scholarly journals INHBB Is a Novel Prognostic Biomarker Associated with Cancer-Promoting Pathways in Colorectal Cancer

2020 ◽  
Vol 2020 ◽  
pp. 1-14
Author(s):  
Jinpeng Yuan ◽  
Aosi Xie ◽  
Qiangjian Cao ◽  
Xinxin Li ◽  
Juntian Chen
Keyword(s):  
Colorectal Cancer ◽  
Signaling Pathways ◽  
Signaling Pathway ◽  
Transforming Growth Factor ◽  
Cox Regression ◽  
Prognostic Biomarker ◽  
Disease Free Survival ◽  
Gene Set Enrichment Analysis ◽  
The Cancer Genome Atlas ◽  
Receptor Interaction

Background. Inhibin subunit beta B (INHBB) is a protein-coding gene that participated in the synthesis of the transforming growth factor-β (TGF-β) family members. The study is aimed at exploring the clinical significance of INHBB in patients with colorectal cancer (CRC) by bioinformatics analysis. Methods. Real-time PCR and analyses of Oncomine, Gene Expression Omnibus (GEO), and The Cancer Genome Atlas (TCGA) databases were utilized to evaluate the INHBB gene transcription level of colorectal cancer (CRC) tissue. We evaluated the INHBB methylation level and the relationship between expression and methylation levels of CpG islands in CRC tissue. The corresponding clinical data were obtained to further explore the association of INHBB with clinical and survival features. In addition, Gene Set Enrichment Analysis (GSEA) was performed to explore the gene ontology and signaling pathways of INHBB involved. Results. INHBB expression was elevated in CRC tissue. Although the promoter of INHBB was hypermethylated in CRC, methylation did not ultimately correlate with the expression of INHBB. Overexpression of INHBB was significantly and positively associated with invasion depth, distant metastasis, and TNM stage. Cox regression analyses and Kaplan-Meier survival analysis indicated that high expression of INHBB was correlated with worse overall survival (OS) and disease-free survival (DFS). GSEA showed that INHBB was closely correlated with 5 cancer-promoting signaling pathways including the Hedgehog signaling pathway, ECM receptor interaction, TGF-β signaling pathway, focal adhesion, and pathway in cancer. INHBB expression significantly promoted macrophage infiltration and inhibited memory T cell, mast cell, and dendritic cell infiltration. INHBB expression was positively correlated with stromal and immune scores of CRC samples. Conclusion. INHBB might be a potential prognostic biomarker and a novel therapeutic target for CRC.

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

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.

scholarly journals APLN: A potential novel biomarker for cervical cancer

2021 ◽  
Vol 104 (2) ◽  
pp. 003685042110113
Author(s):  
Yusha Chen ◽  
Xiaoqian Lin ◽  
Jinwen Zheng ◽  
Jiancui Chen ◽  
Huifeng Xue ◽  
...  
Keyword(s):  
Cervical Cancer ◽  
Cox Regression ◽  
Clinical Stage ◽  
Mapk Signaling ◽  
Gene Set Enrichment Analysis ◽  
The Cancer Genome Atlas ◽  
High Expression ◽  
Receptor Interaction ◽  
Primary Therapy ◽  
Advanced Clinical Stage

Apelin (APLN) is recently demonstrated a direct association with many malignant diseases. However, its effects on cervical cancer remain unclear. This study therefore aims to evaluate the association between APLN expression and cervical cancer using publicly available data from The Cancer Genome Atlas (TCGA). The Pearson χ2 test and Fish exact test, as well as logistic regression, were used to evaluate the relationship between clinicopathological factors in cervical cancer and the expression of APLN. Additionally, the Cox regression and Kaplan-Meier methods were conducted to analyze the Overall Survival (OS) of cervical cancer patients in TCGA. Finally, gene set enrichment analysis (GSEA) was performed to establish its biological functions. High expression of APLN in cervical cancer was significantly associated with a more advanced clinical stage (OR = 1.91 (1.21–3.05) for Stage II, Stage III, and Stage IV vs Stage I, p = 0.006). Additionally, it was associated with poor outcome after primary therapy (OR = 2.14 (1.03–4.59) for Progressive Disease (PD), Stable Disease (SD), and Partial Response (PR) vs Complete Remission (CR), p = 0.045) and high histologic grade (OR = 1.67 (1.03–2.72) for G3 and G4 vs G1 and G2, p = 0.037). Moreover, multivariate analysis showed that high expression of APLN was associated with a shorter OS. GSEA demonstrated that six KEGG pathways, including PPAR signaling, ECM-receptor interaction, focal adhesion, MAPK signaling, TGF-beta signaling, and Gap junction pathways were differentially enriched in the high expression APLN phenotype. The recent study suggests that APLN plays an important role in the progression of cervical cancer and might be a promising prognostic biomarker of the disease.

scholarly journals Comprehensive analysis of tumor microenvironment landscape and potential therapeutic agents based on tumor-infiltrating immune cells in colorectal cancer

2021 ◽  
Author(s):  
Wenhui Zhong ◽  
Feng Zhang ◽  
Xin Lu ◽  
Kaijun Huang ◽  
Junming Bi ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Tumor Microenvironment ◽  
Immune Cells ◽  
Transforming Growth Factor ◽  
Immune Cell ◽  
Cancer Therapeutics ◽  
The Cancer Genome Atlas ◽  
Receptor Interaction ◽  
Chemotherapy Drugs ◽  
Drug Compounds

Abstract Background: Tumor-infiltrating immune cells (TIIC) are the major components of the tumor microenvironment (TME) and play vital roles in the tumorigenesis and progression of colorectal cancer (CRC). Increasing evidence has elucidated their significances in predicting prognosis and therapeutic efficacy. Nonetheless, the immune infiltrative landscape of CRC remains largely unknown. Methods: All the RNA-seq transcriptome data and full clinical annotation of 1213 colorectal cancer patients were downloaded from The Cancer Genome Atlas (TCGA) and Gene-Expression Omnibus (GEO) database. The “CIBERSORT” and “estimate” R package were applied to calculate 22 infiltrated immune cell fractions and stromal and immune score. Three TIIC patterns were determined by Unsupervised clustering methods. Through using principal-component analysis, TIIC scores were established. Data for potential agents comes from the Profiling Relative Inhibition Simultaneously in Mixtures (PRISM) and Cancer Therapeutics Response Portal database (CTRP). Results：In this study, we identified three distinct TIIC patterns characterized by distinct immunological features in 1213 CRC samples from multiple platforms. Base on the TIIC-related gene signatures from three clusters, we constructed a scoring system to quantify the immune infiltration level of individual samples in the CRC cohort and the clinical benefits of different groups. The high TIIC score group was marked by increased immune activation status and favorable prognosis. Conversely, low TIIC score group was featured with immune-desert phenotype and poor prognosis, along with the activation of transforming growth factor-β (TGF-β), WNT, ECM receptor interaction, and VEGF signaling pathways. Meanwhile, the high TIIC score group was also correlated with enhanced efficacy of immunotherapy. Additional, four chemotherapy drugs, seven CTRP-derived drug compounds and six PRISM-derived drug compounds were identified as potential drug for CRC among high and low TIIC subgroups.Conclusions: Collectively, as an effective prognostic biomarker and predictive indicator, the TIIC score plays an important role in the evaluation of CRC prognosis and the response of immunotherapy. Investigation of the TIIC patterns might provide us a promising target for improving immunotherapeutic efficacy in CRC.

scholarly journals SERPINE1 associated with remodeling of the tumor microenvironment in colon cancer progression: a novel therapeutic target

BMC Cancer ◽  
2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Shaokun Wang ◽  
Li Pang ◽  
Zuolong Liu ◽  
Xiangwei Meng
Keyword(s):  
Colorectal Cancer ◽  
Colon Cancer ◽  
Immune Cells ◽  
Immune Cell ◽  
Cox Regression ◽  
Gene Set Enrichment Analysis ◽  
The Cancer Genome Atlas ◽  
Cell Infiltration ◽  
Immune Cell Infiltration ◽  
The Relationship

