title: The AURKA/TPX2 axis drives colon tumorigenesis cooperatively with MYC.
abstract: 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.
  
  
  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.
authors: Department of Surgery, Kyushu University Beppu Hospital, Beppu; Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita.
authors: Y
authors: Y
authors: Takahashi
authors: Laboratory of DNA Information Analysis, Human Genome Center, Institute of Medical Science, University of Tokyo, Tokyo.
authors: P
authors: P
authors: Sheridan
authors: Laboratory of DNA Information Analysis, Human Genome Center, Institute of Medical Science, University of Tokyo, Tokyo.
authors: A
authors: A
authors: Niida
authors: Department of Surgery, Kyushu University Beppu Hospital, Beppu; Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita.
authors: G
authors: G
authors: Sawada
authors: Department of Surgery, Kyushu University Beppu Hospital, Beppu.
authors: R
authors: R
authors: Uchi
authors: Department of Discovery Research, Kamakura Research Laboratories, Chugai Pharmaceutical Co., Ltd, Kamakura.
authors: H
authors: H
authors: Mizuno
authors: Department of Surgery, Kyushu University Beppu Hospital, Beppu.
authors: J
authors: J
authors: Kurashige
authors: Department of Surgery, Kyushu University Beppu Hospital, Beppu.
authors: K
authors: K
authors: Sugimachi
authors: Department of Surgery, Omori Red Cross Hospital, Tokyo.
authors: S
authors: S
authors: Sasaki
authors: Division of Gastrointestinal Oncology, National Cancer Center Hospital, Tokyo.
authors: Y
authors: Y
authors: Shimada
authors: Department of Surgery, National Defense Medical College, Tokorozawa.
authors: K
authors: K
authors: Hase
authors: Department of Surgery, Mie University, Tsu.
authors: M
authors: M
authors: Kusunoki
authors: Digestive Disease Center, Showa University Northern Yokohama Hospital, Yokohama.
authors: S
authors: S
authors: Kudo
authors: Department of Surgery, Kitasato University, Sagamihara.
authors: M
authors: M
authors: Watanabe
authors: Department of Surgery, Takano Hospital, Kumamoto.
authors: K
authors: K
authors: Yamada
authors: Department of Surgery, Tokyo Medical and Dental University, Tokyo.
authors: K
authors: K
authors: Sugihara
authors: Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita.
authors: H
authors: H
authors: Yamamoto
authors: Division of Cancer Genetics, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan.
authors: A
authors: A
authors: Suzuki
authors: Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita.
authors: Y
authors: Y
authors: Doki
authors: Laboratory of DNA Information Analysis, Human Genome Center, Institute of Medical Science, University of Tokyo, Tokyo.
authors: S
authors: S
authors: Miyano
authors: Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita.
authors: M
authors: M
authors: Mori
authors: Department of Surgery, Kyushu University Beppu Hospital, Beppu. Electronic address: kmimori@beppu.kyushu-u.ac.jp.
authors: K
authors: K
authors: Mimori
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use; D064096:Aurora Kinase A / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D049109:Cell Proliferation; D002470:Cell Survival; D002890:Chromosomes, Human, Pair 20; D002898:Chromosomes, Human, Pair 8; D015179:Colorectal Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000401:mortality / Q000473:pathology; D019295:Computational Biology; D005784:Gene Amplification; D018628:Gene Dosage; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D045325:HCT116 Cells; D006801:Humans; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D011379:Prognosis; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D015398:Signal Transduction / Q000187:drug effects; D016019:Survival Analysis; D013997:Time Factors; D014162:Transfection
chemical_list: D000970:Antineoplastic Agents; D018797:Cell Cycle Proteins; C489427:MYC protein, human; D008869:Microtubule-Associated Proteins; D009687:Nuclear Proteins; D047428:Protein Kinase Inhibitors; D016271:Proto-Oncogene Proteins c-myc; C122167:TPX2 protein, human; C576917:AURKA protein, human; D064096:Aurora Kinase A
keywords: AURKA; MYC; TPX2; co-amplification; synthetic lethality