Forkhead box C1 induces epithelial-mesenchymal transition and is a potential therapeutic target in nasopharyngeal carcinoma

Rheumatoid arthritis (RA) is an autoimmune disease that can cause damage to the joints, cartilage and bone. There is no cure but early diagnosis can help mitigate damage. Sometimes RA is particularly difficult to treat, for example when the disease took a long time to be diagnosed. Associate Professor Masao Tanaka, Graduate School of Medicine, Kyoto University, Japan, leads a team of researchers working to improve understanding of the causes of poor response to treatment in RA with a long morbidity. The goal is to restore patients' therapeutic responsiveness, thereby improving outcomes. A previous focus for Tanaka was on a protein called FSTL1. He is now exploring DIP2 as a binding molecule for FSTL1. Other important mechanisms Tanaka is exploring are DNA methylation and the mechanisms of carnitine, which has been found to decrease a variety of activation signalling by inhibiting ceramide production in T cells. He and the team are exploring the involvement of these mechanisms in DIP2. In his most recent investigations, Tanaka is exploring DIP2C as a novel regulator for epithelial-mesenchymal transition of RA synovium and a potential therapeutic target. He is focusing on molecules that are expressed in the cells in joints, making the work directly applicable to RA. The team is carrying out a cohort study called KURAMA (Kyoto University Rheumatoid Arthritis Management Alliance) that involves around 2,000 outpatients with RA. Ultimately, Tanaka hopes to identify a reproducible combination of patient conditions and therapeutic interventions that achieve better treatment results for RA patients.

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Coupling of Cell Surface Biotinylation and SILAC-Based Quantitative Proteomics Identified Myoferlin as a Potential Therapeutic Target for Nasopharyngeal Carcinoma Metastasis

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.621810 ◽

2021 ◽

Vol 9 ◽

Author(s):

Maoyu Li ◽

Fang Peng ◽

Guoqiang Wang ◽

Xujun Liang ◽

Meiying Shao ◽

...

Keyword(s):

Nasopharyngeal Carcinoma ◽

Cell Surface ◽

Therapeutic Target ◽

Surface Proteins ◽

Differentially Expressed ◽

Attractive Potential ◽

Potential Therapeutic Target ◽

Cell Surface Proteins ◽

Mesenchymal Transition ◽

Cell Surface Biotinylation

Distant metastasis is a major cause of treatment failure in nasopharyngeal carcinoma (NPC) patients. Cell surface proteins represent attractive targets for cancer diagnosis or therapy. However, the cell surface proteins associated with NPC metastasis are poorly understood. To identify potential therapeutic targets for NPC metastasis, we isolated cell surface proteins from two isogenic NPC cell lines, 6-10B (low metastatic) and 5-8F (highly metastatic), through cell surface biotinylation. Stable isotope labeling by amino acids in cell culture (SILAC) based proteomics was applied to comprehensively characterize the cell surface proteins related with the metastatic phenotype. We identified 294 differentially expressed cell surface proteins, including the most upregulated protein myoferlin (MYOF), two receptor tyrosine kinases(RTKs) epidermal growth factor receptor (EGFR) and ephrin type-A receptor 2 (EPHA2) and several integrin family molecules. These differentially expressed proteins are enriched in multiple biological pathways such as the FAK-PI3K-mTOR pathway, focal adhesions, and integrin-mediated cell adhesion. The knockdown of MYOF effectively suppresses the proliferation, migration and invasion of NPC cells. Immunohistochemistry analysis also showed that MYOF is associated with NPC metastasis. We experimentally confirmed, for the first time, that MYOF can interact with EGFR and EPHA2. Moreover, MYOF knockdown could influence not only EGFR activity and its downstream epithelial–mesenchymal transition (EMT), but also EPHA2 ligand-independent activity. These findings suggest that MYOF might be an attractive potential therapeutic target that has double effects of simultaneously influencing EGFR and EPHA2 signaling pathway. In conclusion, this is the first study to profile the cell surface proteins associated with NPC metastasis and provide valuable resource for future researches.

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β-catenin activates TGF-β-induced epithelial–mesenchymal transition in adenomyosis

Experimental & Molecular Medicine ◽

10.1038/s12276-020-00514-6 ◽

2020 ◽

Vol 52 (10) ◽

pp. 1754-1765

Author(s):

Jung-Yoon Yoo ◽

Bon Jeong Ku ◽

Tae Hoon Kim ◽

Jong Il Ahn ◽

Ji Yeon Ahn ◽

...

Keyword(s):

Pelvic Pain ◽

Therapeutic Target ◽

Chronic Pelvic Pain ◽

Epithelial Mesenchymal Transition ◽

Strong Positive Correlation ◽

Potential Therapeutic Target ◽

Common Cause ◽

Mesenchymal Transition ◽

Ishikawa Cells ◽

Cell Invasiveness

Abstract Adenomyosis is defined as the presence of ectopic nests of endometrial glands and stroma within the myometrium. Adenomyosis is a common cause of dysmenorrhea, menorrhagia, and chronic pelvic pain but is often underdiagnosed. Despite its prevalence and severity of symptoms, its pathogenesis and etiology are poorly understood. Our previous study showed that aberrant activation of β-catenin results in adenomyosis through epithelial–mesenchymal transition. Using transcriptomic and ChIP-seq analysis, we identified activation of TGF-β signaling in the uteri of mutant mice that expressed dominant stabilized β-catenin in the uterus. There was a strong positive correlation between β-catenin and TGF-β2 proteins in women with adenomyosis. Furthermore, treatment with pirfenidone, a TGF-β inhibitor, increased E-cadherin expression and reduced cell invasiveness in Ishikawa cells with nuclear β-catenin. Our results suggest that β-catenin activates TGF-β-induced epithelial–mesenchymal transition in adenomyosis. This finding describes the molecular pathogenesis of adenomyosis and the use of TGF-β as a potential therapeutic target for adenomyosis.

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CtBP1 is involved in epithelial-mesenchymal transition and is a potential therapeutic target for hepatocellular carcinoma

Oncology Reports ◽

10.3892/or.2013.2537 ◽

2013 ◽

Vol 30 (2) ◽

pp. 809-814 ◽

Cited By ~ 13

Author(s):

XIAO-LING ZHANG ◽

CHENG-XIN HUANG ◽

JIE ZHANG ◽

AKIRA INOUE ◽

SI-EN ZENG ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Therapeutic Target ◽

Epithelial Mesenchymal Transition ◽

Potential Therapeutic Target ◽

Mesenchymal Transition

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An epithelial-mesenchymal transition (EMT) gene signature to predict resistance to EGFR inhibition and AXL identification as a therapeutic target in head and neck squamous cell carcinoma.

Journal of Clinical Oncology ◽

10.1200/jco.2013.31.15_suppl.6011 ◽

2013 ◽

Vol 31 (15_suppl) ◽

pp. 6011-6011

Author(s):

Robert Cardnell ◽

Lixia Diao ◽

Jing Wang ◽

David Bearss ◽

Steven Warner ◽

...

Keyword(s):

Lung Cancer ◽

Squamous Cell Carcinoma ◽

Cell Carcinoma ◽

Therapeutic Target ◽

Drug Response ◽

Epithelial Mesenchymal Transition ◽

Egfr Inhibitor ◽

Potential Therapeutic Target ◽

Mesenchymal Transition ◽

Inhibitor Resistance

6011 Background: Epithelial-mesenchymal transition (EMT) has been associated with EGFR inhibitor resistance in preclinical studies of head and neck squamous cell carcinoma (HNSCC). Recently, we developed an EMT signature that predicts EGFR inhibitor resistance in lung cancer. Using this signature, we explored the association between EMT and drug response in HNSCC, focusing on the tyrosine kinase Axl as a potential therapeutic target. Methods: We conducted an integrated molecular and drug response analysis in HNSCC. A 76-gene EMT signature previously developed and validated in lung cancer was tested in HNSCC cell lines (n>50) and patient tumors from The Cancer Genome Atlas (TCGA) (n=113) and a MDACC cohort (n=105). Reverse phase protein array (RPPA) and proliferation assays were used to measure protein expression and sensitivity to erlotinib and the Axl inhibitors SGI-7079 and TP-0930. Results: The EMT signature identified distinct epithelial and mesenchymal subsets of HNSCC among cell lines and patient tumors. RPPA experiments revealed higher protein levels of the receptor tyrosine kinase Axl, vimentin, and N-cadherin and lower expression of E-cadherin and beta-catenin in mesenchymal HNSCC (p-values <0.02). Elevated Axl expression was also associated with significantly shorter overall survival in patients with locally advanced HNSCC (p<0.001 in TCGA cohort; p=0.003 MDACC). Consistent with previous studies, mesenchymal HNSCC cells exhibited resistance to erlotinib (IC50 >10μM); however, we discovered that mesenchymal HNSCC were highly sensitive to two Axl inhibitors, SGI-7079 and TP-0930 (IC50s ≤1.2μM and 0.2uM, respectively). Conclusions: Our EMT gene expression signature identified discrete epithelial and mesenchymal subgroups of HNSCC. Mesenchymal HNSCC cells expressed higher levels of Axl protein and exhibited sensitivity to Axl inhibition, but resistance to erlotinib. These results highlight differences in drug response between epithelial and mesenchymal cancers and support Axl as a potential therapeutic target and predictive marker of EGFR inhibitor resistance in HNSCC. (Funded in part by 5 P50 CA097007-10)

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Narrower insight to SIRT1 role in cancer: A potential therapeutic target to control epithelial-mesenchymal transition in cancer cells

Journal of Cellular Physiology ◽

10.1002/jcp.26302 ◽

2018 ◽

Vol 233 (6) ◽

pp. 4443-4457 ◽

Cited By ~ 19

Author(s):

Jalal Choupani ◽

Sima Mansoori Derakhshan ◽

Sahar Bayat ◽

Mohammad Reza Alivand ◽

Mahmoud Shekari Khaniani

Keyword(s):

Cancer Cells ◽

Therapeutic Target ◽

Epithelial Mesenchymal Transition ◽

Potential Therapeutic Target ◽

Mesenchymal Transition

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MiR-30a: A Novel Biomarker and Potential Therapeutic Target for Cancer

Journal of Oncology ◽

10.1155/2018/5167829 ◽

2018 ◽

Vol 2018 ◽

pp. 1-9 ◽

Cited By ~ 20

Author(s):

Lin-hong Jiang ◽

He-da Zhang ◽

Jin-hai Tang

Keyword(s):

Gene Expression ◽

Therapeutic Target ◽

Epithelial Mesenchymal Transition ◽

Myelogenous Leukemia ◽

Transcriptional Unit ◽

Potential Therapeutic Target ◽

Regulate Gene Expression ◽

Mesenchymal Transition ◽

Proliferation And Metastasis ◽

Complementary Binding

MicroRNAs (miRNAs) are small, highly conserved noncoding RNAs molecules, consisting of 18–25 nucleotides that regulate gene expression by binding to complementary binding sites within the 3′untranslated region (3′UTR) of target mRNAs. MiRNAs have been involved in regulating gene expression and diverse physiological and pathological processes. Several studies have reported that miR-30a, situated on chromosome 6q.13, is produced by an intronic transcriptional unit. Moreover, miR-30a has demonstrated its role in biological processes, including inhibiting proliferation and metastasis in many tumors, autophagy in chronic myelogenous leukemia, and regulating TGF-b1-induced epithelial-mesenchymal transition. However, based on the pathogenetic relationship between miR-30a and cancer in tumorigenesis, we believe that miR-30a may serve as tumor promising biomarker. Moreover, it would offer a therapeutic target for the treatment of cancer.