Abstract Background The change of immune cell infiltration essentially influences the process of colorectal cancer development. The infiltration of immune cells can be regulated by a variety of genes. Thus, modeling the immune microenvironment of colorectal cancer by analyzing the genes involved can be more conducive to the in-depth understanding of carcinogenesis and the progression thereof. Methods In this study, the number of stromal and immune cells in malignant tumor tissues were first estimated by using expression data (ESTIMATE) and cell-type identification with relative subsets of known RNA transcripts (CIBERSORT) to calculate the proportion of infiltrating immune cell and stromal components of colon cancer samples from the Cancer Genome Atlas database. Then the relationship between the TMN Classification and prognosis of malignant tumors was evaluated. Results By investigating differentially expressed genes using COX regression and protein-protein interaction network (PPI), the candidate hub gene serine protease inhibitor family E member 1 (SERPINE1) was found to be associated with immune cell infiltration. Gene Set Enrichment Analysis (GSEA) further projected the potential pathways with elevated SERPINE1 expression to carcinogenesis and immunity. CIBERSORT was subsequently utilized to investigate the relationship between the expression differences of SERPINE1 and immune cell infiltration and to identify eight immune cells associated with SERPINE1 expression. Conclusion We found that SERPINE1 plays a role in the remodeling of the colon cancer microenvironment and the infiltration of immune cells.

scholarly journals Upregulation of GNPNAT1 Predicts Poor Prognosis and Correlates With Immune Infiltration in Lung Adenocarcinoma

2021 ◽  
Vol 8 ◽  
Author(s):  
Wenting Liu ◽  
Kaiting Jiang ◽  
Jingya Wang ◽  
Ting Mei ◽  
Min Zhao ◽  
...  
Keyword(s):  
Lung Adenocarcinoma ◽  
Signaling Pathways ◽  
Poor Prognosis ◽  
Cox Regression ◽  
Clinical Stage ◽  
Gene Set Enrichment Analysis ◽  
The Cancer Genome Atlas ◽  
Clinical Value ◽  
Cox Regression Analysis ◽  
Normal Tissues

BackgroundGlucosamine 6-phosphate N-acetyltransferase (GNPNAT1) is a key enzyme in the hexosamine biosynthetic pathway (HBP), which functions as promoting proliferation in some tumors, yet its potential biological function and mechanism in lung adenocarcinoma (LUAD) have not been explored.MethodsThe mRNA differential expression of GNPNAT1 in LUAD and normal tissues was analyzed using the Cancer Genome Atlas (TCGA) database and validated by real-time PCR. The clinical value of GNPNAT1 in LUAD was investigated based on the data from the TCGA database. Then, immunohistochemistry (IHC) of GNPNAT1 was applied to verify the expression and clinical significance in LUAD from the protein level. The relationship between GNPNAT1 and epigenetics was explored using the cBioPortal database, and the miRNAs regulating GNPNAT1 were found using the miRNA database. The association between GNPNAT1 expression and tumor-infiltrating immune cells in LUAD was observed through the Tumor IMmune Estimation Resource (TIMER). Finally, Gene set enrichment analysis (GSEA) was used to explore the biological signaling pathways involved in GNPNAT1 in LUAD.ResultsGNPNAT1 was upregulated in LUAD compared with normal tissues, which was verified through qRT-PCR in different cell lines (P < 0.05), and associated with patients’ clinical stage, tumor size, and lymphatic metastasis status (all P < 0.01). Kaplan–Meier (KM) analysis suggested that patients with upregulated GNPNAT1 had a relatively poor prognosis (P < 0.0001). Furthermore, multivariate Cox regression analysis indicated that GNPNAT1 was an independent prognostic factor for LUAD (OS, TCGA dataset: HR = 1.028, 95% CI: 1.013–1.044, P < 0.001; OS, validation set: HR = 1.313, 95% CI: 1.130–1.526, P < 0.001). GNPNAT1 overexpression was correlated with DNA copy amplification (P < 0.0001), low DNA methylation (R = −0.52, P < 0.0001), and downregulation of hsa-miR-30d-3p (R = −0.17, P < 0.001). GNPNAT1 expression was linked to B cells (R = −0.304, P < 0.0001), CD4+T cells (R = −0.218, P < 0.0001), and dendritic cells (R = −0.137, P = 0.002). Eventually, GSEA showed that the signaling pathways of the cell cycle, ubiquitin-mediated proteolysis, mismatch repair and p53 were enriched in the GNPNAT1 overexpression group.ConclusionGNPNAT1 may be a potential prognostic biomarker and novel target for intervention in LUAD.

scholarly journals Identification of a Hypoxia - Related lncRNA Signature For The Prognosis of Colorectal Cancer

