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Up-regulation of miR-21 by HER2/neu signaling promotes cell invasion.

ABSTRACT: The cell surface receptor tyrosine kinase HER2/neu enhances tumor metastasis. Recent studies suggest that deregulated microRNA (miRNA) expression promotes invasion and metastasis of cancer cells; we therefore explored the possibility that HER2/neu signaling induces the expression of specific miRNAs involved in this process. We identified a putative oncogenic miRNA, miR-21, whose expression is correlated with HER2/neu up-regulation and is functionally involved in HER2/neu-induced cell invasion. We show that miR-21 is up-regulated via the MAPK (ERK1/2) pathway upon stimulation of HER2/neu signaling in breast cancer cells, and overexpression of other ERK1/2 activators such as RASV12 or ID-1 is sufficient to induce miR-21 up-regulation in HER2/neu-negative breast cancer cells. Furthermore, the metastasis suppressor protein PDCD4 (programmed cell death 4) is down-regulated by miR-21 in breast cancer cells expressing HER2/neu. Our data reveal a mechanism for HER2/neu-induced cancer cell invasion via miRNA deregulation. In addition, our results identify miR-21 as a potential therapeutic target for the prevention of breast cancer invasion and metastasis.

SUBMITTER: Huang TH

PROVIDER: S-EPMC2709372 | biostudies-literature | 2009 Jul

REPOSITORIES: biostudies-literature

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Up-regulation of miR-21 by HER2/neu signaling promotes cell invasion.

Huang Tzu-Hsuan TH Wu Fangting F Loeb Gabriel B GB Hsu Ruby R Heidersbach Amy A Brincat Allison A Horiuchi Dai D Lebbink Robert J RJ Mo Yin-Yuan YY Goga Andrei A McManus Michael T MT

The Journal of biological chemistry 20090506 27

The cell surface receptor tyrosine kinase HER2/neu enhances tumor metastasis. Recent studies suggest that deregulated microRNA (miRNA) expression promotes invasion and metastasis of cancer cells; we therefore explored the possibility that HER2/neu signaling induces the expression of specific miRNAs involved in this process. We identified a putative oncogenic miRNA, miR-21, whose expression is correlated with HER2/neu up-regulation and is functionally involved in HER2/neu-induced cell invasion. W ...[more]

PMID: 19419954

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Project description:Accumulating evidence has indicated that circular RNAs (circRNAs) serve crucial roles in the progression of a diverse range of different types of cancer, including osteosarcoma (OS). The present study determined the expression pattern and function of circRNA homeodomain interacting protein kinase 3 (circHIPK3), a novel circular RNA, in OS. It was revealed that circHIPK3 expression was upregulated in OS tissue samples and OS cell lines. A localization assay revealed that circHIPK3 was primarily located in the cytoplasm. Using loss?of?function proliferation and Transwell assays, the present study revealed that circHIPK3?knockdown suppressed OS cell proliferation, migration and invasion. Furthermore, the present study screened potential microRNAs that may interact with circHIPK3. It was revealed that microRNA?637 (miR?637) expression was downregulated in OS according to a Gene Expression Omnibus data analysis. In addition, the present study demonstrated that miR?637 expression was downregulated in OS cell lines. A fluorescence in situ hybridization assay revealed that both miR?637 and circHIPK3 were located in the cytoplasm. An in?depth mechanism investigation demonstrated that circHIPK3 expression was inversely correlated with miR?637 expression, and that circHIPK3 was a target of miR?637. In addition, it was revealed that histone deacetylase 4 (HDAC4) was another downstream target gene of miR?637, as demonstrated using a luciferase assay. It was revealed that miR?637 suppressed OS cell proliferation, migration and invasion via targeting of HDAC4. Finally, the present study demonstrated that circHIPK3 sponged miR?637 to promote HDAC4 expression and OS cell proliferation, migration and invasion. In conclusion, the present study uncovered the role of the circHIPK3/miR?637/HDAC4 axis in OS cell proliferation, migration and invasion. It was demonstrated that circHIPK3 promoted OS cell proliferation, migration and invasion by modulating miR?637/HDAC4 signaling.

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Up-regulation of miR-21 by HER2/neu signaling promotes cell invasion.

Publications

Up-regulation of miR-21 by HER2/neu signaling promotes cell invasion.

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