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

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.

scholarly journals CDX2 inhibits epithelial–mesenchymal transition in colorectal cancer by modulation of Snail expression and β-catenin stabilisation via transactivation of PTEN expression

2020 ◽  
Vol 124 (1) ◽  
pp. 270-280
Author(s):  
Junhui Yu ◽  
Shan Li ◽  
Zhengshui Xu ◽  
Jing Guo ◽  
Xiaopeng Li ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Nuclear Translocation ◽  
Epithelial Mesenchymal Transition ◽  
Pten Expression ◽  
Invasion And Metastasis ◽  
Snail Expression ◽  
Mesenchymal Transition

Abstract Background Emerging evidence suggests the involvement of caudal-related homoeobox transcription factor 2 (CDX2) in tumorigenesis of various cancers. Although CDX2 functions in cancer invasion and metastasis, fewer studies focus on the role of CDX2 during the induction of epithelial–mesenchymal transition (EMT) in colorectal cancer (CRC). Methods Immunohistochemical analysis of CDX2 was performed. A series of in vitro and in vivo experiments were conducted to reveal the role of CDX2 in the invasion and metastasis of CRC. Results CDX2 was downregulated in CRC tissues and reduced CDX2 correlated with poor prognosis. Knockdown of CDX2 promoted colon cancer cell invasion in vitro and facilitated liver metastasis in vivo with inducing EMT phenotypes. Further investigation indicated that CDX2 retarded Akt and GSK-3β phosphorylation, and thereby diminished Snail expression, β-catenin stabilisation and nuclear translocation. The depletion of β-catenin neutralised the regulation of Slug and ZEB1 by CDX2 knockdown. Mechanistically, CDX2 antagonised PI3K/Akt activity in CRC by modulating PTEN expression. CDX2 directly bound to the promoter of PTEN and transactivated its expression. Conclusions Our study first uncovered that CDX2 inhibits EMT and metastasis of CRC by regulation of Snail expression and β-catenin stabilisation via transactivation of PTEN expression.

scholarly journals Impaired AGO2/miR-185-3p/NRP1 axis promotes colorectal cancer metastasis

2021 ◽  
Vol 12 (4) ◽  
Author(s):  
Xisheng Liu ◽  
Xiaole Meng ◽  
Xiao Peng ◽  
Qianlan Yao ◽  
Fangming Zhu ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cancer Metastasis ◽  
Epithelial Mesenchymal Transition ◽  
Human Cancer ◽  
Mesenchymal Transition ◽  
Mirna Processing ◽  
Neuropilin 1 ◽  
Microrna Sequencing

AbstractIncreasing evidence suggests that global downregulation of miRNA expression is a hallmark of human cancer, potentially due to defects in the miRNA processing machinery. In this study, we found that the protein expression of Argonaute 2 (AGO2), a key regulator of miRNA processing, was downregulated in colorectal cancer (CRC) tissues, which was also consistent with the findings of the Clinical Proteomic Tumor Analysis Consortium (CPTAC). Furthermore, the correlation between the levels of AGO2 and epithelial-mesenchymal transition (EMT) markers (E-cadherin and vimentin) indicated that reduced levels of AGO2 promoted EMT in CRC. Low expression of AGO2 was an indicator of a poor prognosis among CRC patients. Knockdown of AGO2 in CRC cells promoted migration, invasion and metastasis formation in vitro and in vivo but had no influence on proliferation. To provide detailed insight into the regulatory roles of AGO2, we performed integrated transcriptomic, quantitative proteomic and microRNA sequencing (miRNA-seq) analyses of AGO2 knockdown cells and the corresponding wild-type cells and identified neuropilin 1 (NRP1) as a new substrate of AGO2 via miR-185-3p. Our data provided evidence that knockdown of AGO2 resulted in a reduction of miR-185-3p expression, leading to the upregulation of the expression of NRP1, which is a direct target of miR-185-3p, and elevated CRC cell metastatic capacity. Inhibition of NRP1 or treatment with a miR-185-3p mimic successfully rescued the phenotypes of impaired AGO2, which suggested that therapeutically targeting the AGO2/miR-185-3p/NRP1 axis may be a potential treatment approach for CRC.

scholarly journals LncRNA RPPH1 promotes colorectal cancer metastasis by interacting with TUBB3 and by promoting exosomes-mediated macrophage M2 polarization

2019 ◽  
Vol 10 (11) ◽  
Author(s):  
Zhen-xing Liang ◽  
Hua-shan Liu ◽  
Feng-wei Wang ◽  
Li Xiong ◽  
Chi Zhou ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Tumor Progression ◽  
Cancer Metastasis ◽  
Epithelial Mesenchymal Transition ◽  
Tumor Resection ◽  
Poor Prognostic Factor ◽  
Mesenchymal Transition ◽  
M2 Polarization

Abstract Metastasis is a well-known poor prognostic factor in cancer. However, the mechanisms how long non-coding RNAs (lncRNAs) regulate metastasis in colorectal cancer (CRC) remain largely unknown. Besides, tumor-associated macrophages (TAMs) play an important role in tumor progression, yet the contribution of lncRNA-mediated crosstalk between TAMs and CRC cells to tumor progression is not well understood. In this study, we report that lncRNA RPPH1 was significantly upregulated in CRC tissues, and the RPPH1 overexpression was associated with advanced TNM stages and poor prognosis. RPPH1 was found to promote CRC metastasis in vitro and in vivo. Mechanistically, RPPH1 induced epithelial–mesenchymal transition (EMT) of CRC cells via interacting with β-III tubulin (TUBB3) to prevent its ubiquitination. Furthermore, CRC cell-derived exosomes transported RPPH1 into macrophages which mediate macrophage M2 polarization, thereby in turn promoting metastasis and proliferation of CRC cells. In addition, exosomal RPPH1 levels in blood plasma turned out to be higher in treatment-naive CRC patients but lower after tumor resection. Compared to CEA and CA199, exosomal RPPH1 in CRC plasma displayed a better diagnostic value (AUC = 0.86). Collectively, RPPH1 serves as a potential therapeutic and diagnostic target in CRC.

scholarly journals NFATc1 Promotes Epithelial-Mesenchymal Transition and Facilitates Colorectal Cancer Metastasis by Targeting SNAI1

2020 ◽  
Author(s):  
Tianli Shen ◽  
Chenyang Yue ◽  
Xingjie Wang ◽  
Zijun Wang ◽  
Yunhua Wu ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Molecular Mechanisms ◽  
Cancer Metastasis ◽  
Epithelial Mesenchymal Transition ◽  
Activated T Cells ◽  
In Vivo Models ◽  
Mesenchymal Transition ◽  
Clinical Stages

Abstract BackgroundMetastatic recurrence remains a major cause of colorectal cancer (CRC) mortality. In this study, we focused on the role and the potential underlying mechanisms of nuclear factor of activated T cells 1 (NFATc1) in CRC metastasis. MethodsWe examined the expression of NFATc1 in 140 cases of CRC tissues and 35 corresponding adjacent tissues, as well as analyzed the correlation between NFATc1 expression levels and clinical stages. The role of NFATc1 in CRC metastasis and the molecular mechanisms were investigated in both in vitro and in vivo models. ResultsThe results showed that NFATc1 expression was increased in metastatic CRC tissues and positively associated with clinical stages (Stage I vs. Stage II, III or IV) of CRC. Overexpression of NFATc1 promoted CRC cell migration, invasion and epithelial-mesenchymal transition (EMT). Moreover, SNAI1 was verified as the direct transcriptional target of NFATc1 and interacted with Slug to promote EMT. Remarkably, our lung and liver double metastasis mouse model demonstrated that NFATc1 overexpression accelerated CRC metastasis, and treatment with FK506, a calcineurin-NFAT pathway inhibitor, could suppress CRC metastasis in vivo. ConclusionsTaken together, our findings suggest that NFATc1 could transcriptionally activate SNAI1, which in turn could interact with Slug to mediate EMT and to promote CRC metastasis, making NFATc1 a promising target in CRC treatment.

scholarly journals Knockdown of ARK5 Expression Suppresses Invasion and Metastasis of Gastric Cancer

2017 ◽  
Vol 42 (3) ◽  
pp. 1025-1036 ◽  
Author(s):  
Dehu Chen ◽  
Guiyuan Liu ◽  
Ning Xu ◽  
Xiaolan You ◽  
Haihua Zhou ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Western Blot ◽  
Cancer Metastasis ◽  
Epithelial Mesenchymal Transition ◽  
Migration And Invasion ◽  
Invasion And Metastasis ◽  
Ags Cells ◽  
Mesenchymal Transition

Background/Aims: Gastric cancer (GC) is a common and lethal malignancy, and AMP-activated protein kinase-related kinase 5 (ARK5) has been discovered to promote cancer metastasis in certain types of cancer. In this study, we explored the role of ARK5 in GC invasion and metastasis. Methods: ARK5 and epithelial-mesenchymal transition (EMT)-related markers were determined by immunohistochemistry and western blot in GC specimens. Other methods including stably transfected against ARK5 into SGC7901 and AGS cells, western blot, migration and invasion assays in vitro and nude mice tumorigenicity in vivo were also employed. Results: The results demonstrated that ARK5 expression was increased and positively correlated with metastasis, EMT-related markers and poor prognosis in patients with GC. Knockdown of ARK5 expression remarkably suppressed GC cells invasion and metastasis via regulating EMT, rather than proliferation in vitro and in vivo. And knockdown of ARK5 expression in GC cells resulted in the down-regulation of the mTOR/p70S6k signals, Slug and SIP1. Conclusion: The elevated ARK5 expression was closely associated with cancer metastasis and patient survival, and it seemed to function in GC cells migration and invasion via EMT alteration, together with the alteration of the mTOR/p70S6k signals, Slug and SIP1, thus providing a potential therapeutic target for GC.

