Upregulation of Ets1 expression by NFATc2 and NFKB1/RELA promotes breast cancer cell invasiveness

Kim, Gi-Cheon; Kwon, Ho-Keun; Lee, Choong-Gu; Verma, Ravi; Rudra, Dipayan; Kim, Taemook; Kang, Keunsoo; Nam, Jong Hee; Kim, Young; Im, Sungbin

doi:10.1038/s41389-018-0101-3

Cited by 39 publications

(31 citation statements)

References 60 publications

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“…Overexpression of VCAN may have a role in initiation and progression of gastric cancer since changes were observed between normal and pathological stages and between each stage. VCAN may play an oncogenic role in gastric cancer, promoting disease progression from early to advance stage in accordance with several reports linking upregulated gene expressions with carcinogenesis and disease progression (34)(35)(36)(37)(38)(39)(40). Immunohistochemical examination of VCAN expression also confirmed our findings, with a higher protein expression in cancer tissues than normal tissues.…”

Section: Discussionsupporting

confidence: 89%

VCAN – A novel prognostic marker for gastric cancer

Binang

Wang

Tewara³

et al. 2019

Preprint

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Background Versican (VCAN) is a large aggregating extracellular matrix proteoglycan implicated in the pathogenesis of most human cancers but its role in gastric cancer is not yet elucidated. We designed the present study to investigate the expression, prognostic value, relationship between genetic alterations and patient’s outcome, disease associations, as well as genetic and protein interactions of VCAN in gastric cancer. Methods Expression of VCAN in tumor and normal tissues was studied with ONCOMINE, UALCAN, and GEPIA databases and the human protein atlas. UALCAN, GEPIA, OncoLnc and Kaplan-Meier plotter were used to assess the prognostic values of VCAN in gastric cancer. Subgroup analysis of the clinical significance of VCAN in gastric cancer was done using Kaplan-Meier plotter. Genetic alterations of VCAN and their associations with patient’s outcome were studied with cBioPortal. Open targets platform was used to study diseases associated with VCAN, GeneMANIA was used to obtain the neighbor genes interaction network of VCAN, and STRING was used to examine VCAN interaction with other proteins. Results VCAN was upregulated and associated with clinical cancer stages. High VCAN expression predicted unfavorable outcome for all patients; subgroup analysis showed worse outcomes for patients treated with surgery or other adjuvants (other than 5-FU based adjuvant) but better outcome for patients treated with 5-FU based adjuvant, associating VCAN expression with chemosensitivity to 5-FU based adjuvants, but chemoresistance to other adjuvants. Genetic alteration of VCAN correlated with a favorable outcome in terms of disease-free survival for patients. Also, open targets platform showed that VCAN is associated with gastric cancer and is a potential therapeutic target for the disease. Finally, interaction of VCAN with neighbor genes and proteins revealed that VCAN interacts with genes and proteins that drive tumorigenesis and cancer progression. Conclusion The results of this study show that VCAN is an oncogene in gastric cancer whose expression can be applied as a biomarker for prognostic prediction, selection of appropriate chemotherapy drugs/monitoring of treatment response, and is a potential therapeutic target for gastric cancer.

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Section: Discussionsupporting

confidence: 89%

VCAN – A novel prognostic marker for gastric cancer

Binang

Wang

Tewara³

et al. 2019

Preprint

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“…Another well‐known transcription regulator that promotes EMT and cancer is NF‐κB (Chan et al, 2004; Kim et al, 2018; Park & Hong, 2016; Xia, Shen, & Verma, 2014). When NF‐κB is activated, it is translocated from the cytoplasm into the nucleus where it regulates gene expression responsible for cell transformation, proliferation, apoptosis, invasion, and metastasis (Shishodia & Aggarwal, 2004).…”

Section: Resultsmentioning

confidence: 99%

Downregulation of uPAR promotes urokinase translocation into the nucleus and epithelial to mesenchymal transition in neuroblastoma

Semina

Рубина

Шмакова

et al. 2020

Journal Cellular Physiology

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The urokinase system is involved in a variety of physiological processes, such as fibrinolysis, matrix remodeling, wound healing, and regeneration. Upon binding to its cognate receptor urokinase-type plasminogen activator receptor (uPAR), urokinase-type plasminogen activator (uPA) catalyzes the conversion of plasminogen to plasmin and the activation of matrix metalloproteases. Apart from this, uPA-uPAR interaction can lead to the activation of transcription factors, mitogenactivated protein kinase signaling pathways and RTK cascades. Elevated expression of uPA and uPAR is markedly associated with cancer progression and metastasis and correlates with a poor prognosis in clinics. Targeting the urokinase system has proved to be effective in experimental models in vitro and in vivo, however, in clinics the inhibition of the uPA/uPAR system has fallen short of expectations, suggesting that the question of the functional relevance of uPA/uPAR system is far from being moot. Recently, using CRISPR/Cas9 technology, we have shown that uPAR knockout decreases the proliferation of neuroblastoma Neuro2a cells in vitro. In the present study we demonstrate that uPAR expression is essential for maintaining the epithelial phenotype in Neuro2a cells and that uPAR silencing promotes epithelial-mesenchymal transition (EMT) and increased cell migration. Accordingly, uPAR knockout results in the downregulation of epithelial markers (E-cadherin, occludin, and claudin-5) and in the increase of mesenchymal markers (N-cadherin, α-smooth muscle actin, and interleukin-6). In search of the molecular mechanism underlying these changes, we identified uPA as a key component. Two key insights emerged as a result of this work: in the absence of uPAR, uPA is translocated into the nucleus where it is presumably involved in the activation of transcription factors (nuclear factor κB and Snail) resulting in EMT. In uPAR-expressing cells, uPAR functions as a uPA ---

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“…6a), suggesting that the low expression of NTN1 in thymoma is related to the occurrence and development of THYM. The up-regulation of transcription factor ETS1 is related to the invasion of breast cancer 44 . The transcription of NTNG2 in breast cancer is positively regulated by ETS1 (r = 0.2971)( Fig.…”

Section: Methylation and Clinical Analysis Of Netrins In Pan-cancermentioning

confidence: 99%

The pan-cancer landscape of netrin family reveals potential oncogenic biomarkers

Hao

Lin

et al. 2020

Sci Rep

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Recent cancer studies have found that the netrin family of proteins plays vital roles in the development of some cancers. However, the functions of the many variants of these proteins in cancer remain incompletely understood. In this work, we used the most comprehensive database available, including more than 10000 samples across more than 30 tumor types, to analyze the six members of the netrin family. We performed comprehensive analysis of genetic change and expression of the netrin genes and analyzed epigenetic and pathway relationships, as well as the correlation of expression of these proteins with drug sensitivity. Although the mutation rate of the netrin family is low in pan-cancer, among the tumor patients with netrin mutations, the highest number are Uterine Corpus Endometrial Carcinoma patients, accounting for 13.6% of cases (54 of 397). Interestingly, the highest mutation rate of a netrin family member is 38% for NTNG1 (152 of 397). Netrin proteins may participate in the development of endocrine-related tumors and sex hormone-targeting organ tumors. Additionally, the participation of NTNG1 and NTNG2 in various cancers shows their potential for use as new tumor markers and therapeutic targets. this analysis provides a broad molecular perspective of this protein family and suggests some new directions for the treatment of cancer. Cytokines, growth factors, angiogenic factors, and extracellular proteases are secreted to the outside of the cell to produce biological functions 1. These secreted proteins participate in the immune regulation of chronic inflammation 2,3 and the occurrence of lipid metabolism diseases 4 , but also play important roles in tumor invasion, metastasis, immunity, and drug resistance 5-8. For example, CD317 and EGFR are secreted proteins that are potential diagnostic markers for non-small cell lung cancer 9. CD63 is secreted by melanoma into the blood and can be used as a protein marker 10. HGF inhibits the treatment of RAF inhibitors of BRAF mutant melanoma 11. The netrins are neuroguiding factors with axonal guiding function, and are similar to laminin in structure. Netrins were first discovered in C. elegans in 1990 12 , and this family of proteins includes the secreted proteins Netrin-1 (NTN1), Netrin-3 (NTN3), Netrin-4 (NTN4), and Netrin-5 (NTN5). The secreted proteins have a common domain structure, with an N-terminal laminin repeat (Laminin N-terminal), three cysteine-rich EGF modules (V-1, V-2, and V-3), and a positively charged C-terminal domain (NTR) 13. The netrin family also includes two membrane-binding proteins, Netrin-G1 (NTNG1) and Netrin-G2 (NTNG2) 14. Although these proteins also have Laminin N-terminal and Laminin EGF domains, their ends have different functions due to GPI 15. The major binding receptors of the secreted netrin proteins are DCC and UNC5 homologue family UNC5A-D, which are both dependent receptors. Netrin binding to a receptor promotes cell survival, proliferation, and differentiation, and without netrin binding, the receptor induces apoptosis 16,17....

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Upregulation of Ets1 expression by NFATc2 and NFKB1/RELA promotes breast cancer cell invasiveness

Cited by 39 publications

References 60 publications

VCAN – A novel prognostic marker for gastric cancer

VCAN – A novel prognostic marker for gastric cancer

Downregulation of uPAR promotes urokinase translocation into the nucleus and epithelial to mesenchymal transition in neuroblastoma

The pan-cancer landscape of netrin family reveals potential oncogenic biomarkers

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