The AURKA/TPX2 axis drives colon tumorigenesis cooperatively with MYC

被引：63

作者：

Takahashi, Y. ^{[1
,2
]}

Sheridan, P. ^{[3
]}

Niida, A. ^{[3
]}

Sawada, G. ^{[1
]}

Uchi, R. ^{[1
]}

Mizuno, H. ^{[4
]}

Kurashige, J. ^{[1
]}

Sugimachi, K. ^{[1
]}

Sasaki, S. ^{[2
,5
]}

Shimada, Y. ^{[6
]}

Hase, K. ^{[7
]}

Kusunoki, M. ^{[8
]}

Kudo, S. ^{[9
]}

Watanabe, M. ^{[10
]}

Yamada, K. ^{[11
]}

Sugihara, K. ^{[12
]}

Yamamoto, H. ^{[2
]}

Suzuki, A. ^{[13
]}

Doki, Y. ^{[2
]}

Miyano, S. ^{[3
]}

Mori, M. ^{[2
]}

Mimori, K. ^{[1
]}

机构：

[1] Kyushu Univ, Dept Surg, Beppu Hosp, Beppu, Oita 8740838, Japan

[2] Osaka Univ, Grad Sch Med, Dept Gastroenterol Surg, Suita, Osaka, Japan

[3] Univ Tokyo, Inst Med Sci, Ctr Human Genome, Lab DNA Informat Anal, Tokyo, Japan

[4] Chugai Pharmaceut Co Ltd, Kamakura Res Labs, Dept Discovery Res, Kamakura, Kanagawa, Japan

[5] Omori Red Cross Hosp, Dept Surg, Tokyo, Japan

[6] Natl Canc Ctr, Div Gastrointestinal Oncol, Tokyo, Japan

[7] Natl Def Med Coll, Dept Surg, Tokorozawa, Saitama 359, Japan

[8] Mie Univ, Dept Surg, Tsu, Mie 514, Japan

[9] Showa Univ, Northern Yokohama Hosp, Ctr Digest Dis, Yokohama, Kanagawa, Japan

[10] Kitasato Univ, Dept Surg, Sagamihara, Kanagawa 228, Japan

[11] Takano Hosp, Dept Surg, Kumamoto, Japan

[12] Tokyo Med & Dent Univ, Dept Surg, Tokyo, Japan

[13] Kyushu Univ, Med Inst Bioregulat, Div Canc Genet, Fukuoka 812, Japan

来源：

ANNALS OF ONCOLOGY | 2015年 / 26卷 / 05期

基金：

日本学术振兴会; 日本科学技术振兴机构;

关键词：

MYC; AURKA; TPX2; synthetic lethality; co-amplification; C-MYC; BREAST-CANCER; AURORA-A; AMPLIFICATION; KINASE; INHIBITION; ONCOGENE; TPX2; GENE;

D O I：

10.1093/annonc/mdv034

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Background: The MYC oncogene has long been established as a central driver in many types of human cancers including colorectal cancer. However, the realization of MYC-targeting therapies remains elusive; as a result, synthetic lethal therapeutic approaches are alternatively being explored. A synthetic lethal therapeutic approach aims to kill MYC-driven tumors by targeting a certain co-regulator on the MYC pathway. Patients and methods: We analyzed copy number and expression profiles from 130 colorectal cancer tumors together with publicly available datasets to identify co-regulators on the MYC pathway. Candidates were functionally tested by in vitro assays using colorectal cancer and normal fibroblast cell lines. Additionally, survival analyses were carried out on another 159 colorectal cancer patients and public datasets. Results: Our in silico screening identified two MYC co-regulator candidates, AURKA and TPX2, which are interacting mitotic regulators located on chromosome 20q. We found the two candidates showed frequent co-amplification with the MYC locus while expression levels of MYC and the two genes were positively correlated with those of MYC downstream target genes across multiple cancer types. In vitro, the aberrant expression of MYC, AURKA and TPX2 resulted in more aggressive anchorage-independent growth in normal fibroblast cells. Furthermore, knockdown of AURKA or TPX2, or treatment with an AURKA-specific inhibitor effectively suppressed the proliferation of MYC-expressing colorectal cancer cells. Additionally, combined high expression of MYC, AURKA and TPX2 proved to be a poor prognostic indicator of colorectal cancer patient survival. Conclusions: Through bioinformatic analyses and experiments, we proposed TPX2 and AURKA as novel co-regulators on the MYC pathway. Inhibiting the AURKA/TPX2 axis would be a novel synthetic lethal therapeutic approach for MYC-driven cancers.

引用

页码：935 / 942

页数：9

共 21 条

[21] Therapeutic potential of a synthetic lethal interaction between the MYC proto-oncogene and inhibition of aurora-B kinase
Yang, Dun
Liu, Hong
Goga, Andrei
Kim, Suwon
Yuneva, Mariia
Bishop, J. Michael
[J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2010, 107 (31) : 13836 - 13841

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