scholarly journals Towards a consensus microRNA signature of primary and metastatic colorectal cancer

2020 ◽  
Author(s):  
Bastian Fromm ◽  
Eirik Høye ◽  
Paul Heinrich Michael Böttger ◽  
Diana Domanska ◽  
Annette Torgunrud Kristensen ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Epithelial To Mesenchymal Transition ◽  
Bioinformatics Pipeline ◽  
Mesenchymal Transition ◽  
Mirna Sequencing ◽  
Bona Fide ◽  
Cell Type Specific ◽  
Metastatic Process ◽  
Metastatic Sites

AbstractBackgroundAlthough microRNAs (miRNAs) are involved in all hallmarks of cancer, miRNA dysregulation in the metastatic process remains poorly understood. We investigated the role of miRNAs in metastatic evolution of colorectal cancer (CRC) by analyzing smallRNA-seq datasets from primary CRC, metastatic locations (liver, lung and peritoneum), and corresponding adjacent tissues. Addressing main challenges of miRNA analysis, a bioinformatics pipeline was developed that contains bona fide miRNA annotations from MirGeneDB, utilizes the quality control software miRTrace, applies physiologically meaningful cutoffs and accounts for contribution of cell-type specific miRNAs and host tissue effects.ResultsTwo hundred-and-seventy-five miRNA sequencing datasets were analyzed, and after adjusting for the contribution of heterogeneity in cellular composition, strong signatures for primary and metastatic CRC were identified. The signature for primary CRC contained many previously known miRNAs with known functions. Deregulation of specific miRNAs was associated with individual metastatic sites, but the metastatic signatures contained overlapping miRNAs involved in key elements of the metastatic process, such as epithelial-to-mesenchymal transition and hypoxia. Notably, four of these miRNAs (MIR-8, MIR-10, MIR-375, MIR-210) belong to deeply conserved families present in many other organisms, triggering questions about their evolutionary functions and opportunities for experimental validation.ConclusionApplying a meticulous pipeline for the analysis of smallRNA-seq data, miRNA signatures for primary and metastatic CRC were identified, contributing novel insights into miRNA involvement in CRC metastatic evolution and site-specific metastatic adaptations. New datasets can easily be included in this publicly available pipeline to continuously improve the knowledge in the field.

scholarly journals A comprehensive framework for analysis of microRNA sequencing data in metastatic colorectal cancer

NAR Cancer ◽  
2022 ◽  
Vol 4 (1) ◽  
Author(s):  
Eirik Høye ◽  
Bastian Fromm ◽  
Paul H M Böttger ◽  
Diana Domanska ◽  
Annette Torgunrud ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Epithelial To Mesenchymal Transition ◽  
Differential Expression Analysis ◽  
Metastatic Progression ◽  
Sequencing Data ◽  
Bioinformatics Pipeline ◽  
Mesenchymal Transition ◽  
Starting Point ◽  
Microrna Sequencing ◽  
Metastatic Sites

ABSTRACT Although microRNAs (miRNAs) contribute to all hallmarks of cancer, miRNA dysregulation in metastasis remains poorly understood. The aim of this work was to reliably identify miRNAs associated with metastatic progression of colorectal cancer (CRC) using novel and previously published next-generation sequencing (NGS) datasets generated from 268 samples of primary (pCRC) and metastatic CRC (mCRC; liver, lung and peritoneal metastases) and tumor adjacent tissues. Differential expression analysis was performed using a meticulous bioinformatics pipeline, including only bona fide miRNAs, and utilizing miRNA-tailored quality control and processing. Five miRNAs were identified as up-regulated at multiple metastatic sites Mir-210_3p, Mir-191_5p, Mir-8-P1b_3p [mir-141–3p], Mir-1307_5p and Mir-155_5p. Several have previously been implicated in metastasis through involvement in epithelial-to-mesenchymal transition and hypoxia, while other identified miRNAs represent novel findings. The use of a publicly available pipeline facilitates reproducibility and allows new datasets to be added as they become available. The set of miRNAs identified here provides a reliable starting-point for further research into the role of miRNAs in metastatic progression.

scholarly journals The Mechanisms of Colorectal Cancer Cell mesenchymal-epithelial Transition Induced by Hepatocyte Exosome-derived miR-203a-3p

2021 ◽  
Author(s):  
Heyang Xu ◽  
Qiusheng Lan ◽  
Yongliang Huang ◽  
Yang Zhang ◽  
Yujie Zeng ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Liver Metastasis ◽  
Epithelial To Mesenchymal Transition ◽  
Luciferase Reporter ◽  
Mesenchymal Transition ◽  
Real Time Quantitative Pcr ◽  
Mesenchymal To Epithelial Transition ◽  
Reporter Assays ◽  
Phosphatase Of Regenerating Liver

Abstract Background: Liver metastasis is the most common cause of death in patients with colorectal cancer (CRC). Phosphatase of regenerating liver-3 induces CRC metastasis by epithelial-to-mesenchymal transition, which promotes CRC cell liver metastasis. Mesenchymal-to-epithelial transition (MET), the opposite of epithelial-to-mesenchymal transition, has been proposed as a mechanism for the establishment of metastatic neoplasms. However, the molecular mechanism of MET remains unclear. Methods: Using Immunohistochemistry, western blotting，invasion assays, real-time quantitative PCR, chromatin immunoprecipitation, luciferase reporter assays, human miRNA arrays, and xenograft mouse model, we determined the role of hepatocyte exosome-derived miR-203a-3p in CRC MET.Results: In our study, we found that miR-203a-3p derived from hepatocyte exosomes increased colorectal cancer cells E-cadherin expression, inhibited Src expression, and reduced activity. In this way miR-203a-3p induced the decreased invasion rate of CRC cells.Coclusion: MiR-203a-3p derived from hepatocyte exosomes plays an important role of CRC cells to colonize in liver.

scholarly journals UNR/CSDE1 Expression Is Critical to Maintain Invasive Phenotype of Colorectal Cancer through Regulation of c-MYC and Epithelial-to-Mesenchymal Transition

2019 ◽  
Vol 8 (4) ◽  
pp. 560 ◽  
Author(s):  
Javier Martinez-Useros ◽  
Nuria Garcia-Carbonero ◽  
Weiyao Li ◽  
Maria J. Fernandez-Aceñero ◽  
Ion Cristobal ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cell Lines ◽  
Cancer Progression ◽  
Epithelial To Mesenchymal Transition ◽  
Rna Binding ◽  
Human Colon ◽  
Human Colon Cancer ◽  
Mesenchymal Transition ◽  
Colorectal Cancer Progression

CSDE1 (cold shock domain containing E1) gene is located upstream of the N-RAS locus, and codes for an RNA-binding protein named Upstream of N-Ras (UNR). In cancer, CSDE1 has been shown to regulate c-Fos, c-Myc, Pten, Rac1, or Vimentin. UNR/CSDE1 has been studied in breast, melanoma, pancreatic and prostate cancer. Then, the aim of this study is to evaluate the role of CSDE1/UNR in colorectal cancer progression and maintenance of aggressive phenotype. We firstly evaluated UNR/CSDE1 expression in human colon cancer derived cell lines and patient samples. Subsequently, we performed functional experiments by UNR/CSDE1 downregulation. We also evaluated UNR/CSDE1 prognostic relevance in two independent sets of patients. Not only was UNR/CSDE1 expression higher in tumor samples compared to untransformed samples, but also in colonospheres and metastatic origin cell lines than their parental and primary cell lines, respectively. Downregulation of UNR/CSDE1 reduced cell viability and migration throughout a restrain of epithelial-to-mesenchymal transition and increases sensitivity to apoptosis. Interestingly, high UNR/CSDE1 expression was associated with poor prognosis and correlated positively with c-MYC expression in colorectal cancer samples and cell lines. Here, we show for the first time compelling data reporting the oncogenic role of UNR/CSDE1 in human colorectal cancer.

