scholarly journals Systems biomedicine of primary and metastatic colorectal cancer reveals potential therapeutic targets

2020 ◽  
Author(s):  
Mehran Piran ◽  
Mehrdad Piran ◽  
Neda Sepahi ◽  
Ali Ghanbariasad ◽  
Amir Rahimi
Keyword(s):  
Colorectal Cancer ◽  
Cancer Progression ◽  
Molecular Mechanisms ◽  
Epithelial To Mesenchymal Transition ◽  
Meta Analysis ◽  
Ppi Network ◽  
Diagnostic Biomarkers ◽  
Mesenchymal Transition ◽  
Protein Protein Interaction ◽  
Hypoxic Conditions

AbstractColorectal cancer (CRC) is one of the major causes of cancer deaths across the world. Patients survival time at time of diagnosis depends largely on stage of the tumor. Therefore, understanding the molecular mechanisms promoting cancer progression from early stages to high-grade stages is essential for implementing therapeutic approaches. To this end, we performed a unique meta-analysis flowchart by identifying differentially expressed genes (DEGs) between normal, primary and metastatic samples in some test datasets. DEGs were employed to construct a protein-protein interaction (PPI) network. Then, a smaller network containing 39 DEGs were extracted from the PPI network whose nodes expression induction or suppression alone or in combination with each other would inhibit tumor progression or metastasis. A number of these DEGs were then verified by gene expression profiling, survival analysis and a number of validation datasets from different genomic repositories. They were involved in cell proliferation, energy production under hypoxic conditions, epithelial to mesenchymal transition (EMT) and angiogenesis. Multiple combination targeting of these DEGs were proposed to have high potential in preventing cancer progression. Some genes were also presented as diagnostic biomarkers for colorectal cancer. Finally, TMEM131, DARS and SORD genes were identified in this study which had never been associated with any kind of cancer neither as a biomarker nor curative target.

scholarly journals Control of the Epithelial-to-Mesenchymal Transition and Cancer Metastasis by Autophagy-Dependent SNAI1 Degradation

Cells ◽  
2019 ◽  
Vol 8 (2) ◽  
pp. 129 ◽  
Author(s):  
Sahib Zada ◽  
Jin Hwang ◽  
Mahmoud Ahmed ◽  
Trang Lai ◽  
Trang Pham ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Cancer Cell ◽  
Cancer Progression ◽  
Molecular Mechanisms ◽  
Cancer Metastasis ◽  
Epithelial To Mesenchymal Transition ◽  
Nuclear Translocation ◽  
Degradation Process ◽  
Mesenchymal Transition ◽  
Invasion And Migration

Autophagy, an intracellular degradation process, is essential for maintaining cell homeostasis by removing damaged organelles and proteins under various conditions of stress. In cancer, autophagy has conflicting functions. It plays a key role in protecting against cancerous transformation by maintaining genomic stability against genotoxic components, leading to cancerous transformation. It can also promote cancer cell survival by supplying minimal amounts of nutrients during cancer progression. However, the molecular mechanisms underlying how autophagy regulates the epithelial-to-mesenchymal transition (EMT) and cancer metastasis are unknown. Here, we show that starvation-induced autophagy promotes Snail (SNAI1) degradation and inhibits EMT and metastasis in cancer cells. Interestingly, SNAI1 proteins were physically associated and colocalized with LC3 and SQSTM1 in cancer cells. We also found a significant decrease in the levels of EMT and metastatic proteins under starvation conditions. Furthermore, ATG7 knockdown inhibited autophagy-induced SNAI1 degradation in the cytoplasm, which was associated with a decrease in SNAI1 nuclear translocation. Moreover, cancer cell invasion and migration were significantly inhibited by starvation-induced autophagy. These findings suggest that autophagy-dependent SNAI1 degradation could specifically regulate EMT and cancer metastasis during tumorigenesis.

scholarly journals Long Noncoding RNA (lncRNA)-Mediated Competing Endogenous RNA Networks Provide Novel Potential Biomarkers and Therapeutic Targets for Colorectal Cancer

2019 ◽  
Vol 20 (22) ◽  
pp. 5758 ◽  
Author(s):  
Liye Wang ◽  
Kwang Bog Cho ◽  
Yan Li ◽  
Gabriel Tao ◽  
Zuoxu Xie ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Noncoding Rna ◽  
Molecular Mechanisms ◽  
Epithelial To Mesenchymal Transition ◽  
Target Genes ◽  
Protein Coding ◽  
Mesenchymal Transition ◽  
Downstream Target ◽  
Rna Transcripts ◽  
Competitive Endogenous Rnas

Colorectal cancer (CRC) is the third most common cancer and has a high metastasis and reoccurrence rate. Long noncoding RNAs (lncRNAs) play an important role in CRC growth and metastasis. Recent studies revealed that lncRNAs participate in CRC progression by coordinating with microRNAs (miRNAs) and protein-coding mRNAs. LncRNAs function as competitive endogenous RNAs (ceRNAs) by competitively occupying the shared binding sequences of miRNAs, thus sequestering the miRNAs and changing the expression of their downstream target genes. Such ceRNA networks formed by lncRNA/miRNA/mRNA interactions have been found in a broad spectrum of biological processes in CRC, including liver metastasis, epithelial to mesenchymal transition (EMT), inflammation formation, and chemo-/radioresistance. In this review, we summarize typical paradigms of lncRNA-associated ceRNA networks, which are involved in the underlying molecular mechanisms of CRC initiation and progression. We comprehensively discuss the competitive crosstalk among RNA transcripts and the novel targets for CRC prognosis and therapy.

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 WNK3 promotes the invasiveness of glioma cell lines under hypoxia by inducing the epithelial-to-mesenchymal transition

2021 ◽  
Vol 12 (1) ◽  
pp. 320-329
Author(s):  
Yue Wang ◽  
Bingbing Wu ◽  
Shengrong Long ◽  
QiangLiu ◽  
Guangyu Li
Keyword(s):  
Molecular Mechanisms ◽  
Epithelial To Mesenchymal Transition ◽  
Low Grade ◽  
Glioma Invasion ◽  
Mesenchymal Transition ◽  
Hypoxic Conditions ◽  
Immunohistochemistry Analysis ◽  
Hypoxic Environment ◽  
U87 Cells

Abstract Background The primary features of malignant glioma include high rates of mortality and recurrence, uncontrollable invasiveness, strong angiogenesis, and widespread hypoxia. The hypoxic microenvironment is an important factor affecting the malignant progression of glioma. However, the molecular mechanisms underlying glioma adaption in hypoxic microenvironments are poorly understood. Objective The work presented in this paper focuses on the role of WNK3 gene in glioma invasion under hypoxic conditions. Furthermore, we aim to explore its role in epithelial-to-mesenchymal transition (EMT). Methods ShRNA targeting WNK3 transfection was used to knockdown the WNK3 expression in U87 cells. We used western blot analysis to detect the relative expression of proteins in U87 cells. The effect of WNK3 on cell migration was explored using a transwell assay in the U87 cell line. We also evaluated WNK3 expression levels in glioma samples by immunohistochemistry analysis. Results WNK3 expression was significantly higher in high-grade (III and IV) gliomas than in low-grade (I and II) gliomas. WNK3 expression was up-regulated in U87 cells when cultured in a hypoxic environment in addition; WNK3 knockdown inhibited the invasion of U87 glioma cells by regulating the EMT, especially under hypoxic conditions. Conclusion These findings suggested that WNK3 plays an important role in the hypoxic microenvironment of glioma and might also be a candidate for therapeutic application in the treatment of glioma.

scholarly journals Protein-Protein Interaction Network Analysis and Identification of Key Players in nor-NOHA and NOHA Mediated Pathways for Treatment of Cancer through Arginase Inhibition: Insights from Systems Biology

2018 ◽  
Author(s):  
Ishtiaque Ahammad
Keyword(s):  
Systems Biology ◽  
Cancer Progression ◽  
Molecular Mechanisms ◽  
Interaction Network ◽  
Cancer Cell Proliferation ◽  
Biological Processes ◽  
Ppi Network ◽  
Protein Protein Interaction ◽  
Key Players ◽  
Protein Protein Interaction Network

<p>L-arginine is involved in a number of biological processes in our bodies. Metabolism of L-arginine by the enzyme arginase has been found to be associated with cancer cell proliferation. Arginase inhibition has been proposed as a potential therapeutic means to inhibit this process. N-hydroxy-nor-L-Arg (nor-NOHA) and N (omega)-hydroxy-L-arginine (NOHA) has shown promise in inhibiting cancer progression through arginase inhibition. In this study, nor-NOHA and NOHA-associated genes and proteins were analyzed with several Bioinformatics and Systems Biology tools to identify the associated pathways and the key players involved so that a more comprehensive view of the molecular mechanisms including the regulatory mechanisms can be achieved and more potential targets for treatment of cancer can be discovered. Based on the analyses carried out, 3 significant modules have been identified from the PPI network. Five pathways/processes have been found to be significantly associated with nor-NOHA and NOHA associated genes. Out of the 1996 proteins in the PPI network, 4 have been identified as hub proteins- SOD, SOD1, AMD1, and NOS2. These 4 proteins have been implicated in cancer by other studies. Thus, this study provided further validation into the claim of these 4 proteins being potential targets for cancer treatment.</p>

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 Extracellular Matrix Alterations in Metastatic Processes

2019 ◽  
Vol 20 (19) ◽  
pp. 4947 ◽  
Author(s):  
Paolillo ◽  
Schinelli
Keyword(s):  
Extracellular Matrix ◽  
Cancer Cells ◽  
Cancer Progression ◽  
Molecular Mechanisms ◽  
Epithelial To Mesenchymal Transition ◽  
Intercellular Junctions ◽  
Matrix Metalloproteases ◽  
Target Tissue ◽  
Epithelial Tumor ◽  
Mesenchymal Transition

