title: Cancerous inhibitor of protein phosphatase 2A (CIP2A) is an independent prognostic marker in wild-type KRAS metastatic colorectal cancer after colorectal liver metastasectomy.
abstract: BACKGROUND
  The impact of KRAS signaling on cancerous inhibitor of protein phosphatase 2A (CIP2A) expression has not yet been explored. We investigated the impact of KRAS on CIP2A expression in colorectal cancer patients after colorectal liver metastasectomy.
  
  
  METHODS
  We examined CIP2A expression by immunohistochemistry (IHC) and used direct sequencing to identify the mutational status of KRAS exon 2 (codon 12 and 13). The association between CIP2A expression, KRAS genotype, clinicopathological parameters and survival were examined by the Kaplan-Meier method and the Cox proportional hazards model. A combination of immunoblotting and proliferation assays were employed to elucidate the role of CIP2A in signal transduction pathways in wild-type KRAS Caco-2 cells.
  
  
  RESULTS
  A total of 220 colorectal cancer patients who had undergone colorectal liver metastasectomy were included in the study. The mutant KRAS genotype was associated with CIP2A overexpression. CIP2A expression was an independent prognostic marker in patients with wild-type KRAS metastatic colorectal cancer after colorectal liver metastasectomy (relative risk = 1.873, P = 0.019). Targeted silencing of CIP2A in Caco-2 cells (wild-type KRAS) led to decreased expression of pERK/ERK and decreased cell proliferation. Overexpression of mutant KRAS G12D in Caco-2 cells led to an increase in CIP2A expression and cell proliferation. In Caco-2 cells with the KRAS G12D, KRAS overexpression preserved the regulation effect of CIP2A in KRAS and abrogated the impact of CIP2A regulation on pERK/ERK and cell proliferation. CIP2A inhibition also increased the efficacy of cetuximab in Caco-2 cells.
  
  
  CONCLUSIONS
  CIP2A is an independent prognostic marker in patients with wild-type KRAS metastatic colorectal cancer after colorectal liver metastasectomy.
authors.affiliation: Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan. kfchen1970@ntu.edu.tw.|National Center of Excellence for Clinical Trial and Research, National Taiwan University Hospital, Taipei, Taiwan. kfchen1970@ntu.edu.tw.
authors.forename: Kuen-Feng
authors.initials: KF
authors.lastname: Chen
authors.affiliation: Division of Hematology and Oncology, Department of Medicine, Taipei Veterans General Hospital, No. 201, Section 2, Shih-Pai Road, Taipei, Taiwan. ccyen@vghtpe.gov.tw.|National Yang-Ming University School of Medicine, Taipei, Taiwan. ccyen@vghtpe.gov.tw.
authors.forename: Chueh-Chuan
authors.initials: CC
authors.lastname: Yen
authors.affiliation: Division of Colon and Rectal Surgery, Department of Surgery, Taipei Veterans General Hospital, Taipei, Taiwan. jklin@vghtpe.gov.tw.|National Yang-Ming University School of Medicine, Taipei, Taiwan. jklin@vghtpe.gov.tw.
authors.forename: Jen-Kou
authors.initials: JK
authors.lastname: Lin
authors.affiliation: Division of Colon and Rectal Surgery, Department of Surgery, Taipei Veterans General Hospital, Taipei, Taiwan. wschen@vghtpe.gov.tw.|National Yang-Ming University School of Medicine, Taipei, Taiwan. wschen@vghtpe.gov.tw.
authors.forename: Wei-Shone
authors.initials: WS
authors.lastname: Chen
authors.affiliation: Division of Colon and Rectal Surgery, Department of Surgery, Taipei Veterans General Hospital, Taipei, Taiwan. yangsh@vghtpe.gov.tw.|National Yang-Ming University School of Medicine, Taipei, Taiwan. yangsh@vghtpe.gov.tw.
authors.forename: Shung-Haur
authors.initials: SH
authors.lastname: Yang
authors.affiliation: Division of Colon and Rectal Surgery, Department of Surgery, Taipei Veterans General Hospital, Taipei, Taiwan. jkjiang@vghtpe.gov.tw.|National Yang-Ming University School of Medicine, Taipei, Taiwan. jkjiang@vghtpe.gov.tw.
authors.forename: Jeng-Kai
authors.initials: JK
authors.lastname: Jiang
authors.affiliation: Division of Colon and Rectal Surgery, Department of Surgery, Taipei Veterans General Hospital, Taipei, Taiwan. ytlan@vghtpe.gov.tw.|National Yang-Ming University School of Medicine, Taipei, Taiwan. ytlan@vghtpe.gov.tw.
authors.forename: Yuan-Tzu
authors.initials: YT
authors.lastname: Lan
authors.affiliation: Division of Colon and Rectal Surgery, Department of Surgery, Taipei Veterans General Hospital, Taipei, Taiwan. cclin15@vghtpe.gov.tw.|National Yang-Ming University School of Medicine, Taipei, Taiwan. cclin15@vghtpe.gov.tw.
authors.forename: Chun-Chi
authors.initials: CC
authors.lastname: Lin
authors.affiliation: Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan. gane-mai@yahoo.com.tw.|National Center of Excellence for Clinical Trial and Research, National Taiwan University Hospital, Taipei, Taiwan. gane-mai@yahoo.com.tw.
authors.forename: Hui-Chuan
authors.initials: HC
authors.lastname: Yu
authors.affiliation: Division of Colon and Rectal Surgery, Department of Surgery, Taipei Veterans General Hospital, Taipei, Taiwan. hmhsu@vghtpe.gov.tw.|National Yang-Ming University School of Medicine, Taipei, Taiwan. hmhsu@vghtpe.gov.tw.
authors.forename: Hui-Mei
authors.initials: HM
authors.lastname: Hsu
authors.affiliation: Division of Colon and Rectal Surgery, Department of Surgery, Taipei Veterans General Hospital, Taipei, Taiwan. wllin@vghtpe.gov.tw.|National Yang-Ming University School of Medicine, Taipei, Taiwan. wllin@vghtpe.gov.tw.
authors.forename: Wen-Ling
authors.initials: WL
authors.lastname: Lin
authors.affiliation: Division of Hematology and Oncology, Department of Medicine, Taipei Veterans General Hospital, No. 201, Section 2, Shih-Pai Road, Taipei, Taiwan. danny_teng@yahoo.com.tw.|Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan. danny_teng@yahoo.com.tw.|National Yang-Ming University School of Medicine, Taipei, Taiwan. danny_teng@yahoo.com.tw.
authors.forename: Hao-Wei
authors.initials: HW
authors.lastname: Teng
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001324:Autoantigens / Q000096:biosynthesis*; D014408:Biomarkers, Tumor / Q000096:biosynthesis*; D018938:Caco-2 Cells; D015179:Colorectal Neoplasms / Q000175:diagnosis / Q000378:metabolism* / Q000601:surgery; D005260:Female; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008113:Liver Neoplasms / Q000175:diagnosis / Q000378:metabolism* / Q000601:surgery; D008297:Male; D008565:Membrane Proteins / Q000096:biosynthesis*; D059146:Metastasectomy; D008875:Middle Aged; D011379:Prognosis; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis*; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins / Q000096:biosynthesis*
chemical_list: D001324:Autoantigens; D014408:Biomarkers, Tumor; C500266:CIP2A protein, human; D047908:Intracellular Signaling Peptides and Proteins; C117307:KRAS protein, human; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins