The expression of phospho-AKT, phospho-mTOR, and PTEN in extrahepatic cholangiocarcinoma - PubMed (original) (raw)
The expression of phospho-AKT, phospho-mTOR, and PTEN in extrahepatic cholangiocarcinoma
Joon-Yong Chung et al. Clin Cancer Res. 2009.
Abstract
Purpose: 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.
Experimental design: 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.
Conflict of interest statement
Disclosure of Potential Conflicts of Interest
No potential conflicts of interest were disclosed.
Figures
Fig. 1.
Phosphorylated AKT (p-AKT), phosphorylated mTOR (p-mTOR), and PTEN expression by multiplex tissue immunoblotting and immunohistochemical staining. A, signal intensity from maximum to minimum is white-yellow-red-green-blue-black in order. Cases with higher intensity to p-AKTand p-mTOR showed lower intensity to total PTEN. B, immunohistochemical staining of p-AKT, p-mTOR, and PTEN protein and dysplasia and extrahepatic cholangiocarcinoma.
Fig. 2.
Box plot of relative expression rate of p-AKTand p-mTOR protein expressions among normal biliary epithelia, dysplasia, and cancer cases. A, cases with extrahepatic cholangiocarcinoma had significantly higher expression to p-AKT than those with normal and dysplastic epithelia (P < 0.05, post hoc Duncan test). B, cases with extrahepatic cholangiocarcinoma had significantly higher expression to p-mTOR than those with normal and dysplastic epithelia (P < 0.05, post hoc Duncan test). C, correlation between p-AKTand p-mTOR expression (R = 0.45; P < 0.001).
Fig. 3.
Box plot of relative expression rate of PTEN and its association with other clinicopathologic factors. A, cases with T1 classification (mean, 16.1) had a significantly higher relative PTEN expression than those with other classifications; T2, 8.9; T3, 7.2; T4, 4.0 (P < 0.05, post hoc Duncan test). _B_, patients with duodenal invasion (mean, 4.0) had significantly less PTEN expression than those without duodenal invasion (mean, 9.0; _P_ < 0.05, post hoc Duncan test). _C_, patients with higher stage grouping (advanced disease; mean PTEN stage III, 4.0; IIB, 6.5) had significantly less PTEN expression than those with lower stage (IIA, 8.1; IB, 9.6; IA, 17.2; _P_ < 0.05, post hoc Duncan test). _D_, patients with less tumor cell invasion (<0.5 cm of depth of invasion) had a statistically greater PTEN expression (mean PTEN, 3.41) than cases with deeper tumor cell invasion (>1.2 cm invasion, mean PTEN 1.61; P < 0.05, post hoc Duncan test), but no statistical difference with those with depth of invasion between 0.5 and 1.2 cm (PTEN mean, 2.94).
Fig. 4.
A, Kaplan-Meier survival analysis of extrahepatic cholangiocarcinoma according to PTEN expression. Patients with low PTEN expression (median survival, 18 mo; n = 17) had a significantly worse patients’ survival time than those with high PTEN expression (median survival, 39 mo; n = 117; log-rank test, P = 0.004).
Fig. 5.
A, Kaplan-Meier survival analysis of extrahepatic cholangiocarcinoma according to PTEN/p-AKTexpression. Patients with low PTEN/p-AKTexpression (median survival, 18 mo; n = 42) had a significantly worse patients’ survival time than those with high PTEN/p-AKTexpression (median survival, 45 mo; n = 91; log-rank test, P = 0.003). B, Kaplan-Meier survival analysis of EHCC according to PTEN/p-mTOR expression. Patients with low PTEN/p-mTOR expression (median survival, 18 mo; n = 21) had a significantly worse patients’ survival time than those with high PTEN/ p-mTOR expression (median survival, 39 mo; n = 112; P = 0.009).
References
- Hong SM, Kim MJ, Pi DY, et al. Analysis of extrahepatic bile duct carcinomas according to the New American Joint Committee on Cancer staging system focused on tumor classification problems in 222 patients. Cancer 2005;104:802–10. - PubMed
- Nagakawa T, Kayahara M, Ikeda S, et al. Biliary tract cancer treatment: results from the BiliaryTract Cancer Statistics Registry in Japan. J Hepatobiliary Pancreat Surg 2002;9:569–75. - PubMed
- Nathan H, Pawlik TM,Wolfgang CL, Choti MA, Cameron JL, Schulick RD. Trends in survival after surgery for cholangiocarcinoma: a 30-year population-based SEER database analysis. J Gastrointest Surg 2007;11:1488–96. - PubMed
Publication types
MeSH terms
Substances
LinkOut - more resources
Full Text Sources
Other Literature Sources
Research Materials
Miscellaneous