The extracellular matrix (ECM) is a complex network of extracellular-secreted macromolecules, such as collagen, enzymes and glycoproteins, whose main functions deal with structural scaffolding and biochemical support of cells and tissues. ECM homeostasis is essential for organ development and functioning under physiological conditions, while its sustained modification or dysregulation can result in pathological conditions. During cancer progression, epithelial tumor cells may undergo epithelial-to-mesenchymal transition (EMT), a morphological and functional remodeling, that deeply alters tumor cell features, leading to loss of epithelial markers (i.e., E-cadherin), changes in cell polarity and intercellular junctions and increase of mesenchymal markers (i.e., N-cadherin, fibronectin and vimentin). This process enhances cancer cell detachment from the original tumor mass and invasiveness, which are necessary for metastasis onset, thus allowing cancer cells to enter the bloodstream or lymphatic flow and colonize distant sites. The mechanisms that lead to development of metastases in specific sites are still largely obscure but modifications occurring in target tissue ECM are being intensively studied. Matrix metalloproteases and several adhesion receptors, among which integrins play a key role, are involved in metastasis-linked ECM modifications. In addition, cells involved in the metastatic niche formation, like cancer associated fibroblasts (CAF) and tumor associated macrophages (TAM), have been found to play crucial roles in ECM alterations aimed at promoting cancer cells adhesion and growth. In this review we focus on molecular mechanisms of ECM modifications occurring during cancer progression and metastatic dissemination to distant sites, with special attention to lung, liver and bone. Moreover, the functional role of cells forming the tumor niche will also be reviewed in light of the most recent findings.

scholarly journals In Vivo and In Vitro Effects of Tracheloside on Colorectal Cancer Cell Proliferation and Metastasis

Antioxidants ◽  
2021 ◽  
Vol 10 (4) ◽  
pp. 513
Author(s):  
Min-Kyoung Shin ◽  
Yong-Deok Jeon ◽  
Seung-Heon Hong ◽  
Sa-Haeng Kang ◽  
Ji-Ye Kee ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cell Cycle ◽  
Cell Cycle Arrest ◽  
Cancer Progression ◽  
Molecular Mechanisms ◽  
Oxidant Stress ◽  
Mesenchymal Transition ◽  
Cycle Arrest

Recent research suggests a relationship between cancer progression and oxidative mechanisms. Among the phenolic compounds such as tracheloside (TCS) are a major bioactive compound that can combat oxidant stress-related chronic diseases and that also displays anti-tumor activity. Although TCS can inhibit mammalian carcinoma, its effects on colorectal cancer (CRC) have not been clarified. The purpose of this study was to investigate the effects of TCS on the proliferation of CRC cells, the metastasis of CT26 cells, and the molecular mechanisms related to TCS in vitro and in vivo. A cell viability assay showed that TCS inhibited the proliferation of CRC cells. TCS-treated CT26 cells were associated with the upregulation of p16 as well as the downregulation of cyclin D1 and CDK4 in cell cycle arrest. In addition, TCS induced apoptosis of CT26 cells through mitochondria-mediated apoptosis and regulation of the Bcl-2 family. Expression of epithelial–mesenchymal transition (EMT) markers was regulated by TCS treatment in CT26 cells. TCS significantly inhibited the lung metastasis of CT26 cells in a mouse model. These results suggest that TCS, by inducing cell cycle arrest and apoptosis through its anti-oxidant properties, is a novel therapeutic agent that inhibits metastatic phenotypes of murine CRC cells.

scholarly journals Noncoding RNAs in Tumor Epithelial-to-Mesenchymal Transition

2016 ◽  
Vol 2016 ◽  
pp. 1-13 ◽  
Author(s):  
Ching-Wen Lin ◽  
Pei-Ying Lin ◽  
Pan-Chyr Yang
Keyword(s):  
Signaling Pathways ◽  
Cancer Progression ◽  
Molecular Mechanisms ◽  
Cancer Metastasis ◽  
Epithelial To Mesenchymal Transition ◽  
Regulation Of Gene Expression ◽  
Noncoding Rnas ◽  
Protein Translation ◽  
Gene Expressions ◽  
Mesenchymal Transition

Epithelial-derived tumor cells acquire the capacity for epithelial-to-mesenchymal transition (EMT), which enables them to invade adjacent tissues and/or metastasize to distant organs. Cancer metastasis is the main cause of cancer-related death. Molecular mechanisms involved in the switch from an epithelial phenotype to mesenchymal status are complicated and are controlled by a variety of signaling pathways. Recently, a set of noncoding RNAs (ncRNAs), including miRNAs and long noncoding RNAs (lncRNAs), were found to modulate gene expressions at either transcriptional or posttranscriptional levels. These ncRNAs are involved in EMT through their interplay with EMT-related transcription factors (EMT-TFs) and EMT-associated signaling. Reciprocal regulatory interactions between lncRNAs and miRNAs further increase the complexity of the regulation of gene expression and protein translation. In this review, we discuss recent findings regarding EMT-regulating ncRNAs and their associated signaling pathways involved in cancer progression.

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