title: CLIC4, ERp29, and Smac/DIABLO derived from metastatic cancer stem-like cells stratify prognostic risks of colorectal cancer.
abstract: OBJECTIVE
  Cancer stem-like cells have been well accepted to be involved in recurrence and metastasis of cancers, but the prognostic potential of biomarkers integrating with metastasis and cancer stem-like cells for colorectal cancer is unclear.
  
  
  METHODS
  We identified three proteins, CLIC4, ERp29, and Smac/DIABLO, from metastatic cancer stem-like cells of colorectal cancer and verified the proteins' role in metastatic behaviors. The proteins were detected by IHC in colorectal cancer tumors and matched colonic mucosa from patients with colorectal cancer who underwent radical surgery in the training cohort. The associations between proteins expression levels and five-year disease-specific survival (DSS) were evaluated to predict the survival probability in the training cohort of 421 cases and the validation cohort of 228 cases.
  
  
  RESULTS
  A three-protein panel including CLIC4, ERp29, and Smac/DIABLO, which was generated from multivariate analysis by excluding clinicopathologic characteristics from the training cohort, distinguished patients with colorectal cancer into very low-, low-, middle-, and high-risk groups with significant differences in five-year DSS probability (88.6%, 63.3%, 30.4%, 11.4%; P < 0.001). The panel is independent from tumor-node-metastasis staging system and histologic grading to predict prognosis, and also enables classification of validation cohort into four risk stratifications (five-year DSS probability is 98.2%, 80.2%, 25.6%, and 2.7%; P < 0.001).
  
  
  CONCLUSIONS
  CLIC4, ERp29, and Smac/DIABLO integrated into a novel panel based on cancer stem-like cells in association with metastasis stratify the prognostic risks of colorectal cancer. Prediction of risks with molecular markers will benefit clinicians to make decisions of individual management with postoperative colorectal cancer patients.
authors.affiliation: Authors' Affiliations: Departments of Pathology and Department of Pathology, School of Basic Medical Sciences; Guangdong Provincial Key Laboratory of Molecular Tumour Pathology; dengyj@smu.edu.cn dyq@fimmu.com.
authors.forename: Yong-Jian
authors.initials: YJ
authors.lastname: Deng
authors.affiliation: Department of Pathology, School of Basic Medical Sciences; Department of Pathology, Shenzhen People's Hospital, Shenzhen; and.
authors.forename: Na
authors.initials: N
authors.lastname: Tang
authors.affiliation: Department of Pathology, School of Basic Medical Sciences; Department of Pathology, Guangdong General Hospital;
authors.forename: Chao
authors.initials: C
authors.lastname: Liu
authors.affiliation: Department of Pathology, School of Basic Medical Sciences; Department of Pathology, Guangdong Women and Children Hospital, Guangzhou;
authors.forename: Jiang-Yu
authors.initials: JY
authors.lastname: Zhang
authors.affiliation: Department of Biostatistics, Southern Medical University;
authors.forename: Sheng-Li
authors.initials: SL
authors.lastname: An
authors.affiliation: Department of Pathology, School of Basic Medical Sciences;
authors.forename: Yin-Li
authors.initials: YL
authors.lastname: Peng
authors.affiliation: Department of Pathology, School of Basic Medical Sciences;
authors.forename: Li-Li
authors.initials: LL
authors.lastname: Ma
authors.affiliation: Department of Pathology, School of Basic Medical Sciences;
authors.forename: Guang-Qiu
authors.initials: GQ
authors.lastname: Li
authors.affiliation: Department of Pathology, School of Basic Medical Sciences;
authors.forename: Qiang
authors.initials: Q
authors.lastname: Jiang
authors.affiliation: Department of Pathology, School of Basic Medical Sciences;
authors.forename: Chun-Ting
authors.initials: CT
authors.lastname: Hu
authors.affiliation: General Surgery, Nanfang Hospital;
authors.forename: Ya-Nan
authors.initials: YN
authors.lastname: Wang
authors.affiliation: General Surgery, Nanfang Hospital;
authors.forename: Yao-Ze
authors.initials: YZ
authors.lastname: Liang
authors.affiliation: Department of Pathology, Southwest Hospital, Third Military Medical University, Chongqing;
authors.forename: Xiu-Wu
authors.initials: XW
authors.lastname: Bian
authors.affiliation: Department of Pathology, Peking University School of Basic Medical Sciences, Beijing, China.
authors.forename: Wei-Gang
authors.initials: WG
authors.lastname: Fang
authors.affiliation: Authors' Affiliations: Departments of Pathology and Department of Pathology, School of Basic Medical Sciences; Guangdong Provincial Key Laboratory of Molecular Tumour Pathology; dengyj@smu.edu.cn dyq@fimmu.com.
authors.forename: Yan-Qing
authors.initials: YQ
authors.lastname: Ding
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D051017:Apoptosis Regulatory Proteins; D014408:Biomarkers, Tumor / Q000378:metabolism*; D018118:Chloride Channels / Q000378:metabolism*; D015179:Colorectal Neoplasms / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D018572:Disease-Free Survival; D005260:Female; D006360:Heat-Shock Proteins / Q000378:metabolism*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D053208:Kaplan-Meier Estimate; D008207:Lymphatic Metastasis; D008297:Male; D008875:Middle Aged; D024101:Mitochondrial Proteins / Q000378:metabolism*; D015999:Multivariate Analysis; D014411:Neoplastic Stem Cells / Q000378:metabolism*; D011379:Prognosis; D012372:ROC Curve; D012306:Risk; D055815:Young Adult
chemical_list: D051017:Apoptosis Regulatory Proteins; D014408:Biomarkers, Tumor; C464459:CLIC4 protein, human; D018118:Chloride Channels; C412403:DIABLO protein, human; C491738:ERP29 protein, human; D006360:Heat-Shock Proteins; D047908:Intracellular Signaling Peptides and Proteins; D024101:Mitochondrial Proteins