The brain microenvironment negatively regulates miRNA-768-3p to promote K-ras expression and lung cancer metastasis.
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.
Division of Hematology and Oncology, University of Cincinnati College of Medicine, Cincinnati, OH 45267-0508, USA.
Arasukumar
A
Subramani
Samer
S
Alsidawi
Sajjeev
S
Jagannathan
Kazutaka
K
Sumita
Atsuo T
AT
Sasaki
Bruce
B
Aronow
Ronald E
RE
Warnick
Sean
S
Lawler
James J
JJ
Driscoll
D001253:Astrocytes / Q000378:metabolism* / Q000473:pathology; D001932:Brain Neoplasms / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement; D002470:Cell Survival; D015536:Down-Regulation; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism* / Q000473:pathology; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D016283:Proto-Oncogene Proteins p21(ras); D012333:RNA, Messenger / Q000378:metabolism*; D015398:Signal Transduction; D059016:Tumor Microenvironment / Q000502:physiology*; D018631:ras Proteins / Q000378:metabolism*
C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins