PAUF promotes adhesiveness of pancreatic cancer cells by modulating focal adhesion kinase

Pancreatic cancer is a notorious disease with a poor prognosis and low survival rates, which is due to limited advances in understanding of the molecular mechanism and inadequate development of effective treatment options over the decades. In previous studies, we demonstrated that a novel soluble protein named pancreatic adenocarcinoma up-regulated factor (PAUF) acts on tumor and immune cells and plays an important role in metastasis and progression of pancreatic cancer. Here we show that PAUF promotes adhesiveness of pancreatic cancer cells to various extracellular matrix (ECM). Our results further support a positive correlation of activation and expression of focal adhesion kinase (FAK), a key player in tumor cell metastasis and survival, with PAUF expression. PAUF-mediated adhesiveness was significantly attenuated upon blockade of the FAK pathway. Moreover, PAUF appeared to enhance resistance of pancreatic cancer cells to anoikis via modulation of FAK. Our results suggest that PAUF-mediated FAK activation plays an important role in pancreatic cancer progression.

Pancreatic adenocarcinoma up-regulated factor (PAUF) enhances the expression of beta-catenin, leading to a rapid proliferation of pancreatic cells

It is not yet understood how the enhanced expression of pancreatic adenocarcinoma up-regulated factor (PAUF; a novel oncogene identified in our recent studies), contributes to the oncogenesis of pancreatic cells. We herein report that PAUF up-regulates the expression and transcriptional activity of beta-catenin while the suppression of PAUF by shRNA down-regulates beta-catenin. The induction of beta-catenin by PAUF is mediated by the activities of Akt and GSK-3beta, but inhibition of downstream ERK does not reduce beta-catenin expression. To test whether PAUF emulates either the Wnt3a-mediated or the protein kinase A-mediated signaling pathway for the stabilization of beta-catenin, we examined the phosphorylation status of beta-catenin in the presence of PAUF compared with that of beta-catenin during treatment with Wnt3a or dibutyryl cAMP, a cell permeable cyclic AMP analogue. PAUF expression induces phosphorylation at Ser-33/37/Thr-41 and Ser-675 of beta-catenin but no phosphorylation at Ser-45, indicating that a unique phosphorylation pattern of beta-catenin is caused by PAUF. Finally, the expression of PAUF up-regulates both cyclin-D1 and c-Jun, target genes of beta-catenin, leading to a rapid proliferation of pancreatic cells; conversely decreased PAUF expression (by shRNA) results in the reduced proliferation of pancreatic cells. Treatment with hexachlorophene (an inhibitor of beta-catenin) reduces the proliferation of pancreatic cells despite the presence of PAUF. Taken together, we propose that PAUF can up-regulate and stabilize beta-catenin via a novel pattern of phosphorylation, thereby contributing to the rapid proliferation of pancreatic cancer cells.

Alta frecuencia de un haplotipo susceptible del gen Mannose Binding Lectin, en las islas AnapiaSuana del Lago Titicaca / High frequency of a haplotipo capable of the gene Mannose Binding Lectin, in the islands AnapiaSuana of the Lake Titicaca

Se determinaron las combinaciones de variantes genéticas en 4 sitios del gen de la proteína asociada al sistema inmune MBL (mannose binding lectin), en 19 pobladores de las islas de Anapia-Suana del Lago Titicaca. Se encuentran solamente 3 combinaciones (haplotipos): LYPB, HYPA y LYPA y se observa alta frecuencia (0.58) del haplotipo defectuoso LYPB en las mencionadas islas sobrepasando a otras frecuencias previamente reportadas en el mundo. Este haplotipo es poco frecuente en poblaciones europeas, asiáticas y africanas. La deficiencia sérica de LYPB predispone a infecciones como tuberculosis, VIH-1 y a enfermedades autoinmunes como artritis reumatoide y lupus eritematoso entre otras. Con estos antecedentes nuestros futuros esfuerzos se dirigirán a investigar la razón de la alta frecuencia de LYPB en estas islas y determinar la de las otras islas aledañas.

We have analized the combination of variants at 4 sites of the gene MBL (mannose binding lectin) which is part of the immune system, in 19 normal individuals from the islands of Anapia-Suana in the Lake Titicaca. OnIy 3 combinations (haplotypes) were registered: LYPB, HYPA and LYPA; the proportion of the pressumed defective haplotype LYPB is 0.58 being the highest ever recorded. This haplotype is rare among European, Asian and African populations. It predisposes to infectious diseases as tuberculosis and AIDS as well as autoimmune diseases like reumatoid arthritis and lupus erithematosumo This finding lead our future efforts to elucidate the reason of this high frequency of LYPB and to determine its proportion in other islands of the Titicaca Lake.