دورية أكاديمية
EVI1 promotes metastasis by downregulating TIMP2 in metastatic colon and breast cancer cells.
| العنوان: | EVI1 promotes metastasis by downregulating TIMP2 in metastatic colon and breast cancer cells. |
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| المؤلفون: | Pradeepa; Cancer Biology Group, Institute of Life Sciences, Nalco Square, Bhubaneswar, Odisha 751023, India., Suresh V; Tumor Microenvironment and Animal Models Group, Institute of Life Sciences, Nalco Square, Bhubaneswar 751023, India., Singh VK; Cancer Biology Group, Institute of Life Sciences, Nalco Square, Bhubaneswar, Odisha 751023, India., Nayak KB; Cancer Biology Group, Institute of Life Sciences, Nalco Square, Bhubaneswar, Odisha 751023, India., Senapati S; Tumor Microenvironment and Animal Models Group, Institute of Life Sciences, Nalco Square, Bhubaneswar 751023, India., Chakraborty S; Cancer Biology Group, Institute of Life Sciences, Nalco Square, Bhubaneswar, Odisha 751023, India. Electronic address: soumen_ils@yahoo.co.in. |
| المصدر: | The international journal of biochemistry & cell biology [Int J Biochem Cell Biol] 2022 Jan; Vol. 142, pp. 106118. Date of Electronic Publication: 2021 Nov 18. |
| نوع المنشور: | Journal Article |
| اللغة: | English |
| بيانات الدورية: | Publisher: Elsevier Country of Publication: Netherlands NLM ID: 9508482 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1878-5875 (Electronic) Linking ISSN: 13572725 NLM ISO Abbreviation: Int J Biochem Cell Biol |
| أسماء مطبوعة: | Publication: Amsterdam : Elsevier Original Publication: Exeter, England ; Tarrytown, NY, U.S.A. : Pergamon, c1995- |
| مواضيع طبية MeSH: | MDS1 and EVI1 Complex Locus Protein*/genetics , MDS1 and EVI1 Complex Locus Protein*/metabolism , Tissue Inhibitor of Metalloproteinase-2*/metabolism , Tissue Inhibitor of Metalloproteinase-2*/genetics , Breast Neoplasms*/pathology , Breast Neoplasms*/genetics , Breast Neoplasms*/metabolism , Colonic Neoplasms*/pathology , Colonic Neoplasms*/genetics , Colonic Neoplasms*/metabolism , Gene Expression Regulation, Neoplastic* , Neoplasm Metastasis* , Down-Regulation*, Humans ; Female ; Animals ; Cell Line, Tumor ; Mice ; Promoter Regions, Genetic/genetics ; Cell Movement ; Mice, Nude ; DNA Methylation |
| مستخلص: | Ecotropic viral integration site-1 (EVI1) is an oncogenic zinc finger transcription factor whose expression is frequently upregulated in a variety of cancers, including both myeloid malignancies and solid tumors. Previously, our group has shown that EVI1 knockdown minimizes the metastatic potential of colon cancer cells compared to that of control cells. In this study, to identify the potential targets that regulate cancer metastasis, control and EVI1 knockdown colon cancer cells were subjected to microarray. Differential gene expression analysis revealed significant downregulation of tissue inhibitor of matrix metalloproteinase-2 (TIMP2) in EVI1 expressing cells. EVI1 knockdown increased TIMP2 protein expression levels and reduced wound healing and migration capacity in metastatic cells. Mechanistically, the TIMP2 promoter harbors potential binding sites for EVI1; EVI1 binds to TIMP2 promoter and represses its expression, as observed using ChIP and luciferase assay, respectively. TIMP2 is an important metastasis suppressor gene; however, its function is suppressed in many cancers through hypermethylation. Thus, demethylation could prove to be a potential alternative to reactivate TIMP2 functional activity. Immunoprecipitation analysis showed that DNA-methyltransferase 1 (DNMT1), which plays a vital role in maintaining the genome methylation pattern during DNA replication and repair, interacts with EVI1 to promote TIMP2 silencing. Treating cancer cells in vitro with a known demethylation agent, 5-aza-2'-deoxycytidine (Aza-D), restored the optimal TIMP2 expression without altering EVI1 binding efficiency and reduced relative wound healing potential of cancer cells. Animal studies showed that Aza-D treated cells injected through the intravenous route exhibited reduced liver and skin metastasis when compared to non-treated cells. Furthermore, Aza-D treatment in mice delayed the metastasis progression compared to the vehicle treated group. Thus, the present study provides an insight into the therapeutic applications of demethylating agents to reduce cancer metastasis in models with EVI1 overexpressing tumors. (Copyright © 2021 Elsevier Ltd. All rights reserved.) |
| فهرسة مساهمة: | Keywords: Aza-D; DNMT1; EVI1; Metastasis; TIMP2 |
| المشرفين على المادة: | 0 (MDS1 and EVI1 Complex Locus Protein) 0 (MECOM protein, human) 127497-59-0 (Tissue Inhibitor of Metalloproteinase-2) 0 (TIMP2 protein, human) |
| تواريخ الأحداث: | Date Created: 20211120 Date Completed: 20240724 Latest Revision: 20240724 |
| رمز التحديث: | 20240726 |
| DOI: | 10.1016/j.biocel.2021.106118 |
| PMID: | 34800694 |
| قاعدة البيانات: | MEDLINE |
Full Text Finder | تدمد: | 1878-5875 |
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| DOI: | 10.1016/j.biocel.2021.106118 |