Loss of E-cadherin and B-catenin nuclear translocation in the invasion front is the central phenomenon of epithelial mesenchymal transition in colorectal cancer

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.

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Circulating microRNA-762 promotes colorectal cancer proliferation and invasion by upregulating the Wnt-1/β-catenin pathway

10.21203/rs.2.17898/v1 ◽

2019 ◽

Author(s):

Peng-Sheng Lai ◽

Wei-Min Chang ◽

Ying-Yin Chen ◽

Yi-Feng Lin ◽

Hui-Fen Liao ◽

...

Keyword(s):

Colorectal Cancer ◽

Cell Viability ◽

Distant Metastasis ◽

Molecular Mechanisms ◽

Nuclear Translocation ◽

Epithelial Mesenchymal Transition ◽

Circulating Microrna ◽

Mesenchymal Transition ◽

Investigation Methods ◽

Cell Implantation

Abstract Background: A number of microRNAs (miRNAs) have been demonstrated to be associated with the diagnosis, progression and prognosis of colorectal cancer (CRC). However, the function of miRNA-762 (miR-762) in CRC remains unclear, and the molecular mechanisms underlying the effects of miR‑762 in CRC require further investigation. Methods: The circulating miRNAs from BALB/c mice with CRC CT26 cell implantation were assayed by microarray. Then, miR-762 mimic and inhibitor were transfected to CT26 cells for analysis of cell viability, invasion, and epithelial-mesenchymal transition (EMT), cell cycle, and regulatory molecule expression. Human subjects were included for comparison the circulating miR-762 levels in CRC patients and control donors, as well as the patients with and without distant metastasis. Results: The screening for miRNA levels in mice with CRC cell implantation indicated that plasma miR-762 was upregulated. Transfection of miR-762 mimic to CT26 cells increased cell viability, invasion, and EMT, whereas transfection of miR-762 inhibitor decreased the above abilities. Western blot analysis showed that miR-762 mimic transfection upregulated the expression of Wnt-1 and b-catenin, as well as increased the nuclear translocation of b-catenin. Further analysis showed that serum miR-762 levels in CRC patients were higher than in control donors. Among the CRC patients (n = 20), six patients with distant metastasis showed higher serum miR-762 levels than the patients without distant metastasis. Conclusions: Circulating miR-762 could promote CRC disease development and progression through the Wnt/b-catenin signaling. miR-762 might be used as a biomarker for CRC diagnosis and targeted therapy.

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Thymosin β-4 in colorectal cancer is localized predominantly at the invasion front in tumor cells undergoing epithelial mesenchymal transition

Cancer Biology & Therapy ◽

10.4161/cbt.13.4.18691 ◽

2012 ◽

Vol 13 (4) ◽

pp. 191-197 ◽

Cited By ~ 23

Author(s):

Sonia Nemolato ◽

Angelo Restivo ◽

Tiziana Cabras ◽

Pierpaolo Coni ◽

Luigi Zorcolo ◽

...

Keyword(s):

Colorectal Cancer ◽

Tumor Cells ◽

Epithelial Mesenchymal Transition ◽

Mesenchymal Transition ◽

Invasion Front

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Atypical role of sprouty in colorectal cancer: sprouty repression inhibits epithelial–mesenchymal transition

Oncogene ◽

10.1038/onc.2015.365 ◽

2015 ◽

Vol 35 (24) ◽

pp. 3151-3162 ◽

Cited By ~ 16

Author(s):

Q Zhang ◽

T Wei ◽

K Shim ◽

K Wright ◽

K Xu ◽

...

Keyword(s):

