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Title: Hand1 overexpression inhibits medulloblastoma metastasis

Abstract

Medulloblastoma (MB) is the most frequent malignant pediatric brain tumor. Current treatment includes surgery, radiation and chemotherapy. However, ongoing treatment in patients is further classified according to the presence or absence of metastasis. Since metastatic medulloblastoma are refractory to current treatments, there is need to identify novel biomarkers that could be used to reduce metastatic potential, and more importantly be targeted therapeutically. Previously, we showed that ionizing radiation-induced uPAR overexpression is associated with increased accumulation of β-catenin in the nucleus. We further demonstrated that uPAR protein act as cytoplasmic sequestration factor for a novel basic helix-loop-helix transcription factor, Hand1. Among the histological subtypes classical and desmoplastic subtypes account for the majority while large cell/anaplastic variant is most commonly associated with metastatic disease. In this present study using immunohistochemical approach and patient data mining for the first time, we demonstrated that Hand1 expression is observed to be downregulated in all the subtypes of medulloblastoma. Previously we showed that Hand1 overexpression regulated medulloblastoma angiogenesis and here we investigated the role of Hand1 in the context of Epithelial-Mesenchymal Transition (EMT). Moreover, UW228 and D283 cells overexpressing Hand1 demonstrated decreased-expression of mesenchymal markers (N-cadherin, β-catenin and SOX2); metastatic marker (SMA); and increased expression ofmore » epithelial marker (E-cadherin). Strikingly, human pluripotent stem cell antibody array showed that Hand1 overexpression resulted in substantial decrease in pluripotency markers (Nanog, Oct3/4, Otx2, Flk1) suggesting that Hand1 expression may be essential to attenuate the EMT and our findings underscore a novel role for Hand1 in medulloblastoma metastasis. - Highlights: • Hand1 expression is downregulated in Medulloblastoma. • Hand1 over expression reduce the expression of signaling from WNT, SHH and Group 3 medulloblastoma subgroups. • Hand1 overexpression reduced metastatic abilities by reducing the expression of β-catenin and N-cadherin.« less

Authors:
;  [1];  [2]; ;  [3];  [4];  [1];  [5];  [5];  [1];  [5]
  1. Department of Cancer Biology and Pharmacology, University of Illinois College of Medicine at Peoria, Peoria, IL 61656 (United States)
  2. Department of Pathology, University of Illinois College of Medicine at Peoria, Peoria, IL 61656 (United States)
  3. Department of Pediatrics, University of Illinois College of Medicine at Peoria, Peoria, IL 61656 (United States)
  4. Department of Neurosurgery, University of Illinois College of Medicine at Peoria, Peoria, IL 61656 (United States)
  5. (United States)
Publication Date:
OSTI Identifier:
22606158
Resource Type:
Journal Article
Resource Relation:
Journal Name: Biochemical and Biophysical Research Communications; Journal Volume: 477; Journal Issue: 2; Other Information: Copyright (c) 2016 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; ANGIOGENESIS; ANTIBODIES; BIOLOGICAL MARKERS; BRAIN; CHEMOTHERAPY; IONIZING RADIATIONS; METASTASES; NEOPLASMS; PATIENTS; PEDIATRICS; REFRACTORIES; STEM CELLS; SURGERY; TRANSCRIPTION; TRANSCRIPTION FACTORS

Citation Formats

Asuthkar, Swapna, Guda, Maheedhara R., Martin, Sarah E., Antony, Reuben, Fernandez, Karen, Lin, Julian, Tsung, Andrew J., Department of Neurosurgery, University of Illinois College of Medicine at Peoria, Peoria, IL 61656, Illinois Neurological Institute, Peoria, IL 61656, Velpula, Kiran K., E-mail: velpula@uic.edu, and Department of Neurosurgery, University of Illinois College of Medicine at Peoria, Peoria, IL 61656. Hand1 overexpression inhibits medulloblastoma metastasis. United States: N. p., 2016. Web. doi:10.1016/J.BBRC.2016.06.045.
Asuthkar, Swapna, Guda, Maheedhara R., Martin, Sarah E., Antony, Reuben, Fernandez, Karen, Lin, Julian, Tsung, Andrew J., Department of Neurosurgery, University of Illinois College of Medicine at Peoria, Peoria, IL 61656, Illinois Neurological Institute, Peoria, IL 61656, Velpula, Kiran K., E-mail: velpula@uic.edu, & Department of Neurosurgery, University of Illinois College of Medicine at Peoria, Peoria, IL 61656. Hand1 overexpression inhibits medulloblastoma metastasis. United States. doi:10.1016/J.BBRC.2016.06.045.
Asuthkar, Swapna, Guda, Maheedhara R., Martin, Sarah E., Antony, Reuben, Fernandez, Karen, Lin, Julian, Tsung, Andrew J., Department of Neurosurgery, University of Illinois College of Medicine at Peoria, Peoria, IL 61656, Illinois Neurological Institute, Peoria, IL 61656, Velpula, Kiran K., E-mail: velpula@uic.edu, and Department of Neurosurgery, University of Illinois College of Medicine at Peoria, Peoria, IL 61656. Fri . "Hand1 overexpression inhibits medulloblastoma metastasis". United States. doi:10.1016/J.BBRC.2016.06.045.
@article{osti_22606158,
title = {Hand1 overexpression inhibits medulloblastoma metastasis},
author = {Asuthkar, Swapna and Guda, Maheedhara R. and Martin, Sarah E. and Antony, Reuben and Fernandez, Karen and Lin, Julian and Tsung, Andrew J. and Department of Neurosurgery, University of Illinois College of Medicine at Peoria, Peoria, IL 61656 and Illinois Neurological Institute, Peoria, IL 61656 and Velpula, Kiran K., E-mail: velpula@uic.edu and Department of Neurosurgery, University of Illinois College of Medicine at Peoria, Peoria, IL 61656},
abstractNote = {Medulloblastoma (MB) is the most frequent malignant pediatric brain tumor. Current treatment includes surgery, radiation and chemotherapy. However, ongoing treatment in patients is further classified according to the presence or absence of metastasis. Since metastatic medulloblastoma are refractory to current treatments, there is need to identify novel biomarkers that could be used to reduce metastatic potential, and more importantly be targeted therapeutically. Previously, we showed that ionizing radiation-induced uPAR overexpression is associated with increased accumulation of β-catenin in the nucleus. We further demonstrated that uPAR protein act as cytoplasmic sequestration factor for a novel basic helix-loop-helix transcription factor, Hand1. Among the histological subtypes classical and desmoplastic subtypes account for the majority while large cell/anaplastic variant is most commonly associated with metastatic disease. In this present study using immunohistochemical approach and patient data mining for the first time, we demonstrated that Hand1 expression is observed to be downregulated in all the subtypes of medulloblastoma. Previously we showed that Hand1 overexpression regulated medulloblastoma angiogenesis and here we investigated the role of Hand1 in the context of Epithelial-Mesenchymal Transition (EMT). Moreover, UW228 and D283 cells overexpressing Hand1 demonstrated decreased-expression of mesenchymal markers (N-cadherin, β-catenin and SOX2); metastatic marker (SMA); and increased expression of epithelial marker (E-cadherin). Strikingly, human pluripotent stem cell antibody array showed that Hand1 overexpression resulted in substantial decrease in pluripotency markers (Nanog, Oct3/4, Otx2, Flk1) suggesting that Hand1 expression may be essential to attenuate the EMT and our findings underscore a novel role for Hand1 in medulloblastoma metastasis. - Highlights: • Hand1 expression is downregulated in Medulloblastoma. • Hand1 over expression reduce the expression of signaling from WNT, SHH and Group 3 medulloblastoma subgroups. • Hand1 overexpression reduced metastatic abilities by reducing the expression of β-catenin and N-cadherin.},
doi = {10.1016/J.BBRC.2016.06.045},
journal = {Biochemical and Biophysical Research Communications},
number = 2,
volume = 477,
place = {United States},
year = {Fri Aug 19 00:00:00 EDT 2016},
month = {Fri Aug 19 00:00:00 EDT 2016}
}