2021 ◽  
Author(s):  
HUA HUANG ◽  
Shanshan Xu ◽  
Youran Li ◽  
Yunfei Gu ◽  
Lijiang Ji
Keyword(s):  
Colorectal Cancer ◽  
Roc Analysis ◽  
Cox Regression ◽  
Differential Expression Analysis ◽  
Enrichment Analysis ◽  
Gene Set Enrichment Analysis ◽  
Receptor Interaction ◽  
Prognostic Signature ◽  
Gene Set Enrichment ◽  
Gene Set

Abstract Background: Colorectal cancer (CRC), the commonly seen malignancy, ranks the 3rd place among the causes of cancer-associated mortality. As suggested by more and more studies, long coding RNAs (lncRNAs) have been considered as prognostic biomarkers for CRC. But the significance of hypoxic lncRNAs in predicting CRC prognosis remains unclear.Methods: The gene expressed profiles for CRC cases were obtained based on the Cancer Genome Atlas (TCGA) and applied to estimate the hypoxia score using a single-sample gene set enrichment analysis (ssGSEA) algorithm. Overall survival (OS) of high- and low-hypoxia score group was analyzed by the Kaplan–Meier (KM) plot. To identify differentially expressed lncRNAs (DELs) between two hypoxia score groups, this study carried out differential expression analysis, and then further integrated with the DELs between controls and CRC patients to generate the hypoxia-related lncRNAs for CRC. Besides, prognostic lncRNAs were screened by the univariate Cox regression, which were later utilized for constructing the prognosis nomogram for CRC by adopting the least absolute shrinkage and selection operator (LASSO) algorithm. In addition, both accuracy and specificity of the constructed prognostic signature were detected through the receiver operating characteristic (ROC) analysis. Moreover, our constructed prognosis signature also was validated in the internal testing test. This study operated gene set enrichment analysis (GSEA) for exploring potential biological functions associated with the prognostic signature. Finally, the ceRNA network of the prognostic lncRNAs was constructed.Results: Among 2299 hypoxia-related lncRNAs of CRC in total, LINC00327, LINC00163, LINC00174, SYNPR-AS1, and MIR31HG were identified as prognostic lncRNAs by the univariate Cox regression, and adopted for constructing the prognosis signature for CRC. ROC analysis showed the predictive power and accuracy of the prognostic signature. Additionally, the GSEA revealed that ECM-receptor interaction, PI3K-Akt pathway, phagosome, and Hippo pathway were mostly associated with the high-risk group. 352 miRNAs-mRNAs pairs and 177 lncRNAs-miRNAs were predicted.Conclusion: To conclude , we identified 5 hypoxia-related lncRNAs to establish an accurate prognostic signature for CRC, providing important prognostic markers and therapeutic target.

scholarly journals FABP4 Might be an Indicator of the Status of Tumor Microenvironment in Colorectal Cancer

2021 ◽  
Author(s):  
Lijun Ning ◽  
Yuqing Yan ◽  
Tianying Tong ◽  
Ziyun Gao ◽  
Zhe Cui ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
T Cells ◽  
Tumor Microenvironment ◽  
Cox Regression ◽  
Nk Cell ◽  
Gene Set Enrichment Analysis ◽  
The Cancer Genome Atlas ◽  
Fatty Acid Binding ◽  
Cox Regression Analysis ◽  
The Status

Abstract Background: As tumor microenvironment (TME) play an indispensable role in tumorigenesis of colorectal cancer, this study performs a bunch of bioinformatics analysis to identify the indicator of the status of TME in Colorectal cancer (CRC). Results: In the presented study, we applied CIBERSORT and ESTIMATE computational methods to calculate the proportion of tumor-infiltrating immune cells (TICs) and the amount of immune and stromal components in 444 COAD-READ cases from The Cancer Genome Atlas (TCGA) database. The differentially expressed genes (DEGs) were analyzed by COX regression analysis and protein–protein interaction (PPI) network construction. Then, fatty acid-binding protein four ( FABP4 ) was determined as a predictive factor by the intersection analysis of univariate COX and PPI. Further analysis revealed that FABP4 expression was positively correlated with the clinical pathologic characteristics (clinical stage, distant metastasis) and negatively correlated with the survival of CRC patients. Gene Set Enrichment Analysis (GSEA) showed that the genes in the high-expression FABP4 group were mainly enriched in immune-related activities. In the low-expression FABP4 group, the genes were enriched in metabolic pathways. CIBERSORT analysis for the proportion of TICs revealed that NK cell, CD4 + T cells and CD8 + T cells were negatively correlated with FABP4 expression, suggesting that FABP4 might be a potential prognostic factor of CRC patients. Conclusion: Our study has developed a new biomarker (FABP4) that can predict the status of tumor microenvironment in Colorectal cancer. Keywords: FABP4, tumor microenvironment, ESTIMATE, CIBERSORT, colorectal cancer

scholarly journals Identification of a Hypoxia-Related LncRNA Signature for the Prognosis of Colorectal Cancer

2021 ◽  
Author(s):  
Hua Huang ◽  
Mingjia Gu ◽  
Shanshan Xu ◽  
Youran Li ◽  
Yunfei Gu ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Roc Analysis ◽  
Cox Regression ◽  
Differential Expression Analysis ◽  
Enrichment Analysis ◽  
Gene Set Enrichment Analysis ◽  
Receptor Interaction ◽  
Prognostic Signature ◽  
Gene Set Enrichment ◽  
Gene Set

Abstract Background:Colorectal cancer (CRC), the commonly seen malignancy, ranks 3rd place among the causes of cancer-associated mortality. As suggested by more and more studies, long non-coding RNAs (lncRNAs)have been considered as prognostic biomarkers for CRC. But the significance of hypoxic lncRNAs in predicting CRC prognosis remains unclear.Methods:The gene expressed profiles for CRC cases were obtained based on the Cancer Genome Atlas (TCGA) and applied to estimate the hypoxia score using a single-sample gene set enrichment analysis (ssGSEA) algorithm. Overall survival (OS) of the high- and low-hypoxia score group was analyzed by the Kaplan–Meier (KM) plot. To identify differentially expressed lncRNAs (DELs) between two hypoxia score groups, this study carried out differential expression analysis, and then further integrated with the DELs between controls and CRC patients to generate the hypoxia-related lncRNAs for CRC. Besides, prognostic lncRNAs were screened by the univariate Cox regression, which was later utilized for constructing the prognosis nomogram for CRC by adopting the least absolute shrinkage and selection operator (LASSO) algorithm. In addition, both accuracy and specificity of the constructed prognostic signature were detected through the receiver operating characteristic (ROC) analysis. Moreover, our constructed prognosis signature also was validated in the internal testing test. This study operated gene set enrichment analysis (GSEA) for exploring potential biological functions associated with the prognostic signature. Finally, the ceRNA network of the prognostic lncRNAs was constructed.Results:Among 2299 hypoxia-related lncRNAs of CRC in total, LINC00327, LINC00163, LINC00174, SYNPR-AS1, and MIR31HG were identified as prognostic lncRNAs by the univariate Cox regression and adopted for constructing the prognosis signature for CRC. ROC analysis showed the predictive power and accuracy of the prognostic signature. Additionally, the GSEA revealed that ECM-receptor interaction, PI3K-Akt pathway, phagosome, and Hippo pathway were mostly associated with the high-risk group. 352 miRNAs-mRNAs pairs and 177 lncRNAs-miRNAs were predicted.Conclusion:To conclude, we identified 5 hypoxia-related lncRNAs to establish an accurate prognostic signature for CRC, providing important prognostic markers and therapeutic targets.

scholarly journals Exploration of the Key Proteins in the Normal-Adenoma-Carcinoma Sequence of Colorectal Cancer Evolution Using In-Depth Quantitative Proteomics

2021 ◽  
Vol 2021 ◽  
pp. 1-19
Author(s):  
Yin Zhang ◽  
Chun-Yuan Li ◽  
Wei Ge ◽  
Yi Xiao
Keyword(s):  
Colorectal Cancer ◽  
Quantitative Proteomics ◽  
Prognostic Value ◽  
Cox Regression ◽  
Epithelial Mesenchymal Transition ◽  
Disease Free Survival ◽  
Gene Set Enrichment Analysis ◽  
Mesenchymal Transition ◽  
Cox Regression Analysis ◽  
Proteomic Data

Purpose. In most cases, the carcinogenesis of colorectal cancer (CRC) follows the normal-adenoma-carcinoma (N-A-C) sequence. In this study, we aimed to identify the key proteins in the N-A-C sequence. Methods. Differentially expressed proteins (DEPs) in normal, adenoma, and carcinoma tissues were identified using the Tandem Mass Tag- (TMT-) based quantitative proteomics approach. The landscape of proteomic variation in the N-A-C sequence was explored using gene set enrichment analysis (GSEA) and Proteomaps. Key proteins in the N-A-C sequence were identified, verified, and validated based on our proteomic data, external proteomic data, and external transcriptomic data in the ProteomeXchange, CPTAC, GEO, and TCGA databases. The prognostic value of the key proteins in our database was evaluated by univariate and multivariate Cox regression analysis. The effects of the key proteins on adenoma organoids and colorectal cancer cells were explored in functional studies. Results. Based on our proteomic profiles, we identified 1,294 DEPs between the carcinoma (CG) and normal (NG) groups, 919 DEPs between the adenoma group (AG) and NG, and 1,030 DEPs between the CG and AG. Ribosome- and spliceosome-related pathways were mainly enriched in the N-A process. Extracellular matrix- and epithelial-mesenchymal transition- (EMT-) related pathways were mainly enriched in the A-C process. RRP12 and SERPINH1 were identified, verified, and validated as candidate key proteins in the N-A and A-C processes, respectively. Furthermore, RRP12 and SERPINH1 knockdown impeded the viability and proliferation of adenoma organoids. SERPINH1 was validated as a risk factor for disease-free survival (DFS) based on the TCGA and our database, whereas RRP12 did not show prognostic value. SERPINH1 knockdown was accompanied by EMT-related protein variation, increased apoptosis, and reduced proliferation, invasion, and migration of CRC cells in vitro. Conclusions. RRP12 and SERPINH1 may play an important role in the N-A and A-C processes, respectively. Furthermore, SERPINH1 showed favorable prognostic value for DFS in CRC patients. We speculate that SERPINH1 might promote not only the A-C process but also the development of CRC.

scholarly journals TM4SF1 promotes EMT and cancer stemness via the Wnt/β-catenin/SOX2 pathway in colorectal cancer

2020 ◽  
Vol 39 (1) ◽  
Author(s):  
Qiang Tang ◽  
Jinhuang Chen ◽  
Ziyang Di ◽  
Wenzheng Yuan ◽  
Zili Zhou ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Poor Prognosis ◽  
Transforming Growth Factor ◽  
Gene Set Enrichment Analysis ◽  
The Cancer Genome Atlas ◽  
Dependent Manner ◽  
Cancer Stemness ◽  
Mesenchymal Transition ◽  
Sphere Formation

Abstract Background Transmembrane 4 L six family member 1 (TM4SF1) is upregulated in several epithelial cancers and is closely associated with poor prognosis. However, the role of TM4SF1 and its potential mechanism in colorectal cancer (CRC) remain elusive. Methods We investigated the expression of TM4SF1 in the Oncomine, the Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases and confirmed the results by immunohistochemistry (IHC), qPCR and Western blotting (WB) of CRC tissues. The effect of TM4SF1 on the epithelial-to-mesenchymal transition (EMT) and cancer stemness of CRC cells was investigated by Transwell, wound healing and sphere formation assays. A series of in vitro and in vivo experiments were conducted to reveal the mechanisms by which TM4SF1 modulates EMT and cancer stemness in CRC. Results TM4SF1 expression was markedly higher in CRC tissues than in non-tumour tissues and was positively correlated with poor prognosis. Downregulation of TM4SF1 inhibited the migration, invasion and tumour sphere formation of SW480 and LoVo cells. Conversely, TM4SF1 overexpression significantly enhanced the migration, invasion and tumoursphere formation potential of CRC cells, Additionally, TM4SF1 silencing inhibited the EMT mediated by transforming growth factor-β1 (TGF-β1). Mechanistically, gene set enrichment analysis (GSEA) predicted that the Wnt signalling pathway was one of the most impaired pathways in TM4SF1-deficient CRC cells compared to controls. The results were further validated by WB, which revealed that TM4SF1 modulated SOX2 expression in a Wnt/β-catenin activation-dependent manner. Furthermore, we found that knockdown of TM4SF1 suppressed the expression of c-Myc, leading to decreased c-Myc binding to the SOX2 gene promoter. Finally, depletion of TM4SF1 inhibited metastasis and tumour growth in a xenograft mouse model. Conclusion Our study substantiates a novel mechanism by which TM4SF1 maintains cancer cell stemness and EMT via the Wnt/β-catenin/c-Myc/SOX2 axis during the recurrence and metastasis of CRC.

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