Abstract
BackgroundThe Hippo pathway regulates organ size by inhibiting cell proliferation and promoting cell apoptosis upon its activation. The Yes Associated Protein 1 (YAP1) is a nuclear effector of the Hippo pathway that promotes cell growth as a transcription co-activator. In human cancer, the YAP1 gene was reported as amplified and over-expressed in several tumor types.MethodsImmunohistochemical staining of YAP1 protein was used to assess the expression of YAP1 in pancreatic tumor tissues. siRNA oligonucleotides were used to knockdown the expression of YAP1 and their effects on pancreatic cancer cells were investigated using cell proliferation, apoptosis, and anchorage-independent growth assays. The Wilcoxon signed-rank, Pearson correlation coefficient, Kendall's Tau, Spearman's Rho, and an independent two-sample t (two-tailed) test were used to determine the statistical significance of the data.ResultsImmunohistochemistry studies in pancreatic tumor tissues revealed YAP1 staining intensities were moderate to strong in the nucleus and cytoplasm of the tumor cells, whereas the adjacent normal epithelial showed negative to weak staining. In cultured cells, YAP1 expression and localization was modulated by cell density. YAP1 total protein expression increased in the nuclear fractions in BxPC-3 and PANC-1, while it declined in HPDE6 as cell density increased. Additionally, treatment of pancreatic cancer cell lines, BxPC-3 and PANC-1, with YAP1-targeting siRNA oligonucleotides significantly reduced their proliferation in vitro. Furthermore, treatment with YAP1 siRNA oligonucleotides diminished the anchorage-independent growth on soft agar of pancreatic cancer cells, suggesting a role of YAP1 in pancreatic cancer tumorigenesis.ConclusionsYAP1 is overexpressed in pancreatic cancer tissues and potentially plays an important role in the clonogenicity and growth of pancreatic cancer cells.
Highlights
As one of the most lethal forms of human disease, pancreatic cancer has a one-year and five-year survival rate of 26% and 6%, respectively [1]
Yes Associated Protein 1 (YAP1) is overexpressed in pancreatic ductal adenocarcinomas (PDA)
The YAP1 antibody showed both nuclear and cytoplasmic staining, which is consistent with the known cellular function of YAP1 protein – YAP1 is localized in cytoplasm when it is inactivated and it is translocated into nucleus when activated
Summary
As one of the most lethal forms of human disease, pancreatic cancer has a one-year and five-year survival rate of 26% and 6%, respectively [1]. The Hippo pathway regulates organ size by inhibiting cell proliferation and promotes cell apoptosis [2,3]. Components of Hippo pathway were identified in genetic mosaic screens in Drosophila, which consist of the Hippo (Hpo) kinase, the Salvador (Sav) adaptor protein, the Wts protein kinase, the Mats adaptor protein, and the Yorkie (Yki) nuclear transcriptional co-activator. The components of the Hippo pathway are highly conserved homologs, which include MST1/2 (Hpo), WW45 (Sav), LATS1/2 (Wts), MOB1 (Mats), and YAP1 (Yki) [4,5,6,7,8]. The Hippo pathway regulates organ size by inhibiting cell proliferation and promoting cell apoptosis upon its activation. The YAP1 gene was reported as amplified and over-expressed in several tumor types
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