Tumor suppression by miR-26 overrides potential oncogenic activity in intestinal tumorigenesis.
Down-regulation of miR-26 family members has been implicated in the pathogenesis of multiple malignancies. In some settings, including glioma, however, miR-26-mediated repression of PTEN promotes tumorigenesis. To investigate the contexts in which the tumor suppressor versus oncogenic activity of miR-26 predominates in vivo, we generated miR-26a transgenic mice. Despite measureable repression of Pten, elevated miR-26a levels were not associated with malignancy in transgenic animals. We documented reduced miR-26 expression in human colorectal cancer and, accordingly, showed that miR-26a expression potently suppressed intestinal adenoma formation in Apc(min/+) mice, a model known to be sensitive to Pten dosage. These studies reveal a tumor suppressor role for miR-26 in intestinal cancer that overrides putative oncogenic activity, highlighting the therapeutic potential of miR-26 delivery to this tumor type.
Medical Scientist Training Program, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA; Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA;
Lauren R
LR
Zeitels
Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA;
Asha
A
Acharya
Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA;
Guanglu
G
Shi
Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA;
Divya
D
Chivukula
Department of Medicine, The Massachusetts General Hospital, Boston, Massachusetts 02115, USA;
Raghu R
RR
Chivukula
Department of Surgery.
Joselin L
JL
Anandam
Department of Surgery.
Abier A
AA
Abdelnaby
Department of Surgery.
Glen C
GC
Balch
Department of Surgery.
John C
JC
Mansour
Department of Surgery.
Adam C
AC
Yopp
Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA; Department of Pathology.
James A
JA
Richardson
Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA; Simmons Cancer Center, Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA joshua.mendell@utsouthwestern.edu.
Joshua T
JT
Mendell
D000236:Adenoma / Q000235:genetics / Q000503:physiopathology*; D000818:Animals; D063646:Carcinogenesis / Q000235:genetics*; D002465:Cell Movement; D049109:Cell Proliferation; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007413:Intestinal Mucosa / Q000166:cytology / Q000503:physiopathology; D007414:Intestinal Neoplasms / Q000235:genetics / Q000503:physiopathology*; D051379:Mice; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D014407:Tumor Cells, Cultured
D035683:MicroRNAs; C528163:MIRN26 microRNA, human; C543693:Mirn26 microRNA, mouse
colon cancer; intestine; miR-26; microRNA