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Rho kinase proteins display aberrant upregulation in vascular tumors and
contribute to vascular tumor growth
#MMPMID28709411
Amaya CN
; Mitchell DC
; Bryan BA
BMC Cancer
2017[Jul]; 17
(1
): 485
PMID28709411
show ga
BACKGROUND: The serine/threonine protein kinases ROCK1 and 2 are key
RhoA-mediated regulators of cell shape and cytoskeletal dynamics. These proteins
perform multiple functions in vascular endothelial cell physiology and are
attractive targets for cancer therapy based on their roles as oncogenes and
metastatic promoters. Given their critical functions in both of these processes,
we hypothesized that molecular targeting of ROCK proteins would be exceedingly
effective against vascular tumors such as hemangiomas and angiosarcomas, which
are neoplasms composed of aberrant endothelial cells. METHODS: In this study, we
compared ROCK1 and 2 protein expression in a large panel of benign and malignant
vascular tumors to that of normal vasculature. We then utilized shRNA technology
to knockdown the expression of ROCK1 and 2 in SVR tumor-forming vascular cells,
and evaluated tumor size and proliferation rate in a xenograft model. Finally, we
employed proteomics and metabolomics to assess how knockdown of the ROCK paralogs
induced alterations in protein expression/phosphorylation and metabolite
concentrations in the xenograft tumors. RESULTS: Our findings revealed that ROCK1
was overexpressed in malignant vascular tumors such as hemangioendotheliomas and
angiosarcomas, and ROCK2 was overexpressed in both benign and malignant vascular
tumors including hemangiomas, hemangioendotheliomas, hemangiopericytomas, and
angiosarcomas. shRNA-mediated knockdown of ROCK2, but not ROCK1, in xenograft
vascular tumors significantly reduced tumor size and proliferative index compared
to control tumors. Proteomics and metabolomics analysis of the xenograft tumors
revealed both overlapping as well as unique roles for the ROCK paralogs in
regulating signal transduction and metabolite concentrations. CONCLUSIONS:
Collectively, these data indicate that ROCK proteins are overexpressed in diverse
vascular tumors and suggest that specific targeting of ROCK2 proteins may show
efficacy against malignant vascular tumors.
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