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The brain microenvironment negatively regulates miRNA-768-3p to promote K-ras expression and lung cancer metastasis.

ABSTRACT: The brain microenvironment promotes metastasis through mechanisms that remain elusive. Co-culture of lung cancer cells with astrocytes - the most abundant cell type within the metastatic brain niche - lead to downregulation of miRNA-768-3p which drives K-ras expression and key signaling pathways, enhances cell viability and promotes chemotherapeutic resistance. Vector-based forced expression of miRNA-768-3p complementary sequence or a chemically-engineered miRNA-768-3p inhibitor recapitulated the astrocyte effect to increase tumor cell viability. The miRNA-768-3p inhibitor targeted the K-ras 3'-UTR as demonstrated by increased luminescence from a luciferase reporter and strikingly increased the K-ras protein and the downstream effectors ERK1/2 and B-Raf. miRNA-768-3p was reduced in patient brain metastases compared to normal brain tissue and was lower in patient tissue from brain metastases compared to same-patient primary tumour tissue. The brain microenvironment negatively regulates miRNA-768-3p to enhance K-ras and promote metastasis. We propose that therapeutic replacement of the metastasis suppressor miRNA-768-3p holds clinical promise.

SUBMITTER: Subramani A

PROVIDER: S-EPMC3738968 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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The brain microenvironment negatively regulates miRNA-768-3p to promote K-ras expression and lung cancer metastasis.

Subramani Arasukumar A Alsidawi Samer S Jagannathan Sajjeev S Sumita Kazutaka K Sasaki Atsuo T AT Aronow Bruce B Warnick Ronald E RE Lawler Sean S Driscoll James J JJ

Scientific reports 20130101

The brain microenvironment promotes metastasis through mechanisms that remain elusive. Co-culture of lung cancer cells with astrocytes - the most abundant cell type within the metastatic brain niche - lead to downregulation of miRNA-768-3p which drives K-ras expression and key signaling pathways, enhances cell viability and promotes chemotherapeutic resistance. Vector-based forced expression of miRNA-768-3p complementary sequence or a chemically-engineered miRNA-768-3p inhibitor recapitulated th ...[more]

PMID: 23928793

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Dataset Information

The brain microenvironment negatively regulates miRNA-768-3p to promote K-ras expression and lung cancer metastasis.

Publications

The brain microenvironment negatively regulates miRNA-768-3p to promote K-ras expression and lung cancer metastasis.

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