The expression of phospho-AKT, phospho-mTOR, and PTEN in extrahepatic cholangiocarcinoma.
OBJECTIVE
The protein kinase B (AKT) pathway plays a key role in the regulation of cellular survival, apoptosis, and protein translation, and has been shown to have prognostic significance in a number of cancers. We sought to define its role in extrahepatic cholangiocarcinoma.


METHODS
Two hundred twenty-one extrahepatic cholangiocarcinoma patients with clinicopathologic data, including survival, were arrayed into tissue microarrays. Phosphorylated AKT (p-AKT), phosphorylated mammalian target of rapamycin (p-mTOR), and total phosphatase and tensin homolog deleted on chromosome 10 (PTEN) protein expressions were studied with multiplex tissue immunoblotting assay.


RESULTS
Expressions of p-AKT and p-mTOR were significantly increased in extrahepatic cholangiocarcinoma cases compared with normal and dysplastic bile duct epithelium (P < 0.05 both). Decreased PTEN expression was observed in patients with increasing depth of invasion (P < 0.05), T classification (P < 0.05), and stage grouping (P < 0.05), and the presence of invasion of the pancreas (P < 0.05) and duodenum (P < 0.05). Decreased PTEN expression (P = 0.004) as well as decreased PTEN/p-AKT (P = 0.003) and PTEN/p-mTOR (P = 0.009) expression showed shorter survival by univariate but not by multivariate analysis.


CONCLUSIONS
The AKT pathway is activated in a subset of extrahepatic cholangiocarcinoma. Elevated PTEN expression correlates with longer survival. Quantitative data obtained by multiplex tissue immunoblotting may provide additional information than assessment of immunohistochemistry alone. Quantitative analysis of PTEN, PTEN/p-AKT and PTEN/p-mTOR shows differences in survival by univariate analysis.
Chung
Joon-Yong
JY
Tissue Array Research Program, Laboratory of Pathology, National Cancer Institute, NIH, Bethesda, Maryland, USA.
Hong
Seung-Mo
SM
Choi
Byeong Yeob
BY
Cho
Hyungjun
H
Yu
Eunsil
E
Hewitt
Stephen M
SM
D000368:Aged; D017209:Apoptosis; D018281:Cholangiocarcinoma / Q000378:metabolism*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D051059:PTEN Phosphohydrolase / Q000096:biosynthesis / Q000378:metabolism / Q000502:physiology*; D010766:Phosphorylation; D011494:Protein Kinases / Q000096:biosynthesis / Q000502:physiology*; D040901:Proteomics / Q000379:methods; D051057:Proto-Oncogene Proteins c-akt / Q000096:biosynthesis / Q000502:physiology*; D058570:TOR Serine-Threonine Kinases
D011494:Protein Kinases; C546842:MTOR protein, human; C494918:AKT1 protein, human; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human