These findings suggest that activation of both the p-ERK1/2 and PI-3K/AKT signaling pathways might be involved in malignant transformation and progression of gallbladder adenocarcinoma. On multivariate analysis, there was a significant association between p-ERK1/2 over-expression and reduced survival

(Table 4). To our knowledge, this is the first Selleckchem IPI-549 report showing a correlation of p-EKR1/2 and PI3-K expression with clinical and pathological features, including tumor size, lymph node metastasis and surround tissue invasion. Hori et al [11] demonstrated that 77% of extra-hepatic biliary tract cancer showed positive staining for p-MAPK and 47% for p-AKT. However, those results showed no positive correlation between p-MAPK/p-AKT expression and clinical and pathological features, including tumor stage and pT category in extra-hepatic biliary tract cancer. The study performed by Hori et al was based on a small cohort with 30 patients including 15 with gallbldadder cancer, 13 with bile duct cancer MK-1775 clinical trial and 2 with ampullary cancer. Another study by Wu et al. also revealed elevated level of p-AKT in 74.1% (20 of 27) of human gallbladder cancer specimens [12]. A number of other studies showed similar positive

rates of expression of p-MAPK/p-ERK1/2 or p-AKT in cholangiocarcinoma [7], intra-hepatic cholangiocarcinoma [8], and cholangiocarcinoma [13], but the association with clinical and pathological features remain inconclusive. Javle et al. demonstrated that expression of p-AKT may be associated

with improved Topoisomerase inhibitor survival [13]. However, in another study Schmitz et al. showed that neither p-ERK1/2 nor p-AKT expression had an impact on patients survival in a larger and more homogenous cohort of solely intra-hepatic cholangiocarcinoma [8]. ERK1/2 and PI3-K signaling pathways are associated with cell proliferation, transformation and survival. The exact molecular mechanism Mannose-binding protein-associated serine protease in which ERK1/2 and/or AKT remains constitutively activated in a variety of human cancers is however not well understood. EGFR activation triggers multiple signaling cascades which include MAPK/ERK1/2 and PI3-K/AKT pathways, resulting in cell proliferation, differentiation, angiognenesis, metastasis, and inhibition of apoptosis [14, 15]. Over-expression of EGFR was found in patients with malignancies of gallbladder, ampullary and common bile duct [16–19]. Somatic mutations of EGFR in the tyrosine kinase domain have been identified in a subgroup of patients with cholangiocarcinoma or gallbladder carcinoma [15]. The mutations lead to sustained activation of signaling and results in cell survival and proliferation. Mutations of oncogenes have also been identified in cholangiocarcinoma. For example, K-Ras and B-Raf mutations were found in 22% and 45% of cholangiocarcinoma, respectively [20].