Colorectal Cancer ◽

Colon Cancer ◽

Cell Migration ◽

Cancer Cells ◽

Epithelial Mesenchymal Transition ◽

Migration And Invasion ◽

Colon Cancer Cells ◽

Mesenchymal Transition ◽

E Cadherin

Abstract Sprouty (SPRY) appears to act as a tumor suppressor in cancer, whereas we demonstrated that SPRY2 functions as a putative oncogene in colorectal cancer (CRC) (Oncogene, 2010, 29: 5241–5253). We investigated the mechanisms by which SPRY regulates epithelial–mesenchymal transition (EMT) in CRC. SPRY1 and SPRY2 mRNA transcripts were significantly upregulated in human CRC. Suppression of SPRY2 repressed AKT2 and EMT-inducing transcription factors and significantly increased E-cadherin expression. Concurrent downregulation of SPRY1 and SPRY2 also increased E-cadherin and suppressed mesenchymal markers in colon cancer cells. An inverse expression pattern between AKT2 and E-cadherin was established in a human CRC tissue microarray. SPRY2 negatively regulated miR-194-5p that interacts with AKT2 3′ untranslated region. Mir-194 mimics increased E-cadherin expression and suppressed cancer cell migration and invasion. By confocal microscopy, we demonstrated redistribution of E-cadherin to plasma membrane in colon cancer cells transfected with miR-194. Spry1 −/− and Spry2 −/− double mutant mouse embryonic fibroblasts exhibited decreased cell migration while acquiring several epithelial markers. In CRC, SPRY drive EMT and may serve as a biomarker of poor prognosis.

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Roles of STAT3 and ZEB1 Proteins in E-cadherin Down-regulation and Human Colorectal Cancer Epithelial-Mesenchymal Transition

Journal of Biological Chemistry ◽

10.1074/jbc.m111.295964 ◽

2011 ◽

Vol 287 (8) ◽

pp. 5819-5832 ◽

Cited By ~ 177

Author(s):

Hua Xiong ◽

Jie Hong ◽

Wan Du ◽

Yan-wei Lin ◽

Lin-lin Ren ◽

...

Keyword(s):

Colorectal Cancer ◽

Epithelial Mesenchymal Transition ◽

Human Colorectal Cancer ◽

Down Regulation ◽

Mesenchymal Transition ◽

E Cadherin

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Curcumin Suppresses Intestinal Fibrosis by Inhibition of PPARγ-Mediated Epithelial-Mesenchymal Transition

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2017/7876064 ◽

2017 ◽

Vol 2017 ◽

pp. 1-12 ◽

Cited By ~ 11

Author(s):

Su Xu ◽

Bin Jiang ◽

Hui Wang ◽

Cunsi Shen ◽

Hao Chen ◽

...

Keyword(s):

Nuclear Translocation ◽

Epithelial Mesenchymal Transition ◽

Smooth Muscle Actin ◽

Peroxisome Proliferator ◽

Colon Tissue ◽

Peroxisome Proliferator Activated Receptor ◽

Smad Pathway ◽

Mesenchymal Transition ◽

Intestinal Fibrosis ◽

E Cadherin

Intestinal fibrotic stricture is a major complication of Crohn’s disease (CD) and epithelial-to-mesenchymal transition (EMT) is considered as an important contributor to the formation of intestinal fibrosis by increasing extracellular matrix (ECM) proteins. Curcumin, a compound derived from rhizomes ofCurcuma, has been demonstrated with a potent antifibrotic effect. However, its effect on intestinal fibrosis and the potential mechanism is not completely understood. Here we found that curcumin pretreatment significantly represses TGF-β1-induced Smad pathway and decreases its downstreamα-smooth muscle actin (α-SMA) gene expression in intestinal epithelial cells (IEC-6); in contrast, curcumin increases expression of E-cadherin and peroxisome proliferator-activated receptorγ(PPARγ) in IEC-6. Moreover, curcumin promotes nuclear translocation of PPARγand the inhibitory effect of curcumin on EMT could be reversed by PPARγantagonist GW9662. Consistently, in the rat model of intestinal fibrosis induced by 2,4,5-trinitrobenzene sulphonic acid (TNBS), oral curcumin attenuates intestinal fibrosis by increasing the expression of PPARγand E-cadherin and decreasing the expression ofα-SMA, FN, and CTGF in colon tissue. Collectively, these results indicated that curcumin is able to prevent EMT progress in intestinal fibrosis by PPARγ-mediated repression of TGF-β1/Smad pathway.

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PLAGL2 promotes epithelial–mesenchymal transition and mediates colorectal cancer metastasis via β-catenin-dependent regulation of ZEB1

British Journal of Cancer ◽

10.1038/s41416-019-0679-z ◽

2019 ◽

Vol 122 (4) ◽

pp. 578-589

Author(s):

Liang Wu ◽

Zili Zhou ◽

Shengbo Han ◽

Jinhuang Chen ◽

Zhengyi Liu ◽

...

Keyword(s):

Colorectal Cancer ◽

Cancer Metastasis ◽

Nuclear Translocation ◽

Epithelial Mesenchymal Transition ◽

Malignant Tumours ◽

Mesenchymal Transition ◽

Exact Function ◽

Colorectal Cancer Metastasis

Abstract Background We previously demonstrated that the pleomorphic adenoma gene like-2 (PLAGL2) is involved in the pathogenesis of Hirschsprung disease. Enhanced PLAGL2 expression was observed in several malignant tumours. However, the exact function of PLAGL2 and its underlying mechanism in colorectal cancer (CRC) remain largely unknown. Methods Immunohistochemical analysis of PLAGL2 was performed. A series of in vitro and in vivo experiments were conducted to reveal the role of PLAGL2 in the progression of CRC. Results Enhanced PLAGL2 expression was significantly associated with EMT-related proteins in CRC. The data revealed that PLAGL2 promotes CRC cell proliferation, migration, invasion and EMT both in vitro and in vivo. Mechanistically, PLAGL2 promoted the expression of ZEB1. PLAGL2 enhanced the expression and nuclear translocation of β-catenin by decreasing its phosphorylation. The depletion of β-catenin neutralised the regulation of ZEB1 that was caused by enhanced PLAGL2 expression. The small-molecule inhibitor PNU-74654, also impaired the enhancement of ZEB1 that resulted from the modified PLAGL2 expression. The depletion of ZEB1 could block the biological function of PLAGL2 in CRC cells. Conclusions Collectively, our findings suggest that PLAGL2 mediates EMT to promote colorectal cancer metastasis via β-catenin-dependent regulation of ZEB1.

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PDLIM1 Stabilizes the E-Cadherin/β-Catenin Complex to Prevent Epithelial–Mesenchymal Transition and Metastatic Potential of Colorectal Cancer Cells

Cancer Research ◽

10.1158/0008-5472.can-15-1962 ◽

2015 ◽

Vol 76 (5) ◽

pp. 1122-1134 ◽

Cited By ~ 46

Author(s):

Hai-Ning Chen ◽

Kefei Yuan ◽

Na Xie ◽

Kui Wang ◽

Zhao Huang ◽

...

Keyword(s):

Colorectal Cancer ◽

Cancer Cells ◽

Epithelial Mesenchymal Transition ◽

Metastatic Potential ◽

Mesenchymal Transition ◽

Colorectal Cancer Cells ◽

E Cadherin

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Correlation between FAK and EGF-Induced EMT in Colorectal Cancer Cells

Journal of Oncology ◽

10.1155/2020/5428920 ◽

2020 ◽

Vol 2020 ◽

pp. 1-10 ◽

Cited By ~ 3

Author(s):

Kun Huang ◽

Ningning Gao ◽

Donglin Bian ◽

Qixi Zhai ◽

Puxu Yang ◽

...

Keyword(s):

Colorectal Cancer ◽

Cell Migration ◽

Cancer Cells ◽

Signaling Pathway ◽

Epithelial Mesenchymal Transition ◽

Migration And Invasion ◽

Mesenchymal Transition ◽

Egfr Signaling Pathway ◽

Colorectal Cancer Cells ◽

E Cadherin

Epithelial-mesenchymal transition (EMT) plays an important role in the invasion and metastasis of colorectal cancer, which is mediated by FAK and EGF. However, whether FAK participates in EMT in colorectal cancer cells through the EGF/EGFR signaling pathway remains unknown. The aim of this study was to investigate the effector mechanisms of FAK in the process of EGF-induced EMT in colorectal cancer cells and to determine whether miR-217 is involved in this process. Caco-2 cancer cells were routinely cultured with and without treatment with 100 ng/mL EGF, and changes in cell morphology were observed using an inverted microscope. In addition, a transwell assay was used to detect cell migration under the condition of EGF treatment. The expression of FAK, pFAK, E-cadherin, vimentin, and β actin was assessed by western blotting, and the expression of miR-217 was assessed using real-time PCR. We found that EGF induced EMT in colorectal cancer cells and enhanced cell migration and invasion ability. Moreover, FAK was involved in the EGF-induced EMT of colorectal cancer cells. EGF upregulated the expression of E-cadherin in colorectal cancer cells by activating FAK, and miR-217 was found to participate in EGF-induced EMT in colorectal cancer cells. Our findings indicate that EGF induces EMT in colorectal cancer cells by activating FAK, and miR-217 is involved in the EGF/FAK/E-cadherin signaling pathway.

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