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AnnexinA7 promotes epithelial–mesenchymal transition by interacting with Sorcin and contributes to aggressiveness in hepatocellular carcinoma

Cell Death and Disease ◽

10.1038/s41419-021-04287-2 ◽

2021 ◽

Vol 12 (11) ◽

Author(s):

Fei Ling ◽

Huan Zhang ◽

Yunliang Sun ◽

Jinyi Meng ◽

Jaceline Gislaine Pires Sanches ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

High Mortality ◽

Therapeutic Target ◽

Epithelial Mesenchymal Transition ◽

Interacting Proteins ◽

Potential Therapeutic Target ◽

Mesenchymal Transition ◽

Hcc Cells

AbstractHepatocellular carcinoma (HCC) is one of the most common cancers worldwide, and metastasis is the major cause of the high mortality of HCC. In this study, we identified that AnnexinA7 (ANXA7) and Sorcin (SRI) are overexpressed and interacting proteins in HCC tissues and cells. In vitro functional investigations revealed that the interaction between ANXA7 and SRI regulated epithelial–mesenchymal transition (EMT), and then affected migration, invasion, and proliferation in HCC cells. Furthermore overexpression/knockdown of ANXA7 was remarkably effective in promoting/inhibiting tumorigenicity and EMT in vivo. Altogether, our study unveiled a mechanism that ANXA7 promotes EMT by interacting with SRI and further contributes to the aggressiveness in HCC, which provides a novel potential therapeutic target for preventing recurrence and metastasis in HCC.

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TBL1XR1 as a potential therapeutic target that promotes epithelial‑mesenchymal transition in lung squamous cell carcinoma

Experimental and Therapeutic Medicine ◽

10.3892/etm.2018.6955 ◽

2018 ◽

Author(s):

Yuehua Zhao ◽

Hao Lin ◽

Jingwei Jiang ◽

Mengxi Ge ◽

Xiaohua Liang

Keyword(s):

Squamous Cell Carcinoma ◽

Cell Carcinoma ◽

Squamous Cell ◽

Therapeutic Target ◽

Epithelial Mesenchymal Transition ◽

Lung Squamous Cell Carcinoma ◽

Potential Therapeutic Target ◽

Mesenchymal Transition

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LINC00667 Sponges miR-4319 to Promote the Development of Nasopharyngeal Carcinoma by Increasing FOXQ1 Expression

Frontiers in Oncology ◽

10.3389/fonc.2020.632813 ◽

2021 ◽

Vol 10 ◽

Author(s):

Bing Liao ◽

Yun Yi ◽

Lei Zeng ◽

Zhi Wang ◽

Xinhua Zhu ◽

...

Keyword(s):

Nasopharyngeal Carcinoma ◽

Bioinformatics Analysis ◽

Epithelial Mesenchymal Transition ◽

Malignant Tumors ◽

Mechanistic Study ◽

Small Cell Lung ◽

Mesenchymal Transition ◽

Forkhead Box

Accumulating evidence has indicated that lncRNAs regulate various biological and pathological processes in diverse malignant tumors. The roles of LINC00667 in cancer development have been explored in glioma, hepatocellular carcinoma and non-small cell lung cancer, but not in nasopharyngeal carcinoma (NPC). In the present study, we characterize the role and molecular mechanism of LINC00667 in NPC progression. It was found that LINC00667 was overexpressed in NPC cells compared to normal cells. Silencing LINC00667 suppressed the proliferation, migration, invasion and epithelial mesenchymal transition (EMT) in NPC cells. In addition, bioinformatics analysis revealed that LINC00667 acted as a ceRNA to absorb miR-4319. Further investigations illustrated that miR-4319 had low expression in NPC cells and functioned as a tumor suppressor in the progression of NPC. Mechanistic study identified forkhead box Q1 (FOXQ1) as a functional target of miR-4319. The effect of LINC00667 in NPC development was mediated by the miR-4319/FOXQ1 axis. Analysis on tumorxenograft mouse model demonstrated that knockdown of LINC00667 repressed NPC tumor growth in vivo and confirmed the in vitro results. Our present study suggested that LINC00667 promoted the malignant phenotypes of NPC cells by competitively binding to miR-4319 to up-regulate FOXQ1 expression. Our results reveled that LINC00667 could be a diagnostic and therapeutic target for NPC patients.

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