Role of MAML1 in targeted therapy against the esophageal cancer stem cells

Moghbeli, M. and Mosannen Mozaffari, H. and Memar, B. and Forghanifard, M. M. and Gholamin, M. and Abbaszadegan, M. R. (2019) Role of MAML1 in targeted therapy against the esophageal cancer stem cells. Journal of Translational Medicine, 17 (1).

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Abstract

Background: Esophageal cancer is the sixth-leading cause of cancer-related deaths worldwide. Cancer stem cells (CSCs) are the main reason for tumor relapse in esophageal squamous cell carcinoma (ESCC). The NOTCH pathway is important in preservation of CSCs, therefore it is possible to target such cells by targeting MAML1 as the main component of the NOTCH transcription machinery. Methods: In present study we isolated the CD44+ ESCC CSCs and designed a MAML1-targeted therapy to inhibit the NOTCH signaling pathway. CSCs were isolated using magnetic cell sorting utilizing the CD44 cell surface marker. Several stem cell markers were analyzed in the levels of protein and mRNA expression. The isolated CSCs were characterized in vivo in NUDE mice. Biological role of MAML1 was assessed in isolated CD44+ CSCs. A drug resistance assay was also performed to assess the role of MAML1 in CD44+ CSCs with 5FU resistance. Results: The CD44+ CSCs had ability to form tumors in NUDE mice. MAML1 silencing caused a significant decrease (p = 0.019) and ectopic expression caused a significant increase in migration of CD44+ CSCs (p = 0.012). Moreover, MAML1 silencing and ectopic expression significantly increased and decreased 5FU resistance, respectively (p < 0.05). MAML1 silencing significantly increased the number of cells in G1 phase (p = 0.008), and its ectopic expression significantly increased the number of CD44+ CSCS in S phase (p = 0.037). Conclusions: MAML1 may be utilized for targeted therapy with a low side effect to eliminate the CD44+ CSCs through inhibition of canonical NOTCH pathway in ESCC patients. © 2019 The Author(s).

Item Type: Article
Additional Information: Cited By :1 Export Date: 16 February 2020 Correspondence Address: Abbaszadegan, M.R.; Immunology Research Center, Mashhad University of Medical SciencesIran; email: Abbaszadeganmr@mums.ac.ir
Uncontrolled Keywords: ABC transporter Cancer stem cell CD44 ESCC MAML1 NOTCH pathway Hermes antigen mastermind like protein messenger RNA multiprotein complex Notch receptor unclassified drug aged animal experiment animal model animal tissue Article cell cycle G1 phase cell cycle S phase cell migration cell selection controlled study ectopic expression esophageal squamous cell carcinoma human human tissue in vivo study infant male molecularly targeted therapy mouse mRNA expression level nonhuman Notch signaling pathogenesis protein expression level protein function very elderly
Subjects: QW Microbiology and Immunology
Divisions: Mashhad University of Medical Sciences
Depositing User: mr lib1 lib1
Date Deposited: 21 Jun 2020 09:13
Last Modified: 21 Jun 2020 09:13
URI: http://eprints.mums.ac.ir/id/eprint/18518

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