Hand1 overexpression inhibits medulloblastoma metastasis.
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.
Department of Cancer Biology and Pharmacology, University of Illinois College of Medicine at Peoria, Peoria, IL 61656, USA.
Swapna
S
Asuthkar
Department of Cancer Biology and Pharmacology, University of Illinois College of Medicine at Peoria, Peoria, IL 61656, USA.
Maheedhara R
MR
Guda
Department of Pathology, University of Illinois College of Medicine at Peoria, Peoria, IL 61656, USA.
Sarah E
SE
Martin
Department of Pediatrics, University of Illinois College of Medicine at Peoria, Peoria, IL 61656, USA.
Reuben
R
Antony
Department of Pediatrics, University of Illinois College of Medicine at Peoria, Peoria, IL 61656, USA.
Karen
K
Fernandez
Department of Neurosurgery, University of Illinois College of Medicine at Peoria, Peoria, IL 61656, USA.
Julian
J
Lin
Department of Cancer Biology and Pharmacology, University of Illinois College of Medicine at Peoria, Peoria, IL 61656, USA; Department of Neurosurgery, University of Illinois College of Medicine at Peoria, Peoria, IL 61656, USA; Illinois Neurological Institute, Peoria, IL 61656, USA.
Andrew J
AJ
Tsung
Department of Cancer Biology and Pharmacology, University of Illinois College of Medicine at Peoria, Peoria, IL 61656, USA; Department of Neurosurgery, University of Illinois College of Medicine at Peoria, Peoria, IL 61656, USA. Electronic address: velpula@uic.edu.
Kiran K
KK
Velpula
D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism*; D058750:Epithelial-Mesenchymal Transition / Q000502:physiology*; D006801:Humans; D008527:Medulloblastoma / Q000378:metabolism* / Q000473:pathology / Q000556:secondary*; D009361:Neoplasm Invasiveness; D014407:Tumor Cells, Cultured; D015854:Up-Regulation; D060449:Wnt Signaling Pathway; D051176:beta Catenin / Q000378:metabolism*
D051792:Basic Helix-Loop-Helix Proteins; D051176:beta Catenin; C495270:CTNNB1 protein, human; C097341:helix-loop-helix protein, eHAND
EMT; Hand1; Medulloblastoma; Metastasis