title: ALDH1A3, the Major Aldehyde Dehydrogenase Isoform in Human Cholangiocarcinoma Cells, Affects Prognosis and Gemcitabine Resistance in Cholangiocarcinoma Patients.
abstract: OBJECTIVE
  Intrahepatic cholangiocarcinoma is a fatal primary liver cancer resulting from diagnosis at an advanced stage. Understanding the mechanisms of drug resistance and metastasis of cholangiocarcinoma may improve the disease prognosis. Enhanced aldehyde dehydrogenase (ALDH) activity is suggested to be associated with increased drug resistance and the metastasis. This study aims to investigate the roles of the ALDH isoforms in cholangiocarcinoma.
  
  
  METHODS
  Aldefluor assays, RT-PCR, and Western blot analysis were used to identify the major ALDH isoforms contributing to Aldefluor activity in human cholangiocarcinoma cell lines. We manipulated isoform expression in HuCCT1 cells to elucidate the role of ALDH1A3 in the malignant progression of these cells. Finally, we used immunohistochemical staining to evaluate the clinical significance of ALDH1A3 in 77 hepatectomized cholangiocarcinoma patients and an additional 31 patients with advanced cholangiocarcinoma who received gemcitabine-based therapy.
  
  
  RESULTS
  ALDH(high) cholangiocarcinoma cells not only migrated faster but were more resistant to gemcitabine. Among the 19 ALDH isoforms studied, ALDH1A3 was found to be the main contributor to Aldefluor activity. In addition, we also found that knockdown of ALDH1A3 expression in HuCCT1 cells markedly reduced not only their sensitivity to gemcitabine, which might be attributed to a decreased expression of ribonucleotide reductase M1, but also their migration. Most importantly, this enzyme was also identified as an independent poor prognostic factor for patients with intrahepatic cholangiocarcinoma, as well as a prognostic biomarker of gemcitabine-treated patients.
  
  
  CONCLUSIONS
  ALDH1A3 plays an important role in enhancing malignant behavior of cholangiocarcinoma and serves as a new therapeutic target. Clin Cancer Res; 22(16); 4225-35. ©2016 AACR.
authors.affiliation: School of Medicine, National Yang-Ming University, Taipei, Taiwan. Department of Oncology, Taipei Veterans General Hospital, Taipei, Taiwan.
authors.forename: Ming-Huang
authors.initials: MH
authors.lastname: Chen
authors.affiliation: Department of Oncology, Taipei Veterans General Hospital, Taipei, Taiwan. Institute of Biopharmaceutical Sciences, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Jing-Jie
authors.initials: JJ
authors.lastname: Weng
authors.affiliation: Department of Surgery, Chang Gung Memorial Hospital, Chang Gung University, Taoyuan, Taiwan.
authors.forename: Chi-Tung
authors.initials: CT
authors.lastname: Cheng
authors.affiliation: Department of Pathology, Chang Gung Memorial Hospital, Chang Gung University, Taoyuan, Taiwan.
authors.forename: Ren-Chin
authors.initials: RC
authors.lastname: Wu
authors.affiliation: Department of Pathology, Chang Gung Memorial Hospital, Chang Gung University, Taoyuan, Taiwan.
authors.forename: Shih-Chiang
authors.initials: SC
authors.lastname: Huang
authors.affiliation: Department of Hematology-Oncology, Chang Gung Memorial Hospital, Chang Gung University, Taoyuan, Taiwan.
authors.forename: Chiao-En
authors.initials: CE
authors.lastname: Wu
authors.affiliation: Center for Advanced Molecular Imaging and Translation, Chang Gung Memorial Hospital, Taoyuan, Taiwan.
authors.forename: Yi-Hsiu
authors.initials: YH
authors.lastname: Chung
authors.affiliation: School of Medicine, National Yang-Ming University, Taipei, Taiwan. Department of Oncology, Taipei Veterans General Hospital, Taipei, Taiwan.
authors.forename: Chun-Yu
authors.initials: CY
authors.lastname: Liu
authors.affiliation: School of Medicine, National Yang-Ming University, Taipei, Taiwan. Department of Oncology, Taipei Veterans General Hospital, Taipei, Taiwan.
authors.forename: Mu-Hsin
authors.initials: MH
authors.lastname: Chang
authors.affiliation: School of Medicine, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Ming-Han
authors.initials: MH
authors.lastname: Chen
authors.affiliation: Department of Surgery, Chang Gung Memorial Hospital, Keelung; Chang Gung University, Taoyuan, Taiwan.
authors.forename: Kun-Chun
authors.initials: KC
authors.lastname: Chiang
authors.affiliation: Department of Surgery, Chang Gung Memorial Hospital, Chang Gung University, Taoyuan, Taiwan.
authors.forename: Ta-Sen
authors.initials: TS
authors.lastname: Yeh
authors.affiliation: Institute of Biopharmaceutical Sciences, National Yang-Ming University, Taipei, Taiwan. yehchunnan@gmail.com yeusu@ym.edu.tw.
authors.forename: Yeu
authors.initials: Y
authors.lastname: Su
authors.affiliation: Department of Surgery, Chang Gung Memorial Hospital, Chang Gung University, Taoyuan, Taiwan. yehchunnan@gmail.com yeusu@ym.edu.tw.
authors.forename: Chun-Nan
authors.initials: CN
authors.lastname: Yeh
mesh_terms: D000328:Adult; D000368:Aged; D000445:Aldehyde Oxidoreductases / Q000235:genetics* / Q000378:metabolism; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology* / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use; D014408:Biomarkers, Tumor; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D002470:Cell Survival / Q000235:genetics; D018281:Cholangiocarcinoma / Q000175:diagnosis / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality*; D002945:Cisplatin / Q000494:pharmacology; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D004789:Enzyme Activation; D005260:Female; D055785:Gene Knockdown Techniques; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D020033:Protein Isoforms; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics / Q000378:metabolism; D000093542:Gemcitabine
chemical_list: D000964:Antimetabolites, Antineoplastic; D014408:Biomarkers, Tumor; D020033:Protein Isoforms; D003841:Deoxycytidine; D000445:Aldehyde Oxidoreductases; C018699:aldehyde dehydrogenase (NAD(P)+); C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met; D002945:Cisplatin; D000093542:Gemcitabine