MYOCD and SMAD3/SMAD4 form a positive feedback loop and drive TGF-β-induced epithelial–mesenchymal transition in non-small cell lung cancer

Tong, Xin; Wang, Shengjie; Li, Zhe; Li, Chang; Zhang, Cuijuan; Su, Zhiyue; Liu, Xia; Zhao, Jun; Zhang, Hongtao

doi:10.1038/s41388-020-1189-4

Cited by 41 publications

(34 citation statements)

References 51 publications

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“…MYOCD, RSPO1 and ARHGAP20 are examples of this. MYOCD , which encodes myocardin, is required for cardiac and smooth muscle development and is a potent transcriptional co-activator which acts in concert with telomerase [ 32 , 75 , 76 ]. RSPO1 is involved in embryonic development and organogenesis and is predicted to interact with hTERT [ 77 , 78 ].…”

Section: Discussionmentioning

confidence: 99%

“…ARHGAP20 contributes to cellular regulation processes and has been found within a protein network surrounding TERF1 , TERF2 and POT1 [ 79 , 80 ]. MYOCD, RSPO1 and ARHGAP20 have all been implicated in various cancers, including lung cancer [ 75 , 77 , 79 ]. Along with JSRP1, FEN1 and BLM , they have not been previously studied in EC and further investigation is warranted to understand how they may contribute to EC carcinogenesis.…”

Section: Discussionmentioning

confidence: 99%

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Investigating the Role of Telomere and Telomerase Associated Genes and Proteins in Endometrial Cancer

Bradfield

Button

Hill

et al. 2020

MPs

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Endometrial cancer (EC) is the commonest gynaecological malignancy. Current prognostic markers are inadequate to accurately predict patient survival, necessitating novel prognostic markers, to improve treatment strategies. Telomerase has a unique role within the endometrium, whilst aberrant telomerase activity is a hallmark of many cancers. The aim of the current in silico study is to investigate the role of telomere and telomerase associated genes and proteins (TTAGPs) in EC to identify potential prognostic markers and therapeutic targets. Analysis of RNA-seq data from The Cancer Genome Atlas identified differentially expressed genes (DEGs) in EC (568 TTAGPs out of 3467) and ascertained DEGs associated with histological subtypes, higher grade endometrioid tumours and late stage EC. Functional analysis demonstrated that DEGs were predominantly involved in cell cycle regulation, while the survival analysis identified 69 DEGs associated with prognosis. The protein-protein interaction network constructed facilitated the identification of hub genes, enriched transcription factor binding sites and drugs that may target the network. Thus, our in silico methods distinguished many critical genes associated with telomere maintenance that were previously unknown to contribute to EC carcinogenesis and prognosis, including NOP56, WFS1, ANAPC4 and TUBB4A. Probing the prognostic and therapeutic utility of these novel TTAGP markers will form an exciting basis for future research.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Investigating the Role of Telomere and Telomerase Associated Genes and Proteins in Endometrial Cancer

Bradfield

Button

Hill

et al. 2020

MPs

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“…These, in turn, regulate the expression of EMT-mediating genes Twist, Zeb1 and Snail. Following are some selected studies documenting the role of Smad in TGF-β-mediated EMT (Vincent et al 2009;Kim et al 2016;Yu et al 2016;Yeh et al 2018;Tong et al 2020). TGF-β can also induce EMT by altering the mechanical architecture (cytoskeletal remodeling) of cancer cells to a motile phenotype (Gladilin et al 2019).…”

Section: Tgf-βmentioning

confidence: 99%

Cancer drug resistance induced by EMT: novel therapeutic strategies

et al. 2021

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Over the last decade, important clinical benefits have been achieved in cancer patients by using drug-targeting strategies. Nevertheless, drug resistance is still a major problem in most cancer therapies. Epithelial-mesenchymal plasticity (EMP) and tumour microenvironment have been described as limiting factors for effective treatment in many cancer types. Moreover, epithelial-to-mesenchymal transition (EMT) has also been associated with therapy resistance in many different preclinical models, although limited evidence has been obtained from clinical studies and clinical samples. In this review, we particularly deepen into the mechanisms of which intermediate epithelial/mesenchymal (E/M) states and its interconnection to microenvironment influence therapy resistance. We also describe how the use of bioinformatics and pharmacogenomics will help to figure out the biological impact of the EMT on drug resistance and to develop novel pharmacological approaches in the future.

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“…Even though Wnt/β-catenin-related pathways seem to be activated in Cluster A, mutations resulting in protein function aberration of the CTNNB1 gene itself were observed only in Cluster B1. Key players of cell adhesion abnormalities and EMT in Cluster B1 appear to be Cluster B1-specific mutations of the CDH1 ( 44 ), CTNNB1 ( 44 ), MMP9 ( 45 ), TLN2 ( 46 ), ROCK1 ( 47 ), SMAD4 ( 48 ) and VAV2 ( 33 ) genes. In addition, TWIST1 is a master regulator of morphogenesis repressing CDH1 expression, and is required for EMT initiation ( 49 ) and expression regulation of the TWIST1 ( 50 ) gene due to DNA methylation alterations has been reported.…”

Section: Discussionmentioning

confidence: 99%

Cooperative participation of epigenomic and genomic alterations in the clinicopathological diversity of gastric adenocarcinomas: significance of cell adhesion and epithelial–mesenchymal transition-related signaling pathways

Yang

Arai

Takahashi³

et al. 2020

Carcinogenesis

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The present study was conducted to clarify the cooperative significance of epigenomic and genomic abnormalities during gastric carcinogenesis. Using 21 samples of normal control gastric mucosa (C), 109 samples of non-cancerous gastric mucosa (N) and 105 samples of cancerous tissue (T) from 109 patients with primary gastric adenocarcinomas, genome-wide DNA methylation analysis was performed using Infinium assay. Among these samples, 66 paired N and corresponding T samples were subjected to whole-exome and single nucleotide polymorphism array analyses. As had been shown in our previous study, 109 patients were clustered clinicopathologically into least aggressive Cluster A (n=20), most aggressive Cluster B1 (n=20), and Cluster B2 (n=69). Most DNA methylation alterations in each cluster had already occurred even in N samples compared to C samples, and DNA methylation alterations at the precancerous N stage were inherited by the established cancers themselves. Recurrent single-nucleotide variants and insertions/deletions resulting in functional disruption of the proteins encoded by the ABCA10, BNC2, CDH1, CTNNB1, SMAD4 and VAV2 genes were specific to Cluster B1, whereas those of the APC, EGFR, ERBB2, ERBB3, MLH1 and MUC6 genes were specific to Cluster A. MetaCore pathway analysis revealed that the epigenomically affected TWIST1 gene and genomically affected CDH1, CTNNB1, MMP9, TLN2, ROCK1 and SMAD4 genes were accumulated in signaling pathways related to cell adhesion, cytoskeleton remodeling and epithelial-mesenchymal transition in Cluster B1. These data indicate that epigenomic alterations at the precancerous stage are important in gastric carcinogenesis and that epigenomic and genomic alterations cooperatively underlie the aggressiveness of gastric adenocarcinomas.

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MYOCD and SMAD3/SMAD4 form a positive feedback loop and drive TGF-β-induced epithelial–mesenchymal transition in non-small cell lung cancer

Cited by 41 publications

References 51 publications

Investigating the Role of Telomere and Telomerase Associated Genes and Proteins in Endometrial Cancer

Investigating the Role of Telomere and Telomerase Associated Genes and Proteins in Endometrial Cancer

Cancer drug resistance induced by EMT: novel therapeutic strategies

Cooperative participation of epigenomic and genomic alterations in the clinicopathological diversity of gastric adenocarcinomas: significance of cell adhesion and epithelial–mesenchymal transition-related signaling pathways

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