scholarly journals CD36 promotes the epithelial–mesenchymal transition and metastasis in cervical cancer by interacting with TGF-β

2019 ◽  
Vol 17 (1) ◽  
Author(s):  
Min Deng ◽  
Xiaodong Cai ◽  
Ling Long ◽  
Linying Xie ◽  
Hongmei Ma ◽  
...  
Keyword(s):  
Cervical Cancer ◽  
Cancer Cells ◽  
Cancer Metastasis ◽  
Epithelial Mesenchymal Transition ◽  
Mesenchymal Transition ◽  
Expression Levels ◽  
Cd36 Expression ◽  
Cervical Cancer Cells

Abstract Background Accumulating evidence indicates that CD36 initiates metastasis and correlates with an unfavorable prognosis in cancers. However, there are few reports regarding the roles of CD36 in initiation and metastasis of cervical cancer. Methods Using immunohistochemistry, we analyzed 133 cervical cancer samples for CD36 protein expression levels, and then investigated the correlation between changes in its expression and clinicopathologic parameters. The effect of CD36 expression on the epithelial–mesenchymal transition (EMT) in cervical cancer cells was evaluated by Western immunoblotting analysis. In vitro invasion and in vivo metastasis assays were also used to evaluate the role of CD36 in cervical cancer metastasis. Results In the present study, we confirmed that CD36 was highly expressed in cervical cancer samples relative to normal cervical tissues. Moreover, overexpression of CD36 promoted invasiveness and metastasis of cervical cancer cells in vitro and in vivo, while CD36 knockdown suppressed proliferation, migration, and invasiveness. We demonstrated that TGF-β treatment attenuated E-cadherin expression and enhanced the expression levels of CD36, vimentin, slug, snail, and twist in si-SiHa, si-HeLa, and C33a–CD36 cells, suggesting that TGF-β synergized with CD36 on EMT via active CD36 expression. We also observed that the expression levels of TGF-β in si-SiHa cells and si-HeLa cells were down-regulated, whereas the expression levels of TGF-β were up-regulated in C33a–CD36 cells. These results imply that CD36 and TGF-β interact with each other to promote the EMT in cervical cancer. Conclusions Our findings suggest that CD36 is likely to be an effective target for guiding individualized clinical therapy of cervical cancer.

scholarly journals CSN8 is a key regulator in hypoxia-induced epithelial–mesenchymal transition and dormancy of colorectal cancer cells

2020 ◽  
Vol 19 (1) ◽  
Author(s):  
Songwen Ju ◽  
Feng Wang ◽  
Yirong Wang ◽  
Songguang Ju
Keyword(s):  
Colorectal Cancer ◽  
Cancer Cells ◽  
Cancer Progression ◽  
Epithelial Mesenchymal Transition ◽  
Migration And Invasion ◽  
Mesenchymal Transition ◽  
Treatment Conditions ◽  
Colorectal Cancer Cells

AbstractHypoxic stress plays a pivotal role in cancer progression; however, how hypoxia drives tumors to become more aggressive or metastatic and adaptive to adverse environmental stress is still poorly understood. In this study, we revealed that CSN8 might be a key regulatory switch controlling hypoxia-induced malignant tumor progression. We demonstrated that the expression of CSN8 increased significantly in colorectal cancerous tissues, which was correlated with lymph node metastasis and predicted poor patient survival. CSN8 overexpression induces the epithelial-mesenchymal transition (EMT) process in colorectal cancer cells, increasing migration and invasion. CSN8 overexpression arrested cell proliferation, upregulated key dormancy marker (NR2F1, DEC2, p27) and hypoxia response genes (HIF-1α, GLUT1), and dramatically enhanced survival under hypoxia, serum deprivation, or chemo-drug 5-fluorouracil treatment conditions. In particular, silenced CSN8 blocks the EMT and dormancy processes induced by the hypoxia of 1% O2 in vitro and undermines the adaptive capacity of colorectal cancer cells in vivo. The further study showed that CSN8 regulated EMT and dormancy partly by activating the HIF-1α signaling pathway, which increased HIF-1α mRNA expression by activating NF-κB and stabilized the HIF-1α protein via HIF-1α de-ubiquitination. Taken together, CSN8 endows primary colorectal cancer cells with highly aggressive/metastatic and adaptive capacities through regulating both EMT and dormancy induced by hypoxia. CSN8 could serve as a novel prognostic biomarker for colorectal cancer and would be an ideal target of disseminated dormant cell elimination and tumor metastasis, recurrence, and chemoresistance prevention.

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