Downregulation of miR-144 is associated with colorectal cancer progression via activation of mTOR signaling pathway

Takeshi Iwaya, Takehiko Yokobori, Naohiro Nishida, Ryunosuke Kogo, Tomoya Sudo, Fumiaki Tanaka, Kohei Shibata, Genta Sawada, Yusuke Takahashi, Masahisa Ishibashi, Go Wakabayashi, Masaki Mori, Koshi Mimori

Research output: Contribution to journalArticle

118 Citations (Scopus)

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.

Original languageEnglish
Article numberbgs288
Pages (from-to)2391-2397
Number of pages7
JournalCarcinogenesis
Volume33
Issue number12
DOIs
Publication statusPublished - Dec 1 2012

Fingerprint

Sirolimus
Colorectal Neoplasms
Down-Regulation
HT29 Cells
Liver
3' Untranslated Regions
MicroRNAs
Computer Simulation
Multivariate Analysis
Binding Sites
Neoplasm Metastasis
Gene Expression
Recurrence
Cell Line

All Science Journal Classification (ASJC) codes

  • Cancer Research

Cite this

Downregulation of miR-144 is associated with colorectal cancer progression via activation of mTOR signaling pathway. / Iwaya, Takeshi; Yokobori, Takehiko; Nishida, Naohiro; Kogo, Ryunosuke; Sudo, Tomoya; Tanaka, Fumiaki; Shibata, Kohei; Sawada, Genta; Takahashi, Yusuke; Ishibashi, Masahisa; Wakabayashi, Go; Mori, Masaki; Mimori, Koshi.

In: Carcinogenesis, Vol. 33, No. 12, bgs288, 01.12.2012, p. 2391-2397.

Research output: Contribution to journalArticle

Iwaya, T, Yokobori, T, Nishida, N, Kogo, R, Sudo, T, Tanaka, F, Shibata, K, Sawada, G, Takahashi, Y, Ishibashi, M, Wakabayashi, G, Mori, M & Mimori, K 2012, 'Downregulation of miR-144 is associated with colorectal cancer progression via activation of mTOR signaling pathway', Carcinogenesis, vol. 33, no. 12, bgs288, pp. 2391-2397. https://doi.org/10.1093/carcin/bgs288
Iwaya, Takeshi ; Yokobori, Takehiko ; Nishida, Naohiro ; Kogo, Ryunosuke ; Sudo, Tomoya ; Tanaka, Fumiaki ; Shibata, Kohei ; Sawada, Genta ; Takahashi, Yusuke ; Ishibashi, Masahisa ; Wakabayashi, Go ; Mori, Masaki ; Mimori, Koshi. / Downregulation of miR-144 is associated with colorectal cancer progression via activation of mTOR signaling pathway. In: Carcinogenesis. 2012 ; Vol. 33, No. 12. pp. 2391-2397.
@article{849dc99ef80e41039a1d0a9359023113,
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.",
author = "Takeshi Iwaya and Takehiko Yokobori and Naohiro Nishida and Ryunosuke Kogo and Tomoya Sudo and Fumiaki Tanaka and Kohei Shibata and Genta Sawada and Yusuke Takahashi and Masahisa Ishibashi and Go Wakabayashi and Masaki Mori and Koshi Mimori",
year = "2012",
month = "12",
day = "1",
doi = "10.1093/carcin/bgs288",
language = "English",
volume = "33",
pages = "2391--2397",
journal = "Carcinogenesis",
issn = "0143-3334",
publisher = "Oxford University Press",
number = "12",

}

TY - JOUR

T1 - Downregulation of miR-144 is associated with colorectal cancer progression via activation of mTOR signaling pathway

AU - Iwaya, Takeshi

AU - Yokobori, Takehiko

AU - Nishida, Naohiro

AU - Kogo, Ryunosuke

AU - Sudo, Tomoya

AU - Tanaka, Fumiaki

AU - Shibata, Kohei

AU - Sawada, Genta

AU - Takahashi, Yusuke

AU - Ishibashi, Masahisa

AU - Wakabayashi, Go

AU - Mori, Masaki

AU - Mimori, Koshi

PY - 2012/12/1

Y1 - 2012/12/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84870328663&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84870328663&partnerID=8YFLogxK

U2 - 10.1093/carcin/bgs288

DO - 10.1093/carcin/bgs288

M3 - Article

C2 - 22983984

AN - SCOPUS:84870328663

VL - 33

SP - 2391

EP - 2397

JO - Carcinogenesis

JF - Carcinogenesis

SN - 0143-3334

IS - 12

M1 - bgs288

ER -