A Prognosis Marker SLC2A3 Correlates With EMT and Immune Signature in Colorectal Cancer

SLC2A3 is a membrane transporter that belongs to the solute carrier family, whose function includes transmembrane transport and glucose transmembrane transport activity. To clarify the expression and role of SLC2A3 in colorectal cancer (CRC), we analyzed the TCGA and GEO databases and found that SLC2A3 mRNA levels were significantly higher in CRC tissues than that in adjacent non-tumor tissues. Furthermore, high expression of SLC2A3 predicted poor overall survival and disease free survival for CRC patients. For validation, we collected 174 CRC samples and found that SLC2A3 expression was higher in CRC tissues than that in adjacent non-tumor colorectal mucosa tissues by immunohistochemistry staining. Further study showed that high expression of SLC2A3 was enriched in epithelial–mesenchymal transition (EMT) classical pathway, interferon-γ pathway by GSEA analysis enrichment, indicating that SLC2A3 may play a key role in the progression of CRC through EMT and immune response, which also has been validated by the global gene expression profiling of human CRC cell lines. The expression of SLC2A3 was positively correlated with CD4 and CD8+T cells by using TIMER and EPIC algorithm, respectively. SLC2A3 knockdown suppressed migration and inhibited the expression of Vimentin and MMP9 in CRC cell line SW480 and RKO. Meanwhile, PD-L1 expression was also significantly attenuated in SW480 and RKO cells transfected with SLC2A3 siRNA. The result suggests that SLC2A3 may be involved in the immune response of CRC by regulating PD-L1 immune checkpoint. In our series, SLC2A3 and PD-L1 positive expression was 74% (128/174) and 22% (39/174) of CRC, respectively. SLC2A3 expression was significantly associated with perineural invasion in CRC patients. In conclusion, SLC2A3 may play an important role in progression of CRC by regulating EMT and PD-L1 mediated immune responses.

Download Full-text

Epithelial mesenchymal transition in an advanced BRAF mutation type colorectal cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2018.36.4_suppl.693 ◽

2018 ◽

Vol 36 (4_suppl) ◽

pp. 693-693

Author(s):

Jun-Eul Hwang ◽

Woo Kyun Bae ◽

Hyun-Jeong Shim ◽

Sang-Hee Cho ◽

Ik-Joo Chung

Keyword(s):

Colorectal Cancer ◽

Braf Mutation ◽

Poor Prognosis ◽

Epithelial Mesenchymal Transition ◽

Disease Free Survival ◽

Poor Overall Survival ◽

Free Survival ◽

Mesenchymal Transition ◽

Disease Free ◽

Mutation Type

693 Background: BRAF mutation is associated with poor survival in colorectal cancer. We aimed to generate genomic signature associated with BRAF mutation that possibly predict prognosis in colorectal cancer. Methods: A gene expression signature reflecting BRAF mutation was generated in TCGA cohorts (n = 207). The colorectal cancer patients were stratified into two groups according to this signature: BRAF mutation type colorectal cancer or BRAF wild type colorectal cancer. Prognostic significance of BRAF mutation-associated gene signature was tested in three independent cohorts (GSE 17536, GSE 14333, and GSE 39582). Results: The BRAF mutation signature was associated with poor prognosis in two independent cohorts (total n = 522). BRAF mutation type colorectal cancer was associated with poor disease-free survival (median: not reached, P = 0.0303) in GSE14333, and associated with poor overall survival (BRAF mutation vs. wild, P = 0.0355), poor disease-free survival (P = 0.00794), and poor disease-specific survival (P = 0.0341) in GSE 17536. In GSE 39582, BRAF mutation type colorectal cancer demonstrated the trend of poor overall survival according to increase of stage. In a multivariate analysis, BRAF mutation gene signature was independent poor prognostic factor for disease-free survival (hazard ratio 2.7; 95% CI 1.59-2.83: P = 0.001). Gene network analyses suggested epithelial-mesenchymal transition and colon cancer metastasis signaling are the possible explanations for poor prognosis of BRAF mutation type colorectal cancer. Conclusions: BRAF mutation signature is highly associated with poor prognosis in colorectal cancer, especially in advanced stage, and the molecules associated with epithelial-mesenchymal transition can be potential therapeutic targets in BRAF mutation type colorectal cancer.

Download Full-text

AKT3 Expression in Mesenchymal Colorectal Cancer Cells Drives Growth and Is Associated with Epithelial-Mesenchymal Transition

Cancers ◽

10.3390/cancers13040801 ◽

2021 ◽

Vol 13 (4) ◽

pp. 801

Author(s):

Joyce Y. Buikhuisen ◽

Patricia M. Gomez Barila ◽

Arezo Torang ◽

Daniëlle Dekker ◽

Joan H. de Jong ◽

...

Keyword(s):

Colorectal Cancer ◽

Cancer Cells ◽

Epithelial Mesenchymal Transition ◽

Surrogate Marker ◽

High Expression ◽

Mesenchymal Transition ◽

High Propensity ◽

Colorectal Cancer Cells ◽

Epithelial Compartment ◽

Selection Of

Colorectal cancer (CRC) is a heterogeneous disease that can currently be subdivided into four distinct consensus molecular subtypes (CMS) based on gene expression profiling. The CMS4 subtype is marked by high expression of mesenchymal genes and is associated with a worse overall prognosis compared to other CMSs. Importantly, this subtype responds poorly to the standard therapies currently used to treat CRC. We set out to explore what regulatory signalling networks underlie the CMS4 phenotype of cancer cells, specifically, by analysing which kinases were more highly expressed in this subtype compared to others. We found AKT3 to be expressed in the cancer cell epithelium of CRC specimens, patient derived xenograft (PDX) models and in (primary) cell cultures representing CMS4. Importantly, chemical inhibition or knockout of this gene hampers outgrowth of this subtype, as AKT3 controls expression of the cell cycle regulator p27KIP1. Furthermore, high AKT3 expression was associated with high expression of epithelial-mesenchymal transition (EMT) genes, and this observation could be expanded to cell lines representing other carcinoma types. More importantly, this association allowed for the identification of CRC patients with a high propensity to metastasise and an associated poor prognosis. High AKT3 expression in the tumour epithelial compartment may thus be used as a surrogate marker for EMT and may allow for a selection of CRC patients that could benefit from AKT3-targeted therapy.

Download Full-text

Epithelial-Mesenchymal Transition Phenotype, Metformin, and Survival for Colorectal Cancer Patients with Diabetes Mellitus II

Gastroenterology Research and Practice ◽

10.1155/2017/2520581 ◽

2017 ◽

Vol 2017 ◽

pp. 1-10 ◽

Cited By ~ 5

Author(s):

Yaodu Wang ◽

Zhiyang Wu ◽

Likuan Hu

Keyword(s):

Diabetes Mellitus ◽

Colorectal Cancer ◽

Epithelial Mesenchymal Transition ◽

Disease Free Survival ◽

Multivariate Regression Analysis ◽

Stage I ◽

Clinicopathological Parameters ◽

Mesenchymal Transition ◽

Patients With Diabetes ◽

E Cadherin

Objectives. We aimed to explore the association between metformin treatment and epithelial-mesenchymal transition (EMT) phenotype and further appraise the prognostic values of metformin and EMT markers E-cadherin and vimentin for colorectal cancer (CRC) in clinical practice. Methods. We collected specimens and evaluated clinicopathological parameters of 102 stage I to III CRC patients with prediagnosed type 2 diabetes mellitus (DM II). Expression of E-cadherin and vimentin in tumors was detected by immunohistochemistry (IHC), and statistical analysis was performed using SPSS 19.0. Results. In correlation tests, we found a lower tumor cell EMT degree (more E-cadherin (P=0.014) and less vimentin (P=0.011) expression in patients who used metformin, and the expression of E-cadherin and vimentin was associated with serum CA19-9 (P=0.048, P=0.009), tumor invasive depth (T) (P<0.001, P=0.045), and lymph invasion (N) (P=0.013, P=0.001). In Cox multivariate regression analysis, E-cadherin was identified as a prognostic factor for disease-free survival (DFS) (P=0.038) and metformin use (P=0.015P=0.044) and lymph invasion (P=0.016P=0.023) were considered as the prognostic factors for both DFS and overall survival (OS). Conclusion. Our study suggested that metformin may impede the EMT process and improve survival for stage I–III CRC patients with DM II.

Download Full-text

Aldolase B Overexpression is Associated with Poor Prognosis and Promotes Tumor Progression by Epithelial-Mesenchymal Transition in Colorectal Adenocarcinoma

Cellular Physiology and Biochemistry ◽

10.1159/000477484 ◽

2017 ◽

Vol 42 (1) ◽

pp. 397-406 ◽

Cited By ~ 23

Author(s):

Qingguo Li ◽

Yaqi Li ◽

Junyan Xu ◽

Sheng Wang ◽

Ye Xu ◽

...

Keyword(s):

Colorectal Cancer ◽

Colon Cancer ◽

Cancer Metastasis ◽

Epithelial Mesenchymal Transition ◽

Enzymatic Reaction ◽

Disease Free Survival ◽

Migration And Invasion ◽

Mesenchymal Transition ◽

Aldolase B

Background: Glycolysis is considered to be the root of cancer development and progression, which involved a multi-step enzymatic reaction. Our study aimed at figuring out which glycolysis enzyme participates in the development of colorectal cancer and its possible mechanisms. Methods: We firstly screened out Aldolase B (ALDOB) by performing qRT-PCR arrays of glycolysis-related genes in five paired liver metastasis and primary colorectal tissues, and further detected ALDOB protein with immunohistochemistry in tissue microarray (TMA) consisting of 229 samples from stage I-III colorectal cancer patients. CRISPR-Cas9 method was adopted to create knock out colon cancer cell lines (LoVo and SW480) of ALDOB. The effect of ALDOB on cell proliferation and metastasis was examined in vitro using colony formation assay as well as transwell migration and invasion assay, respectively. Results: In TMA, there was 64.6% of samples demonstrated strong intensity of ALDOB. High ALDOB expression were associated with poor overall survival and disease-free survival in both univariate and multivariate regression analyses (P<0.05). In vitro functional studies of CCK-8 demonstrated that silencing ALDOB expression significantly (P<0.05) inhibited proliferation, migration and invasion of colon cancer cells. Mechanically, silencing ALDOB activated epithelial markers and repressed mesenchymal markers, indicating inactivation of ALDOB may lead to inhibition of epithelial-mesenchymal transition (EMT). Conclusion: Upregulation of ALDOB promotes colorectal cancer metastasis by facilitating EMT and acts as a potential prognostic factor and therapeutic target in colorectal cancer.

Download Full-text

Identification of Epithelial-Mesenchymal Transition-Related lncRNAs that Associated With the Prognosis and Immune Microenvironment in Colorectal Cancer

Frontiers in Molecular Biosciences ◽

10.3389/fmolb.2021.633951 ◽

2021 ◽

Vol 8 ◽

Author(s):

Chuan Liu ◽

Chuan Hu ◽

Jianyi Li ◽

Liqing Jiang ◽

Chengliang Zhao

Keyword(s):

Colorectal Cancer ◽

Functional Analysis ◽

Cox Regression ◽

Epithelial Mesenchymal Transition ◽

Risk Group ◽

Differential Expression Analysis ◽

Disease Free Survival ◽

Immune Microenvironment ◽

Mesenchymal Transition ◽

Kaplan Meier

Background: The expression of long non-coding RNA (lncRNA) is associated with the epithelial-mesenchymal transition (EMT) in tumorigenicity, but the role of EMT-related lncRNA in colorectal cancer (CRC) remains unclear.Methods: The clinical data and gene expression profile of CRC patients were obtained from The Cancer Genome Atlas database. Differential expression analysis, Cox regression model, and Kaplan-Meier analysis were used to study the relationship between EMT-related lncRNAs and the prognosis of CRC. Functional analysis and unsupervised clustering analysis were performed to explore the influence of certain lncRNAs on CRC. Finally, Cytoscape was used to construct mRNA-lncRNA networks.Results: Two signatures incorporating six and ten EMT-related lncRNAs were constructed for predicting the overall survival (OS) and disease-free survival (DFS), respectively. Kaplan-Meier survival curves indicated that patients in the high-risk group had a poorer prognosis than those in the low-risk group. The results of the functional analysis suggested that the P53 and ECM-receptor pathways affect the prognosis of CRC, and AL591178.1 is a key prognostic EMT-related lncRNA, which is negatively related to immune cells, P53 pathway, and ECM-receptor pathway.Conclusion: Six OS-related and ten DFS-related EMT-related lncRNAs were correlated with the prognosis of CRC by potentially affecting the immune microenvironment, and AL591178.1 plays a key role as a prognostic factor.

Download Full-text

CARMA3 Promotes Colorectal Cancer Cell Motility and Cancer Stemness via YAP-Mediated NF-κB Activation

Cancers ◽

10.3390/cancers13235946 ◽

2021 ◽

Vol 13 (23) ◽

pp. 5946

Author(s):

Ting-Yu Chang ◽

Cheng-Tien Wu ◽

Meei-Ling Sheu ◽

Rong-Sen Yang ◽

Shing-Hwa Liu

Keyword(s):

Colorectal Cancer ◽

Cell Proliferation ◽

Cancer Cell ◽

Epithelial Mesenchymal Transition ◽

Stem Cell Markers ◽

Poor Overall Survival ◽

Mesenchymal Transition ◽

Cancer Stem Cell Markers ◽

Underlying Mechanisms

CARD-recruited membrane-associated protein 3 (CARMA3) is overexpressed in various cancers and is associated with cancer cell proliferation, metastasis, and tumor progression; however, the underlying mechanisms of CARMA3 in colorectal cancer (CRC) metastasis remain unclear. Here, we found that higher CARMA3 expression was correlated with poor overall survival and metastasis in CRC patients from the TNMplot database and Human Tissue Microarray staining. Elevating CARMA3 expression promoted cell proliferation, epithelial-mesenchymal transition (EMT) induction, migration/invasion abilities, sphere formation, and cancer stem cell markers expression. Knockdown of CARMA3 decreased these processes via the EMT-related transcription factor Slug. Moreover, CARMA3 depletion significantly reduced tumor growth in mice that were consistent with the in vitro results. CRC migration/invasion could be regulated by CARMA3/YAP/Slug signaling axis using genetic inhibition of Yes-associated protein (YAP). Interestingly, CARMA3 induced activation of nuclear factor (NF)-κB through YAP expression, contributing to upregulation of Slug. YAP expression positively correlated with CARMA3, NF-κB, and Slug gene expression and poor clinical outcomes in CRC patients. Our findings demonstrate for the first time that CARMA3 plays an important role in CRC progression, which may serve as a potential diagnostic biomarker and candidate therapeutic target for CRC treatment.

Download Full-text

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

Journal of Oncology ◽

10.1155/2021/5570058 ◽

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.

Download Full-text

Programmed Death–Ligand 1 and Vimentin: A Tandem Marker as Prognostic Factor in NSCLC

Cancers ◽

10.3390/cancers11101411 ◽

2019 ◽

Vol 11 (10) ◽

pp. 1411 ◽

Cited By ~ 2

Author(s):

Julien Ancel ◽

Philippe Birembaut ◽

Maxime Dewolf ◽

Anne Durlach ◽

Béatrice Nawrocki-Raby ◽

...

Keyword(s):

Overall Survival ◽

Epithelial Mesenchymal Transition ◽

Early Stage ◽

Disease Free Survival ◽

Poor Overall Survival ◽

Vimentin Expression ◽

Programmed Death Ligand 1 ◽

Mesenchymal Transition ◽

Resected Nsclc ◽

Programmed Death

In non-metastatic non-small-cell lung cancer (NSCLC), outcomes remain poor. Adjuvant chemotherapies provide a limited improvement in disease-free survival. Recent exploratory studies on early-stage NSCLC show that immunotherapy given according to Programmed Death–Ligand 1 expression generates variable results, emphasizing a need to improve tumor characterization. We aimed to conjointly assess NSCLC, the expression of PD–L1, and epithelial–mesenchymal transition, frequently involved in tumor aggressiveness. 188 resected NSCLCs were analyzed. Among 188 patients with curatively resected NSCLC, 127 adenocarcinomas and 61 squamous cell carcinomas were stained for PD–L1 and vimentin expression. Overall survival has been compared regarding PD–L1 and vimentin statuses both separately and conjointly in Tumor Cancer Genome Atlas databases. PD–L1 and vimentin higher expressions were strongly associated (OR = 4.682, p < 0.0001). This co-expression occurred preferentially in tumors with lymph node invasion (p = 0.033). PD–L1 was significantly associated with high EMT features. NSCLC harboring both PD–L1high/vimentinhigh expressions were significantly associated with poor overall survival (p = 0.019). A higher co-expression of vimentin and PD–L1 was able to identify patients with worse outcomes. Similar to an important prognostic marker in NSCLC, this tandem marker needs to be further presented to anti-PD–L1 immunotherapies to improve outcome.

Download Full-text

PGK1 is a Potential Survival Biomarker and Invasion Promoter by Regulating the HIF-1α–Mediated Epithelial-Mesenchymal Transition Process in Breast Cancer

Cellular Physiology and Biochemistry ◽

10.1159/000495900 ◽

2018 ◽

Vol 51 (5) ◽

pp. 2434-2444 ◽

Cited By ~ 14

Author(s):

Deyuan Fu ◽

Chunlan He ◽

Jinli Wei ◽

Zhengquan Zhang ◽

Yulin Luo ◽

...

Keyword(s):

Breast Cancer ◽

Cancer Progression ◽

Epithelial Mesenchymal Transition ◽

Target Therapy ◽

Enzymatic Reaction ◽

Disease Free Survival ◽

Transition Process ◽

Dependent Manner ◽

Poor Overall Survival ◽

Mesenchymal Transition

Background/Aims: Glycolysis, a multi-step enzymatic reaction, is considered to be the root of cancer development and progression. The aim of this study is to figure out which glycolysis enzyme participates in the progression of breast cancer and its possible mechanisms. Materials: We firstly screened out PGK1 by performing an RT-PCR array of glycolysis-related genes in three paired breast cancer samples, and further investigated PGK1 using TCGA and our own database. The effect and mechanism of PGK1 on cell invasion was further explored both in vitro and using patient samples. Results: PGK1 was most upregulated in T3N0 with distant metastases compared to those with no metastases. In the TCGA database, high PGK1 expression predicted poor overall survival (OS) in breast cancer and some other cancers (P< 0.001). In the validation cohort, high PGK1 expression was significantly correlated with larger tumor size (P=0.011) and advanced TNM stage (P=0.033), and PGK1 expression was an independent prognostic factor for OS and disease free survival (DFS) in both univariate and multivariate regression analyses (P< 0.05). Functional studies indicated that knockdown of PGK1 expression significantly inhibited invasion and reversed the epithelial-mesenchymal transition process in breast cancer cells (P< 0.05). Mechanistically, PGK1 increased HRE luciferase activity in a dose-dependent manner, while silencing PGK1 expression decreased HRE activity. Conclusion: High PGK1 expression was associated with poor prognosis in breast cancer, because PGK1 and HIF-1α formed a positive feed-forward loop and thus stimulated breast cancer progression and metastases. Based on these results, PGK1 may serve as a promising biomarker and target therapy for breast cancer.

Download Full-text

Hypoxia Induces Growth Differentiation Factor 15 to Promote the Metastasis of Colorectal Cancer via PERK-eIF2α Signaling

BioMed Research International ◽

10.1155/2020/5958272 ◽

2020 ◽

Vol 2020 ◽

pp. 1-12

Author(s):

Hongtu Zheng ◽

Yuchen Wu ◽

Tianan Guo ◽

Fangqi Liu ◽

Ye Xu ◽

...

Keyword(s):

Colorectal Cancer ◽

Cancer Cells ◽

Epithelial Mesenchymal Transition ◽

Hypoxic Exposure ◽

Mrna Levels ◽

Mesenchymal Transition ◽

Colorectal Cancer Cells ◽

Positive Correlations ◽

Underlying Mechanisms ◽

The Unfolded Protein Response

Hypoxia plays an essential role in orchestrating Epithelial-mesenchymal transition and promoting metastasis of colorectal cancer. However, the underlying mechanisms are still not well elucidated. Here, we present that hypoxic exposure causes endoplasmic reticulum stress and activates the unfolded protein response pathways, which drives GDF15 expression in colorectal cancer cells. Mechanistically, upregulated CHOP led by activated PERK-eIF2α signaling promotes GDF15 transcription via directly binding to its promoter. Further study implicates that hypoxia-induced GDF15 is required for the EMT and invasion of colorectal cancer cells; enforced expression of GDF15 promotes the mitochondrial oxidation of fatty acids in colorectal cancer cells. Moreover, the abrogation of GDF15 results in smaller xenograft tumors in size and impaired metastasis. GDF15 is expressed much more in tumor tissues of CRC patients and displays positive correlations with CHOP and HIF1α in mRNA levels. Our study demonstrates a novel molecular mechanism underlying hypoxia-promoted metastasis of CRC and provides PERK signaling-regulated GDF15 as a new and promising therapeutic target for clinical treatment and drug discovery.

Download Full-text