Visualization of epithelial-mesenchymal transition in an inflammatory microenvironment-colorectal cancer network.
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ABSTRACT:
SUBMITTER: Ieda T
PROVIDER: S-EPMC6841984 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description: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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Project description:Aims: To combat increases in colorectal cancer (CRC) incidence and mortality, biomarkers among differentially expressed genes (DEGs) have been identified to objectively detect cancer. However, DEGs are numerous, and additional parameters may identify more reliable biomarkers. Here, CRC DEGs were filtered into a prioritized list of biomarkers. Materials & methods: Two independent datasets (COAD-READ [n = 698] and GSE50760 [n = 36]) were input alternatively to the recently published data-driven reference method. Results were filtered based on epithelial-mesenchymal transition enrichment (χ-square statistic: 919.05; p = 2.2e-16) to produce 37 potential CRC biomarkers. Results: All 37 genes reliably classified CRC samples and ETV4, CLDN1 and CA2 together were top-ranked by DDR (accuracy: 89%; F1 score: 0.89). Conclusion: Biological and statistical information were combined to produce a better set of CRC detection biomarkers.
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Project description:Protein inhibitor of activated signal transducer and activator of transcription-1 (PIAS1) is an important regulator of the inflammatory signaling network, the expression of which was decreased in gastric cancer and implicated in the development of cancer. However, its mechanism has not been elucidated. The aim of the present study was to investigate the effect of PIAS1 on epithelial-mesenchymal transition (EMT) of gastric cancer cells within the inflammatory microenvironment. Recombinant adenovirus Ad5/F35-PIASl and Ad5/F35-null plasmids were constructed to transfect SGC7901 cells. Subsequently, these plasmids were confirmed by reverse transcription polymerase chain reaction and western blotting. The cells were treated with IL-6 or Ad5/F35-PIASl+IL-6, and the control cells were treated with Ad5/F35-null+IL-6. The morphological changes to the cells were observed using inverted microscopy. The effect of PIAS1 on cell migration and invasion was evaluated by scratch wound healing and Transwell chamber assays, and the protein expression of EMT markers and phosphatidylinositol 3-kinase (PI3K)/serine/threonine-protein kinase (Akt)/matrix metalloproteinase (MMP)-9 signaling pathway was examined by western blotting. Transfection with Ad5/F35-PIASl markedly increased the PIAS1 expression in SGC7901 cells. The cells acquired the more typical spindle-shape phenotype of mesenchymal cells following co-culture with IL-6; the cells co-cultured with IL-6 and Ad5/F35-PIASl acquired changes concordant with an epithelial phenotype. The overexpression of PIAS1 significantly decreased the migratory and invasive capacities of the SGC7901 cells (P<0.01). Western blotting indicated that the expression levels of E-cadherin protein in the cells treated with Ad5/F35-PIASl+IL-6 were increased significantly and the expression levels of zinc finger protein SNAI, Twist-related protein 1, vimentin and MMP-9, and the activation of PI3K/Akt proteins were decreased when compared with IL-6- or Ad5/F35-null+IL-6-treated cells (both P<0.01). PIAS1 may inhibit EMT in gastric cancer cells within the inflammatory microenvironment via the regulation of PI3K/Akt pathway activation, and may serve an important role in the inhibition of tumor invasion and metastasis with in this microenvironment.
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Project description: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.
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Project description:Metastasis is the leading cause of cancer-related death in almost all types of cancers, including colorectal cancer (CRC). Metastasis is a complex, multistep, dynamic biological event, and epithelial-mesenchymal transition (EMT) is a critical process during the cascade. Ajuba family proteins are LIM domain-containing proteins and are reported to be transcription repressors regulating different kinds of physiological processes. However, the expression and pathological roles of Ajuba family proteins in tumors, especial in tumor metastasis, remain poorly studied. Here, we found that JUB, but not the other Ajuba family proteins, was highly upregulated in clinical specimens and CRC cell lines. Ectopic expression of JUB induced EMT and enhanced motility and invasiveness in CRC, and vice versa. Mechanistic study revealed that JUB induces EMT via Snail and JUB is also required for Snail-induced EMT. The expression of JUB shows an inverse correlation with E-cadherin expression in clinical specimens. Taken together, these findings revealed that the LIM protein JUB serves as a tumor-promoting gene in CRC by promoting EMT, a critical process of metastasis. Thus, the LIM protein JUB may provide a novel target for therapy of metastatic CRC.
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Project description:Epithelial-to-mesenchymal transition (EMT) is well-known to evoke cancer invasion/metastasis, leading to a high frequency of mortality in patients with metastatic colorectal cancer (mCRC). Protein tyrosine phosphatase (PTPase)-targeted therapy has been identified as a novel cancer therapeutic. Previously, we proved that sorafenib with anti-EMT potency prevents TGF-β1-induced EMT/invasion by directly activating SH2-domain-containing phosphatase 1 (SHP-1)-dependent p-STAT3Tyr705 suppression in hepatocellular carcinoma. Regorafenib has a closely related chemical structure as sorafenib and is approved for the pharmacotherapy of mCRC. Herein, we evaluate whether regorafenib activates PTPase SHP-1 in the same way as sorafenib to abolish EMT-related invasion/metastasis in CRC. Notably, regorafenib exerted potent anti-EMT activity to curb TGF-β1-induced EMT/invasion in vitro as well inhibited lung metastatic outgrowth of SW480 mesenchymal cells in vivo. Mechanistically, regorafenib-enhanced SHP-1 activity significantly impeded TGF-β1-induced EMT/invasion via low p-STAT3Tyr705 level as proved by a SHP-1 inhibitor or siRNA-mediated SHP-1 depletion. Conversely, overexpression of SHP-1 further enhanced the inhibitory effects of regorafenib on TGF-β1-induced p-STAT3Tyr705 and EMT/invasion. Regorafenib directly activates SHP-1 by potently relieving the autoinhibited N-SH2 domain of SHP-1 to inhibit TGF-β1-induced p-STAT3Tyr705 and EMT/invasion. Importantly, the clinical evidence indicated that SHP-1 was positively correlated with E-cadherin and that significantly determined the overall survival of CRC patients. This result further confirms our in vitro data that SHP-1 is a negative regulatory PTPase in EMT regulation and serves as a pharmacological target for mCRC therapy. Collectively, activating PTPase SHP-1 by regorafenib focusing on its anti-EMT activity might be a useful pharmacotherapy for mCRC.
