title: Downregulation of miR-144 is associated with colorectal cancer progression via activation of mTOR signaling pathway.
abstract: The mammalian target of rapamycin (mTOR) is a downstream integrator of essential pathways. mTOR signaling is frequently dysregulated in a variety of human cancers, and in silico analysis has revealed two miR-144 binding sites in the mTOR 3' untranslated region. We investigated the clinicopathologic magnitude of the mTOR pathway regulating microRNA, miR-144 in colorectal cancer (CRC) cases. The regulation of mTOR by miR-144 was examined with inhibitor miR-144-transfected cells. We also investigated changes in sensitivity to the mTOR inhibitor, rapamycin, in inhibitor miR-144-transfected cells. Quantitative RT-PCR was used to evaluate the clinicopathologic significance of miR-144 expression in 137 CRC. Furthermore, we assessed the correlation between CRC prognosis and the expression of 16 genes in the Akt/mTOR pathway. In vitro assays showed that mTOR is a direct target of miR-144, and downregulation of miR-144 facilitated proliferation of CRC cell line, HT29. In addition, the viability of HT29 cells with downregulated miR-144 expression was significantly reduced with rapamycin treatment. Low expression levels of miR-144 were associated with enhanced malignant potential such as venous invasion (P = 0.0013), liver metastasis (P = 0.08), liver recurrence (P = 0.0058) and poor prognosis (P = 0.0041). Multivariate analysis indicated that low miR-144 expression was an independent prognostic factor for survival. Among many genes consisting of the mTOR pathway, only high expression of Rictor was associated with poor prognosis of CRC. miR-144 is a meaningful prognostic marker. Downregulation of miR-144 leads to poor prognosis of CRC patients via activation of the mTOR signaling pathway.
authors.affiliation: Department of Surgery, Kyushu University Beppu Hospital, 4546 Tsurumihara, Beppu 874-0838, Japan. takeiwaya@gmail.com
authors.forename: Takeshi
authors.initials: T
authors.lastname: Iwaya
authors.forename: Takehiko
authors.initials: T
authors.lastname: Yokobori
authors.forename: Naohiro
authors.initials: N
authors.lastname: Nishida
authors.forename: Ryunosuke
authors.initials: R
authors.lastname: Kogo
authors.forename: Tomoya
authors.initials: T
authors.lastname: Sudo
authors.forename: Fumiaki
authors.initials: F
authors.lastname: Tanaka
authors.forename: Kohei
authors.initials: K
authors.lastname: Shibata
authors.forename: Genta
authors.initials: G
authors.lastname: Sawada
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Takahashi
authors.forename: Masahisa
authors.initials: M
authors.lastname: Ishibashi
authors.forename: Go
authors.initials: G
authors.lastname: Wakabayashi
authors.forename: Masaki
authors.initials: M
authors.lastname: Mori
authors.forename: Koshi
authors.initials: K
authors.lastname: Mimori
mesh_terms: D049109:Cell Proliferation; D015179:Colorectal Neoplasms / Q000209:etiology* / Q000401:mortality / Q000473:pathology; D018450:Disease Progression; D015536:Down-Regulation; D019073:HT29 Cells; D006801:Humans; D035683:MicroRNAs / Q000037:antagonists & inhibitors / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000502:physiology*
chemical_list: C554293:MIRN144 microRNA, human; D035683:MicroRNAs; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus