Abstract
The hypoxic microenvironment of bone marrow favours the bone metastasis process. Hypoxia
inducible factor (HIF)-1α is hallmark for hypoxia, correlating with poor prognosis
and radio/chemotherapy resistance of primary-breast carcinoma. For bone metastasis,
the molecular mechanisms involved in HIF-1α expression and HIF-1 (α/β heterodimer)-transcription
factor activity are scarcely known. We studied the role played by HIF-1 in the cross-talk
between neoplastic and supportive-microenvironmental cells. Also, WWdomain-containing
oxidoreductase (Wwox) and transcriptional co-activator with PDZ-binding motif (TAZ)
were taken into consideration evaluating whether these Hippo-pathway effectors affect
bone-metastatic phenotype through HIF-1 activity. Considering bone-metastasis specimens,
nuclear HIF-1α–TAZ co-localisation occurred in neoplastic and supportive cells, such
as fibroblasts and endotheliocytes. Based on these data, the functional importance
was verified using 1833-bone metastatic clone under hypoxia: nuclear HIF-1α and TAZ
expression increased and co-immunoprecipitated, activating HIF-1-DNA binding and transactivation.
In contrast, Wwox localised at perinuclear level in neoplastic cells of bone metastasis,
being almost absent in supportive cells, and Wwox-protein expression diminished in
hypoxic-1833 cells. Thus, TAZ regulation of HIF-1 activity might be important for
bone-secondary growth, participating in metastasis-stroma cross-talk. Further, TAZ
and HIF-1α-protein levels seemed correlated. In fact, blocking cyclooxygenase-2 with
NS398 in hypoxic-1833 cells, not only HIF-1α decreased but also molecular-mechanism(s)
upstream of the Hippo pathway were triggered: LATS-dependent TAZ phosphorylation seemed
responsible for TAZ nucleus/cytoplasm translocation and degradation. In the 1833-xenograft
model, NS398 largely prevented the outgrowth of bone-metastatic cells, probably related
to remarkable-extracellular matrix assembly. We gained clinical insight into HIF-1α
and TAZ as candidate biomarkers for bone avidity, relevant for early-therapeutic intervention
against bone metastasis.
Keywords
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Article info
Publication history
Published online: April 08, 2013
Footnotes
☆Grants: This study was supported by CARIPLO Foundation (2010-0737) to M.A.D.; Ministero della Salute (Ricerca Corrente 4064 and 4098) to P.M.
Identification
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© 2013 Elsevier Ltd. Published by Elsevier Inc. All rights reserved.