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Project description:BackgroundColorectal cancer (CRC) is a common cancer worldwide. The main cause of death in CRC includes tumor progression and metastasis. At molecular level, these processes may be triggered by epithelial-mesenchymal transition (EMT) and necessitates specific alterations in cell metabolism. Although several EMT-related metabolic changes have been described in CRC, the mechanism is still poorly understood.ResultsUsing CrossHub software, we analyzed RNA-Seq expression profile data of CRC derived from The Cancer Genome Atlas (TCGA) project. Correlation analysis between the change in the expression of genes involved in glycolysis and EMT was performed. We obtained the set of genes with significant correlation coefficients, which included 21 EMT-related genes and a single glycolytic gene, HK3. The mRNA level of these genes was measured in 78 paired colorectal cancer samples by quantitative polymerase chain reaction (qPCR). Upregulation of HK3 and deregulation of 11 genes (COL1A1, TWIST1, NFATC1, GLIPR2, SFPR1, FLNA, GREM1, SFRP2, ZEB2, SPP1, and RARRES1) involved in EMT were found. The results of correlation study showed that the expression of HK3 demonstrated a strong correlation with 7 of the 21 examined genes (ZEB2, GREM1, TGFB3, TGFB1, SNAI2, TWIST1, and COL1A1) in CRC.ConclusionsUpregulation of HK3 is associated with EMT in CRC and may be a crucial metabolic adaptation for rapid proliferation, survival, and metastases of CRC cells.
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Project description:Background: Tumor microenvironment (TME) has a pivotal impact on tumor progression, and epithelial-mesenchymal transition (EMT) is an extremely crucial initial event in the metastatic process in colorectal cancer (CRC) that is not yet fully understood. Calebin A (an ingredient in Curcuma longa) has been shown to repress CRC tumor growth. However, whether Calebin A is able to abrogate TME-induced EMT in CRC was investigated based on the underlying pathways. Methods: CRC cell lines (HCT116, RKO) were exposed with Calebin A and/or a FAK inhibitor, cytochalasin D (CD) to investigate the action of Calebin A in TME-induced EMT-related tumor progression. Results: TME induced viability, proliferation, and increased invasiveness in 3D-alginate CRC cultures. In addition, TME stimulated stabilization of the master EMT-related transcription factor (Slug), which was accompanied by changes in the expression patterns of EMT-associated biomarkers. Moreover, TME resulted in stimulation of NF-κB, TGF-β1, and FAK signaling pathways. However, these effects were dramatically reduced by Calebin A, comparable to FAK inhibitor or CD. Finally, TME induced a functional association between NF-κB and Slug, suggesting that a synergistic interaction between the two transcription factors is required for initiation of EMT and tumor cell invasion, whereas Calebin A strongly inhibited this binding and subsequent CRC cell migration. Conclusion: We propose for the first time that Calebin A modulates TME-induced EMT in CRC cells, at least partially through the NF-κB/Slug axis, TGF-β1, and FAK signaling. Thus, Calebin A appears to be a potential agent for the prevention and management of CRC.
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Project description:The FOLFOX scheme, based on the association of 5-fluorouracil and oxaliplatin, is the most frequently indicated chemotherapy scheme for patients diagnosed with metastatic colorectal cancer. Nevertheless, development of chemoresistance is one of the major challenges associated with this disease. It has been reported that epithelial-mesenchymal transition (EMT) is implicated in microRNA-driven modulation of tumor cells response to 5-fluorouracil and oxaliplatin. Moreover, from pharmacogenomic research, it is known that overexpression of genes encoding dihydropyrimidine dehydrogenase (DPYD), thymidylate synthase (TYMS), methylenetetrahydrofolate reductase (MTHFR), the DNA repair enzymes ERCC1, ERCC2, and XRCC1, and the phase 2 enzyme GSTP1 impair the response to FOLFOX. It has been observed that EMT is associated with overexpression of DPYD, TYMS, ERCC1, and GSTP1. In this review, we investigated the role of miRNAs as EMT promotors in tumor cells, and its potential effect on the upregulation of DPYD, TYMS, MTHFR, ERCC1, ERCC2, XRCC1, and GSTP1 expression, which would lead to resistance of CRC tumor cells to 5-fluorouracil and oxaliplatin. This constitutes a potential mechanism of epigenetic regulation involved in late-onset of acquired resistance in mCRC patients under FOLFOX chemotherapy. Expression of these biomarker microRNAs could serve as tools for personalized medicine, and as potential therapeutic targets in the future.
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