Pancreatic acini drive early pancreatic fibrosis in the pathogenesis of pancreatitis

Abstract

s / Pancreatology 12 (2012) 502–597 515 expression and identify patients who could potentially benefit from therapy by TKIs. Methods: Transcript levels of KRAS pathway genes SOS1,GRB2, SHC1,KRAS,RAF1,RAC1, MAP2K1/2, MAPK1/3 and all human ABC genes were evaluated by real-time PCRwith relative quantification in tumors and paired adjacent non-neoplastic control tissues from 21 PDAC patients. Differences in transcript levels between tumor and control tissues, between patients divided by stage, grade and KRAS mutation status, and correlations of all transcript levels were then analyzed. Results: KRAS transcript level significantly correlatedwith SHC1,MAP2K1 andMAPK1 in control tissues andwithGRB2andMAPK1 in tumors.MAPK1/3 but not KRAS correlated with fourteen ABCs including ABCB1/PgP and ABCG2/BCRP in control tissues. However, six different ABCs correlated with KRAS level and eight with MAPK1/3 in tumors. Transcript levels of SOS1, MAPK1,ABCB7,ABCC6,ABCC7,ABCG1 and ABCG2 significantly associatedwith tumor size, stage or grade of PDAC. Conclusions: Our study identified potential candidates for drug targets modified by the KRAS signaling pathway. MAPK1 associated with the aggressiveness of PDAC and shall be further followed. Moreover, MAPK1/3 levels modified expression of ABC transporters in PDAC and interactions with therapy by TKIs may be expected.We further aim to validate results in larger independent set and investigate functional aspects of our findings. Study was supported by CSF grant no.: P301/12/1734.