Background/Aim: Pancreatic cancer is one of the deadliest forms of cancer and ranks among the leading causes of cancer-related death worldwide. The most common histological type is ductal adenocarcinoma (PDAC), accounting for approximately 95% of cases. Deregulation of protein synthesis has been found to be closely related to cancer. The rate-limiting step of translation is initiation, which is regulated by a broad range of eukaryotic translation initiation factors (eIFs). Patients and Methods: Human PDAC samples were biochemically analyzed for the expression of various eIF subunits on the protein level (immunohistochemistry, immunoblot analyses) in 174 cases of PDAC in comparison with non-neoplastic pancreatic tissue (n=10). Results: Our investigation revealed a significant down-regulation of four specific eIF subunits, namely eIF1, eIF2D, eIF3C and eIF6. Concomitantly, the protein (immunoblot) levels of eIF1, eIF2D, eIF3C and eIF6 were reduced in PDAC samples as compared with non-neoplastic pancreatic tissue. Conclusion: Members of the eIF family are of relevance in pancreatic tumor biology and may play a major role in translational control in PDAC.Consequently, they might be useful as potential new biomarkers and therapeutic targets in PDAC.
Background Primary sclerosing cholangitis is a chronic cholestatic liver disease. The pathomechanism is still not fully understood, but there is evidence that immune-mediated processes may contribute to disease progression. Methods We studied the prognostic relevance of serum immunoglobulin G (IgG) elevated above the upper limit of normal as a marker for immune activation at initial diagnosis and its influence on transplantation-free survival in a well-defined cohort of PSC patients. Results The final study cohort comprises of 148 PSC patients. Elevated IgG levels were found in 66 patients (44.6%). Apart from their younger age at first diagnosis, there was no significant difference between patients with or without elevated IgG levels. The presence of a concomitant inflammatory bowel disease, an autoimmune hepatitis or immunosuppressive medication was equally distributed between both groups. Patients with elevated IgG levels reached the combined endpoint (34 (59.6%) vs. 23 (40.4%); p = 0.004) significantly more often and had reduced transplantation-free survival (Log-rank: 24.0 (10.2–37.9) vs. 14.0 (8.5–19.5); p < 0.05). Cox regression analysis including age, gender, presence of IBD, presence of dominant stricture (DS), Mayo Risk Score (MRS), immunosuppression, biochemical response to UDCA and elevated IgG-levels confirmed MRS ( p = 0.03), DS ( p = 0.04), biochemical response (p = 0.04) and elevated IgG level (p = 0.04) as independent risk factors for reduced transplantation-free survival. Conclusion We identified elevated serum IgG levels at first diagnosis as an independent risk factor for reduced transplant free-survival in patients with PSC.
Aims: Several lines of evidence indicate that the nuclear enzyme SIRT1 belonging to the class III histone deacetylases is implicated in the initiation and progression of various malignancies. SIRT1 exerts its function by regulating deacetylation of histone and non-histone substrates leading to transcriptional repression of tumor suppressor genes. Recently, SIRT1 gained attraction as druggable target. Since chemotherapeutic treatment options are still very limited in pancreatic cancer we aimed at investigating the potential of SIRT1 in this regard by evaluating the effects of SIRT1 inhibition in vitro and SIRT1 expression in vivo. Methods: Employing immunohistochemistry SIRT1 expression was analyzed in a large cohort of pancreatic ductal adenocarcinomas and subsequently correlated with clinicopathological data and patient survival. Furthermore, we investigated the impact of SIRT1-specific small molecule inhibition and target knock down as well as combinatorial regimens including conventional chemotherapy and small molecule inhibitors directed against the EGFR in pancreatic cancer cell culture models. Using the xCELLigence system, cellular events were measured quantitatively in real time and corroborated by secondary conventional readouts including FACS analysis. Results: We found nuclear SIRT1 expression in 36 (27.9%) of 129 pancreatic carcinomas. SIRT1 expression was significantly higher in poorly differentiated carcinomas (p=0.002). SIRT1 expression was positively correlated with the expression of conventional HDACs suggesting a shared regulation. Strong SIRT1 expression was a significant predictor of poor survival both in univariate (p=0.002) and multivariate (HR 1.65, p=0.045) analysis under inclusion of WHO stage and grade. Small molecule inhibition and target knockdown of SIRT1 lead to a rapid growth arrest and influenced cell viability. This effect was even more pronounced in combinatorial regimens with Gefitinib, but not in combination with Gemcitabine. Conclusions: SIRT1 is shown to be an independent prognostic biomarker for pancreatic adenocarcinomas. Moreover our data suggest that SIRT1 plays an important functional role in pancreatic cancer cell growth, which can be levered out by combinatory small molecule inhibition. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1624. doi:10.1158/1538-7445.AM2011-1624
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