scholarly journals LncRNA TUG1 promotes the progression of colorectal cancer via the miR-138-5p/ZEB2 axis

2020 ◽  
Vol 40 (6) ◽  
Author(s):  
Zhenkun Yan ◽  
Miaomiao Bi ◽  
Qiyu Zhang ◽  
Yumei Song ◽  
Sen Hong
Keyword(s):  
Colorectal Cancer ◽  
Epithelial To Mesenchymal Transition ◽  
Area Under The Curve ◽  
Luciferase Reporter ◽  
Mesenchymal Transition ◽  
Diagnosis And Prognosis ◽  
Non Coding Rna ◽  
Tissue Specimens

Abstract To explore the role of long-chain non-coding RNA (lncRNA) taurine up-regulated gene 1 (TUG1) in the development of colorectal cancer (CRC) via the miR-138-5p/zinc finger E-box-binding homeobox 2 (ZEB2) axis. Eighty-four CRC tissue specimens and 84 corresponding paracancerous tissue specimens were sampled from 84 patients with CRC admitted to the First Hospital of Jilin University from January 2018 to September 2019. The TUG1 expression in the specimens was determined, and its value in diagnosis and prognosis of CRC was analyzed. Additionally, constructed stable and transient overexpresison vectors and inhibition vectors were transfected into CRC cells. The MTT, transwell, and flow cytometry were adopted for analysis on the proliferation, invasion, and apoptosis of transfected cells, respectively, and a dual luciferase reporter (DLR) assay was carried out for correlation determination between TUG1 and miR-138-5p and between miR-138-5p and ZEB2. TUG1 was up-regulated in CRC, and serum TUG1 could be adopted as a diagnostic marker of CRC, with area-under-the-curve (AUC) larger than 0.8. In addition, siRNA-TUG1, shRNA-TUG1, miR-138-5p-mimics, and miR-138-5p-inhibitor were transfected into cells, and it turned out that overexpressing miR-138-5p and inhibiting ZEB2 exerted the same effects. The DLR assay revealed that TUG1 was able to targetedly regulate miR-138-5p, and miR-138-5p could targetedly regulate ZEB2, and in vitro experiments revealed that TUG1 could affect the epithelial-to-mesenchymal transition (EMT) of CRC via the miR-138-5p/ZEB2 axis. TUG1 could promote the development of CRC via the miR-138-5p/ZEB2 axis.

scholarly journals CXCL12/CXCR7/β-arrestin1 Biased Signal Promotes Epithelial-to-Mesenchymal Transition of Colorectal Cancer by Repressing Mirnas Through YAP1 Nuclear Translocation

2021 ◽  
Author(s):  
Mahan Si ◽  
Yujia Song ◽  
Xiaohui Wang ◽  
Dong Wang ◽  
Xiaohui Liu ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Molecular Mechanisms ◽  
Epithelial To Mesenchymal Transition ◽  
Nuclear Translocation ◽  
Luciferase Assay ◽  
Mesenchymal Transition ◽  
Tumor Xenografts ◽  
Signal Activation

Abstract Background: CXCR7 is an atypical chemokine receptor that transmits biased signal independent of G-protein activation. However, whether CXCL12/CXCR7 biased signal activation plays an essential role in colorectal cancer (CRC) progression and metastasis remains obscure. Methods: The functional role of CXCL12/CXCR7 biased signal in CRC was investigated by RNA-sequencing, Transwell assay and in vivo tumor xenografts. YAP1 nuclear translocation and molecular mechanisms were determined by cell transfection, luciferase activity assay, immunofluorescence, coimmunoprecipitation and immunohistochemistry and RT-qPCR analysis.Results: In this study, CXCR7 CXCL12/overexpression promotes Epithelial-to-mesenchymal transition (EMT) and upregulates the expression of stem marker doublecortin-like kinase 1 (DCLK1) in CRC cells with concurrent repression of miR-124-3p and miR-188-5p. Further luciferase assay prove that these miRNAs could regulate EMT by direct targeting vimentin and DCLK1. More importantly, CXCL12/CXCR7/β-arrestin1-mediated biased signal induces YAP1 nuclear translocation, which functions as a transcriptional repressor by interacting with Yin Yang 1 (YY1) and recruiting YY1 to the promoter of miR-124-3p and miR-188-5p. Pharmacological inhibitor of YAP1 recapitulates the anti-tumorigenesis and anti-metastasis effects of YAP1 depletion upon CXCR7 activation in tumor xenografts. Clinically, the expression of CXCR7 was positively correlated with nuclear YAP1 levels and EMT markers. Conclusions: Our findings revealed the novel role of YAP1 nuclear translocation in promoting EMT of CRC by repressing miR-124-3p and miR-188-5p through CXCL12/CXCR7/β-arrestin1 biased signal activation. These findings highlight the potential of targeting YAP1 nuclear translocation in hampering CXCL12/CXCR7 biased signal-induced metastasis of CRC.

scholarly journals The mechanisms of colorectal cancer cell mesenchymal-epithelial transition induced by hepatocyte exosome-derived miR-203a-3p

BMC Cancer ◽  
2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Heyang Xu ◽  
Qiusheng Lan ◽  
Yongliang Huang ◽  
Yang Zhang ◽  
Yujie Zeng ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Liver Metastasis ◽  
Epithelial To Mesenchymal Transition ◽  
Luciferase Reporter ◽  
Mesenchymal Transition ◽  
Real Time Quantitative Pcr ◽  
Mesenchymal To Epithelial Transition ◽  
Reporter Assays ◽  
Phosphatase Of Regenerating Liver

Abstract Background Liver metastasis is the most common cause of death in patients with colorectal cancer (CRC). Phosphatase of regenerating liver-3 induces CRC metastasis by epithelial-to-mesenchymal transition, which promotes CRC cell liver metastasis. Mesenchymal-to-epithelial transition (MET), the opposite of epithelial-to-mesenchymal transition, has been proposed as a mechanism for the establishment of metastatic neoplasms. However, the molecular mechanism of MET remains unclear. Methods Using Immunohistochemistry, western blotting, invasion assays, real-time quantitative PCR, chromatin immunoprecipitation, luciferase reporter assays, human miRNA arrays, and xenograft mouse model, we determined the role of hepatocyte exosome-derived miR-203a-3p in CRC MET. Results In our study, we found that miR-203a-3p derived from hepatocyte exosomes increased colorectal cancer cells E-cadherin expression, inhibited Src expression, and reduced activity. In this way miR-203a-3p induced the decreased invasion rate of CRC cells. Coclusion MiR-203a-3p derived from hepatocyte exosomes plays an important role of CRC cells to colonize in liver.

scholarly journals Role of Epithelial–Mesenchymal Plasticity in Pseudomyxoma Peritonei: Implications for Locoregional Treatments

2020 ◽  
Vol 21 (23) ◽  
pp. 9120
Author(s):  
Maria Luisa Calabrò ◽  
Nayana Lazzari ◽  
Giulia Rigotto ◽  
Marco Tonello ◽  
Antonio Sommariva
Keyword(s):  
Pseudomyxoma Peritonei ◽  
Epithelial Mesenchymal Transition ◽  
Expression Profiles ◽  
Mesenchymal Transition ◽  
Metastatic Process ◽  
Metastatic Sites ◽  
Mesenchymal Epithelial Transition ◽  
Targeted Approach ◽  
Peritoneal Malignancy

The mechanisms by which neoplastic cells disseminate from the primary tumor to metastatic sites, so-called metastatic organotropism, remain poorly understood. Epithelial–mesenchymal transition (EMT) plays a role in cancer development and progression by converting static epithelial cells into the migratory and microenvironment-interacting mesenchymal cells, and by the modulation of chemoresistance and stemness of tumor cells. Several findings highlight that pathways involved in EMT and its reverse process (mesenchymal–epithelial transition, MET), now collectively called epithelial–mesenchymal plasticity (EMP), play a role in peritoneal metastases. So far, the relevance of factors linked to EMP in a unique peritoneal malignancy such as pseudomyxoma peritonei (PMP) has not been fully elucidated. In this review, we focus on the role of epithelial–mesenchymal dynamics in the metastatic process involving mucinous neoplastic dissemination in the peritoneum. In particular, we discuss the role of expression profiles and phenotypic transitions found in PMP in light of the recent concept of EMP. A better understanding of EMP-associated mechanisms driving peritoneal metastasis will help to provide a more targeted approach for PMP patients selected for locoregional interventions involving cytoreductive surgery and hyperthermic intraperitoneal chemotherapy.

scholarly journals The Role of Snail-1 in Thyroid Cancer—What We Know So Far

2021 ◽  
Vol 10 (11) ◽  
pp. 2324
Author(s):  
Katarzyna Wieczorek-Szukala ◽  
Andrzej Lewinski
Keyword(s):  
Thyroid Cancer ◽  
Epithelial To Mesenchymal Transition ◽  
Thyroid Cells ◽  
High Tendency ◽  
Mesenchymal Transition ◽  
Thyroid Carcinomas ◽  
Slow Progression ◽  
Cancer Invasiveness ◽  
Metastatic Process

Thyroid carcinomas, despite the usually indolent behaviour and relatively good overall prognosis, show a high tendency to gain invasive phenotype and metastasise in some cases. However, due to a relatively slow progression, the exact mechanisms governing the metastatic process of thyroid carcinomas, including the epithelial-to-mesenchymal transition (EMT), are poorly described. One of the best-known regulators of cancer invasiveness is Snail-1—a zinc-finger transcription factor that plays a key role as an EMT inducer. More and more attention is being paid to the role of Snail with regard to thyroid cancer development. Apart from the obvious implications in the EMT process, Snail-1 plays an important role in the regulation of chemoresistance of the thyroid cells and cancer stem cell (CSC) formation, and it also interacts with miRNA specific to the thyroid gland. The aim of this review was to summarise the knowledge on Snail-1, especially in the context of thyroid oncogenesis.

scholarly journals TGFβSignaling in Tumor Initiation, Epithelial-to-Mesenchymal Transition, and Metastasis

2015 ◽  
Vol 2015 ◽  
pp. 1-15 ◽  
Author(s):  
Panagiotis Papageorgis
Keyword(s):  
Cancer Progression ◽  
Transforming Growth Factor Beta ◽  
Epithelial To Mesenchymal Transition ◽  
Transforming Growth Factor ◽  
Mesenchymal Transition ◽  
Cellular Context ◽  
Metastatic Process ◽  
Growth Factor Beta ◽  
Signaling Activity

Retaining the delicate balance in cell signaling activity is a prerequisite for the maintenance of physiological tissue homeostasis. Transforming growth factor-beta (TGFβ) signaling is an essential pathway that plays crucial roles during embryonic development as well as in adult tissues. Aberrant TGFβsignaling activity regulates tumor progression in a cancer cell-autonomous or non-cell-autonomous fashion and these effects may be tumor suppressing or tumor promoting depending on the cellular context. The fundamental role of this pathway in promoting cancer progression in multiple stages of the metastatic process, including epithelial-to-mesenchymal transition (EMT), is also becoming increasingly clear. In this review, we discuss the latest advances in the effort to unravel the inherent complexity of TGFβsignaling and its role in cancer progression and metastasis. These findings provide important insights into designing personalized therapeutic strategies against advanced cancers.

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