title: The expression of phospho-AKT1 and phospho-MTOR is associated with a favorable prognosis independent of PTEN expression in intrahepatic cholangiocarcinomas.
abstract: AKT1 signaling pathway is important for the regulation of protein synthesis and cell survival with implications in carcinogenesis. In this study, we explored the prognostic significance of AKT1 pathway in intrahepatic cholangiocarcinomas. We investigated the status of phosphatase and tensin homolog deleted on chromosome 10 (PTEN), phosphorylated (p) AKT1 (p-AKT1), p-mammalian target of rapamycin (p-MTOR), p-p70 ribosomal protein S6 kinase (p-RPS6KB2) and p-eukaryotic initiation factor 4E-binding protein-1 (p-EIF4EBP1) in 101 intrahepatic cholangiocarcinomas by immunohistochemistry. Western blot analysis was performed to verify the expression levels of p-AKT1 and p-MTOR. The relationship of protein expression with clinicopathological data and the correlations of protein expression levels were explored. The overexpression of p-AKT1, p-MTOR, and PTEN was associated with a better survival in patients with intrahepatic cholangiocarcinoma (P=0.0137, 0.0194, and 0.0337, respectively). In a multivariate analysis, PTEN was an independent prognostic factor, and p-AKT1 showed tendency (P=0.032 and 0.051, respectively). The overexpression of p-MTOR was correlated with well-to-moderately differentiated tumors (P<0.001) and tumors without metastasis (P=0.046). Expression levels of the AKT1 signaling pathway proteins in this study showed positive correlations with each other, except for PTEN. Aberrant expressions of p-AKT1 and p-MTOR in intrahepatic cholangiocarcinoma were associated with a favorable prognosis, possibly in a PTEN-independent manner. Our results indicate that dysregulation of the AKT1 pathway may have an important role in the development of intrahepatic cholangiocarcinoma, but not necessarily in the progression of the disease.
authors.affiliation: Department of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
authors.forename: Dakeun
authors.initials: D
authors.lastname: Lee
authors.forename: In-Gu
authors.initials: IG
authors.lastname: Do
authors.forename: Kyusam
authors.initials: K
authors.lastname: Choi
authors.forename: Chang Ohk
authors.initials: CO
authors.lastname: Sung
authors.forename: Kee-Taek
authors.initials: KT
authors.lastname: Jang
authors.forename: Dongwook
authors.initials: D
authors.lastname: Choi
authors.forename: Jin Seok
authors.initials: JS
authors.lastname: Heo
authors.forename: Seoung Ho
authors.initials: SH
authors.lastname: Choi
authors.forename: Jongmin
authors.initials: J
authors.lastname: Kim
authors.forename: Jin Young
authors.initials: JY
authors.lastname: Park
authors.forename: Hyung Jin
authors.initials: HJ
authors.lastname: Cha
authors.forename: Jae-Won
authors.initials: JW
authors.lastname: Joh
authors.forename: Kwan Yong
authors.initials: KY
authors.lastname: Choi
authors.forename: Dae Shick
authors.initials: DS
authors.lastname: Kim
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000032:analysis; D000293:Adolescent; D000328:Adult; D000368:Aged; D001650:Bile Duct Neoplasms / Q000201:enzymology* / Q000401:mortality / Q000473:pathology; D001653:Bile Ducts, Intrahepatic / Q000201:enzymology* / Q000473:pathology; D014408:Biomarkers, Tumor / Q000032:analysis*; D015153:Blotting, Western; D018797:Cell Cycle Proteins; D016009:Chi-Square Distribution; D018281:Cholangiocarcinoma / Q000201:enzymology* / Q000401:mortality / Q000473:pathology; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D051059:PTEN Phosphohydrolase / Q000032:analysis*; D010750:Phosphoproteins / Q000032:analysis; D010766:Phosphorylation; D011379:Prognosis; D016016:Proportional Hazards Models; D051057:Proto-Oncogene Proteins c-akt / Q000032:analysis*; D056910:Republic of Korea; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000032:analysis; D058570:TOR Serine-Threonine Kinases / Q000032:analysis*; D015854:Up-Regulation; D055815:Young Adult
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D014408:Biomarkers, Tumor; D018797:Cell Cycle Proteins; C087000:EIF4EBP1 protein, human; D010750:Phosphoproteins; C546842:MTOR protein, human; C494918:AKT1 protein, human; D051057:Proto-Oncogene Proteins c-akt; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D058570:TOR Serine-Threonine Kinases; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human