesenchymal Transition ◽

Gene Set ◽

Over Expression

Abstract BackgroundKEAP1-NRF2 pathway alterations were identified in many cancers including, esophageal cancer (ESCA). Identifying biomarkers that are associated with mutations in this pathway will aid in defining this cancer subset; and hence in supporting precision and personalized medicine. MethodsIn this study, 182 tumor samples from the Cancer Genome Atlas (TCGA)-ESCA RNA-Seq V2 level 3 data were segregated into two groups KEAP1-NRF2-mutated (22) and wild-type (160).The two groups were subjected to differential gene expression analysis, and we performed Gene Set Enrichment Analysis (GSEA) to determine all significantly affected biological pathways. Then, the enriched gene set was integrated with the differentially expressed genes (DEGs) to identify a gene signature regulated by the KEAP1-NRF2 pathway in ESCA. Furthermore, we validated the gene signature using mRNA expression data of ESCA cell lines provided by the Cancer Cell Line Encyclopedia (CCLE). The identified signature was tested in 3 independent ESCA datasets to assess its prognostic value.ResultsWe identified 11 epithelial-mesenchymal transition (EMT) genes regulated by the KEAP1-NRF2 pathway in ESCA patients. Five of the 11 genes showed significant over-expression in KEAP1-NRF2-mutated ESCA cell lines. In addition, the over-expression of these five genes was significantly associated with poor survival in 3 independent ESCA datasets, including the TCGA-ESCA dataset.ConclusionAltogether, we identified a novel EMT 5-gene signature regulated by the KEAP1-NRF2 axis and this signature is strongly associated with metastasis and drug resistance in ESCA. These 5-genes are potential biomarkers and therapeutic targets for ESCA patients in whom the KEAP1-NRF2 pathway is altered.

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GPD1L Suppresses Colon Adenocarcinoma Via Repressing TGFβ1/EMT

10.21203/rs.3.rs-1120400/v1 ◽

2021 ◽

Author(s):

Yunqi Li ◽

Minghao Liu ◽

zhu xiang ◽

Xuhui Yang ◽

Hui Liu

Keyword(s):

Transforming Growth Factor ◽

Epithelial Mesenchymal Transition ◽

Colon Adenocarcinoma ◽

Gene Set Enrichment Analysis ◽

The Cancer Genome Atlas ◽

Migration And Invasion ◽

Human Beings ◽

Mesenchymal Transition ◽

Adenocarcinoma Cells ◽

Colon Adenocarcinoma Cells

Abstract Colon adenocarcinoma is one of the most prevalent malignant tumors in human beings. Hence, the identification of valuable biomarkers and therapeutic targets is vital for improved treatment and patient outcomes. The role of glycerol-3-phosphate dehydrogenase 1-like (GPD1L) in several tumors has been achieved in recent years. However, the underlying mechanisms of GPD1L in colon adenocarcinoma remain elusive. In this study, we identified that GPD1L was associated with better prognosis in colon adenocarcinoma patients using gene expression omnibus (GEO) and the cancer genome atlas (TCGA) database. In addition, knockdown of GPD1L promoted the proliferation, migration and invasion and reversed by re-expression GPD1L in colon adenocarcinoma cells in vitro. According to gene set enrichment analysis (GSEA), GPD1L is closely correlated with transforming growth factor-β (TGFβ) signaling pathway in colon adenocarcinoma. Moreover, GPD1L downregulates epithelial mesenchymal transition (EMT) marker proteins via TGFβ1 due to Western blot analysis. These findings demonstrate that GPD1L inhibits the growth of colon adenocarcinoma cells by inhibiting EMT induced by TGFβ1. GPD1L may be a promising molecular target for the treatment of colon adenocarcinoma patients.

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

BMC Cancer ◽

10.1186/s12885-020-07615-5 ◽

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.

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Differences in the expression of epithelial–mesenchymal transition related molecules between primary tumors and pulmonary metastatic tumors in colorectal cancer

Surgery Today ◽

10.1007/s00595-012-0344-0 ◽

2012 ◽

Vol 43 (1) ◽

pp. 73-80 ◽

Cited By ~ 10

Author(s):

Hidenori Kouso ◽

Tokujiro Yano ◽

Riichiroh Maruyama ◽

Yasunori Shikada ◽

Tatsuro Okamoto ◽

...

Keyword(s):

Colorectal Cancer ◽

Epithelial Mesenchymal Transition ◽

Metastatic Tumors ◽

Primary Tumors ◽

Mesenchymal Transition

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MYSM1 inhibits human colorectal cancer tumorigenesis by activating miR-200 family members/CDH1 and blocking PI3K/AKT signaling

Journal of Experimental & Clinical Cancer Research ◽

10.1186/s13046-021-02106-2 ◽

2021 ◽

Vol 40 (1) ◽

Author(s):

Xu Chen ◽

Wei Wang ◽

Yufang Li ◽

Yi Huo ◽

Han Zhang ◽

...

Keyword(s):

Colorectal Cancer ◽

Cell Proliferation ◽

Epithelial Mesenchymal Transition ◽

Epigenetic Modification ◽

Clinical Stage ◽

Akt Signaling ◽

Mechanistic Study ◽

Loss Of Function ◽

Predisposing Factor ◽

Mesenchymal Transition

Abstract Background Histone epigenetic modification disorder is an important predisposing factor for the occurrence and development of many cancers, including colorectal cancer (CRC). The role of MYSM1, a metalloprotease that deubiquitinates monoubiquitinated histone H2A, in colorectal cancer was identified to evaluate its potential clinical application value. Methods MYSM1 expression levels in CRC cell lines and tumor tissues were detected, and their associations with patient survival rate and clinical stage were analyzed using databases and tissue microarrays. Gain- and loss-of-function studies were performed to identify the roles of MYSM1 in CRC cell proliferation, apoptosis, cell cycle progression, epithelial-mesenchymal transition (EMT) and metastasis in vitro and in vivo. ChIP, rescue assays and signal pathway verification were conducted for mechanistic study. Immunohistochemistry (IHC) was used to further assess the relationship of MYSM1 with CRC diagnosis and prognosis. Results MYSM1 was significantly downregulated and was related to the overall survival (OS) of CRC patients. MYSM1 served as a CRC suppressor by inducing apoptosis and inhibiting cell proliferation, EMT, tumorigenic potential and metastasis. Mechanistically, MYSM1 directly bound to the promoter region of miR-200/CDH1, impaired the enrichment of repressive H2AK119ub1 modification and epigenetically enhanced miR-200/CDH1 expression. Testing of paired CRC patient samples confirmed the positive regulatory relationship between MYSM1 and miR-200/CDH1. Furthermore, silencing MYSM1 stimulated PI3K/AKT signaling and promoted EMT in CRC cells. More importantly, a positive association existed between MYSM1 expression and a favorable CRC prognosis. Conclusions MYSM1 plays essential suppressive roles in CRC tumorigenesis and is a potential target for reducing CRC progression and distant metastasis.

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COPB2: A Novel Prognostic Biomarker That Affects Progression of HCC

BioMed Research International ◽

10.1155/2021/6648078 ◽

2021 ◽

Vol 2021 ◽

pp. 1-14

Author(s):

Jiayao Zhang ◽

Xiaoyu Wang ◽

Guangbing Li ◽

Jingyi He ◽

Ziwen Lu ◽

...

Keyword(s):

Survival Analysis ◽

Epithelial Mesenchymal Transition ◽

Prognostic Biomarker ◽

Cancer Genome ◽

Gene Set Enrichment Analysis ◽

The Cancer Genome Atlas ◽

Migration And Invasion ◽

Clinicopathologic Characteristics ◽

Mesenchymal Transition ◽

Kaplan Meier

Purpose. This study is aimed at investigating the expression, underlying biological function, and clinical significance of coatomer protein complex subunit beta 2 (COPB2) in hepatocellular carcinoma (HCC). Methods. HCC-related data were extracted from The Cancer Genome Atlas (TCGA) database, International Cancer Genome Consortium (ICGC) database, and Gene Expression Omnibus (GEO) database. A logistic regression module was applied to analyze the relationship between the expression of COPB2 and clinicopathologic characteristics. The Cox proportional hazard regression model and Kaplan–Meier method were used for survival analysis. Gene set enrichment analysis (GSEA) was used to annotate the underlying biological functions. Loss-of-function experiments were conducted to determine the underlying mechanisms. Results. COPB2 was overexpressed in HCC, and high expression of COPB2 was significantly correlated with higher alpha fetoprotein (AFP) (odds ratio OR = 1.616 , >20 vs. ≤20, p < 0.05 ), stage ( OR = 1.744 , III vs. I, p < 0.05 ), and grade ( OR = 1.746 , G4+G3 vs. G2+G1, p < 0.05 ). Kaplan–Meier survival analysis showed that HCC patients with high COPB2 expression had a worse prognosis than those with low COPB2 expression ( p < 0.0001 for TCGA cohort, p < 0.05 for ICGC cohort). The univariate Cox (hazard ratio HR = 1.068 , p < 0.0001 ) and multivariate Cox ( HR = 2.011 , p < 0.05 ) regression analyses suggested that COPB2 was an independent risk factor. GSEA showed that mTOR and other tumor-related signaling pathways were differentially enriched in the high COPB2 expression phenotype. Silencing of COPB2 inhibited the proliferation, migration, and invasion abilities by suppressing epithelial-mesenchymal transition and mTOR signaling. Conclusion. COPB2 is a novel prognostic biomarker and a promising therapeutic target for HCC.

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NKCC1 involvement in the epithelial-to-mesenchymal transition is a prognostic biomarker in gliomas

PeerJ ◽

10.7717/peerj.8787 ◽

2020 ◽

Vol 8 ◽

pp. e8787

Author(s):

Huaiyu Sun ◽

Shengrong Long ◽

Bingbing Wu ◽

Jia Liu ◽

Guangyu Li

Keyword(s):

Epithelial Mesenchymal Transition ◽

Gene Set Enrichment Analysis ◽

The Cancer Genome Atlas ◽

High Expression ◽

Migration And Invasion ◽

Intracranial Tumors ◽

Transwell Assay ◽

Western Blots ◽

Mesenchymal Transition ◽

Expression Levels

Background Gliomas are the most prevalent type of intracranial tumors. NKCC1 is an important regulator in tumor cell volume. We noticed that abnormally high NKCC1 expression resulted in changes in the shape and adhesion of glioma cells. However, little is known about the role of NKCC1 in the epithelial-mesenchymal transition (EMT) of gliomas. This study aims to clarify the biological function of NKCC1 in glioblastoma multiforme (GBM) progression. Methods Using data from The Cancer Genome Atlas (TCGA), we performed a Kaplan–Meier analysis on NKCC1 expression levels to estimate the rate of survival of mesenchymal GBM patients. The correlation between NKCC1 and EMT-related proteins was analyzed from the Gene Expression Profiling Interactive Analysis (GEPIA) server. We conducted Gene Set Enrichment Analysis (GSEA) to verify molecular signatures and pathways. We then studied the expression of NKCC1 in grade I–IV glioma tissue samples collected from patients using immunohistochemistry (IHC). Finally, we evaluated the effects of NKCC1 migration and invasion on the cellular behaviors of U251 cells using the transwell assay and western blots. Results High NKCC1 expression was associated with poor prognoses in mesenchymal GBM. Our results suggest a correlation between NKCC1 and EMT-protein markers: CDH2 and VIM. GSEA showed that gliomas, TGF-beta signaling and EMT were enriched in the NKCC1 high expression phenotype. Higher expression levels of NKCC1 in gliomas correlate with higher glioma grades. Transwell assay and western blot results demonstrated that the knockdown of NKCC1 led to a reduction in migration and invasion, while also inhibiting MMP-2 and MMP-9 expression in U251. Conclusion These results suggest that high expression of NKCC1 regulates EMT in gliomas, providing a new therapeutic strategy for addressing the spread of gliomas by inhibiting the spread of intracranial tumors.

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