The beta subunit of hemoglobin (HBB2/HBB) suppresses neuroblastoma growth and metastasis

Shelly Maman*, Orit Sagi-Assif, Weirong Yuan, Ravit Ginat, Tsipi Meshel, Inna Zubrilov, Yona Keisari, Weiyue Lu, Wuyuan Lu, Isaac P. Witz

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review


Soluble pulmonary factors have been reported to be capable of inhibiting the viability of cancer cells that metastasize to the lung, but the molecular identity was obscure. Here we report the isolation and characterization of the beta subunit of hemoglobin as a lung-derived antimetastatic factor. Peptide mapping in the beta subunit of human hemoglobin (HBB) defined a short C-terminal region (termed Metox) as responsible for activity. In tissue culture, both HBB and murine HBB2 mediated growth arrest and apoptosis of lung-metastasizing neuroblastoma cells, along with a variety of other human cancer cell lines. Metox acted similarly and its administration in human tumor xenograft models limited the development of adrenal neuroblastoma tumors as well as spontaneous lung and bone marrow metastases. Expression studies in mice indicated that HBB2 is produced by alveolar epithelial and endothelial cells and is upregulated in mice bearing undetectable metastasis. Our work suggested a novel function for HBB as a theranostic molecule: an innate antimetastasis factor with potential utility as an anticancer drug and a biomarker signaling the presence of clinically undetectable metastasis.

Original languageEnglish
Pages (from-to)14-26
Number of pages13
JournalCancer Research
Issue number1
StatePublished - 1 Jan 2017


FundersFunder number
Dr. Maya Levin Arama
James and Rita Leibman Endowment Fundfor Cancer Research
Sackler Faculty of Medicine
Sara and Natan Blutinger Foundation
University of Maryland School of Medicine, Baltimore, MD
W.M. Keck Biomedical Mass Spectrometry Laboratory at the University of Virginia Biomedical Research Facility
National Institutes of HealthAI087423
Deutsche ForschungsgemeinschaftBA4027/6-1
Tel Aviv University
National Key Research and Development Program of China2013CB932500


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