title: Decreased expression of DUSP4 is associated with liver and lung metastases in colorectal cancer.
abstract: Dual-specificity protein phosphatase 4 (DUSP4), a negative regulator of extracellular-regulated kinase activity, is a potential mediator of resistance to chemotherapy and a tumor suppressor. The aim of this study is to clarify the association between DUSP4 gene expression and clinical outcome in patients with colorectal cancer. Patients who underwent surgery for colorectal cancer were enrolled in this study (n = 212). We investigated DUSP4 gene expression by real-time reverse transcription polymerase chain reaction in colorectal cancer tissue and paired normal mucosa. Immunohistochemical analyses of DUSP4 and ERK1/2 were also conducted. Additionally, we examined the relationship between gene expression and KRAS mutation in 74 of the 212 patients. DUSP4 expression in tumor tissues was significantly higher than that in matched normal mucosa (P < 0.0001). Decreased DUSP4 expression was significantly associated with advanced T classification, lymphatic invasion, vascular invasion, advanced stage, and liver and lung metastases. Logistic regression analysis revealed that decreased DUSP4 expression was an independent risk factor for synchronous distant metastases (P = 0.006). Increased DUSP4 expression was significantly associated with better prognosis (P = 0.0162). Immunohistochemical examination showed DUSP4 expression in the nucleus and cytoplasm of cancer cells, and no correlation was observed between DUSP4 and ERK1/2 expression. There was no significant correlation between DUSP4 expression and KRAS mutation. In conclusion, DUSP4 expression in colorectal cancer was negatively correlated with factors reflecting tumor progression, including distant metastases. Our data suggest that DUSP4 may act as a tumor suppressor in colorectal cancer.
authors.affiliation: Department of Gastrointestinal and Pediatric Surgery, Mie Graduate School of Medicine, 2-174 Edobashi, Tsu, Mie 514-8507, Japan. saigusa@clin.medic.mie-u.ac.jp
authors.forename: Susumu
authors.initials: S
authors.lastname: Saigusa
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Inoue
authors.forename: Koji
authors.initials: K
authors.lastname: Tanaka
authors.forename: Yuji
authors.initials: Y
authors.lastname: Toiyama
authors.forename: Yoshinaga
authors.initials: Y
authors.lastname: Okugawa
authors.forename: Tadanobu
authors.initials: T
authors.lastname: Shimura
authors.forename: Junichiro
authors.initials: J
authors.lastname: Hiro
authors.forename: Keiichi
authors.initials: K
authors.lastname: Uchida
authors.forename: Yasuhiko
authors.initials: Y
authors.lastname: Mohri
authors.forename: Masato
authors.initials: M
authors.lastname: Kusunoki
mesh_terms: D000368:Aged; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000473:pathology*; D054637:Dual-Specificity Phosphatases / Q000235:genetics*; D005260:Female; D016147:Genes, Tumor Suppressor; D006801:Humans; D007413:Intestinal Mucosa / Q000473:pathology; D008113:Liver Neoplasms / Q000473:pathology / Q000556:secondary; D008175:Lung Neoplasms / Q000473:pathology / Q000556:secondary; D020935:MAP Kinase Signaling System / Q000235:genetics; D008297:Male; D054639:Mitogen-Activated Protein Kinase Phosphatases / Q000235:genetics*; D009154:Mutation / Q000235:genetics; D009362:Neoplasm Metastasis / Q000235:genetics / Q000473:pathology*; D011379:Prognosis; D011518:Proto-Oncogene Proteins / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins / Q000235:genetics
chemical_list: C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; D054639:Mitogen-Activated Protein Kinase Phosphatases; C490583:DUSP4 protein, human; D054637:Dual-Specificity Phosphatases; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins