Abstract
BackgroundAstrocytomas are the most common and aggressive brain tumors characterized by their highly invasive growth. Gain of chromosome 7 with a hot spot at 7q32 appears to be the most prominent aberration in astrocytoma. Previously reports have shown that microRNA-335 (miR-335) resided on chromosome 7q32 is deregulated in many cancers; however, the biological function of miR-335 in astrocytoma has yet to be elucidated.ResultsWe report that miR-335 acts as a tumor promoter in conferring tumorigenic features such as growth and invasion on malignant astrocytoma. The miR-335 level is highly elevated in C6 astrocytoma cells and human malignant astrocytomas. Ectopic expression of miR-335 in C6 cells dramatically enhances cell viability, colony-forming ability and invasiveness. Conversely, delivery of antagonist specific for miR-335 (antagomir-335) to C6 cells results in growth arrest, cell apoptosis, invasion repression and marked regression of astrocytoma xenografts. Further investigation reveals that miR-335 targets disheveled-associated activator of morphogenesis 1(Daam1) at posttranscriptional level. Moreover, silencing of endogenous Daam1 (siDaam1) could mimic the oncogenic effects of miR-335 and reverse the growth arrest, proapoptotic and invasion repression effects induced by antagomir-335. Notably, the oncogenic effects of miR-335 and siDAAM1 together with anti-tumor effects of antagomir-335 are also confirmed in human astrocytoma U87-MG cells.ConclusionThese findings suggest an oncogenic role of miR-335 and shed new lights on the therapy of malignant astrocytomas by targeting miR-335.
Highlights
Astrocytomas derived from astrocytes or astroglial precursors are the most common malignant cancer affecting the central nervous system, accounting for >60% of primary brain tumors [1]
We found that miR-335 targeted a potential tumor suppressor Dishevelled-associated activator of morphogenesis 1 (Daam1) in astrocytoma cells, which promoted several malignant features such as growth and invasion, whereas miR-335 inhibition could potently induce growth arrest, apoptosis and invasion repression both in vitro and in vivo
MiR-335 is highly expressed in malignant astrocytoma We found 8 expressed miRNAs
Summary
Astrocytomas derived from astrocytes or astroglial precursors are the most common malignant cancer affecting the central nervous system, accounting for >60% of primary brain tumors [1]. MiR-335, which is transcribed from the genomic region chromosome 7q32.2, has been reported to act as a tumor initiation and metastasis suppressor of breast cancer [16,17]. A recent study has shown that miR-335 orchestrates cell proliferation, migration and differentiation in human mesenchymal stem cells [19]. These investigations indicate the important roles of miR-335 in tumor initiation and progression; the biological role of miR-335 in malignant astrocytoma pathogenesis is still largely unknown. Reports have shown that microRNA-335 (miR-335) resided on chromosome 7q32 is deregulated in many cancers; the biological function of miR-335 in astrocytoma has yet to be elucidated
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