Click
here to close Hello! We notice that
you are using Internet Explorer, which is not supported by Echinobase
and may cause the site to display incorrectly. We suggest using a
current version of Chrome,
FireFox,
or Safari.
Oncotarget
2017 Mar 07;810:16356-16366. doi: 10.18632/oncotarget.14633.
Show Gene links
Show Anatomy links
Stiehopus japonieus acidic mucopolysaccharide inhibits the proliferation of pancreatic cancer SW1990 cells through Hippo-YAP pathway.
Li X
,
Liu Y
,
Zhang C
,
Niu Q
,
Wang H
,
Che C
,
Xie M
,
Zhou B
,
Xu Y
,
Zhang Q
,
Wu J
,
Tian Z
.
???displayArticle.abstract???
Previous studies have indicated that stiehopus japonieus acidic mucopolysaccharide (SJAMP) could inhibit the proliferation of pancreatic cancer cell SW1990. However, the mechanism remains unclear. In our study, YAP expression was identified by immunohistochemistry and quantitative Real-time PCR from 45 pairs of human pancreatic ductal adenocarcinoma (PDAC) tissues and their adjacent non-tumor samples. We found that the YAP expression was associated with the histological differentiation degree, and negatively correlated with pancreatic cancer patients'' survival. More YAP localization in nuclear and enhanced expression of YAP mRNA in pancreatic cancer tissue was found in comparison with in the normal tissue. These results identify YAP acts as an amazing regulator in the pathogenesis of pancreatic cancer. After affected by SJAMP, YAP and TEAD1 were down regulated, while MST1 and pYAP were upregulated gradually with the prolong of effect time. SJAMP also improved YAP phosphorylation, nuclear-to-cytoplasmic translocation and inactivation. After successfully knocked-down by YAP siRNA, the inhibition of proliferation of SJAMP to cancer cells was attenuated. Interestingly, we indicated a down-regulation of that TEAD with SJAMP 4 mg/ml, 8 mg/ml for 24 h and with 8 mg/ml SJAMP for 24 h, 48 h even after YAP silencing. That might mean that the SJAMP has other targets, not only YAP, to downregulate TEAD. We proposed a hypothesis that Hippo-YAP pathway involved in carcinogenesis of pancreatic cancer and in the inhibition effect of SJAMP to the proliferation of pancreatic cancer cell, although maybe not the sole signaling pathway.
Figure 1. The expressions of YAP in pancreatic cancer tissues are stronger than in normal pancreatic tissues and SJAMP Inhibits the proliferation of SW1990(A) 1: in normal pancreas tissues, weak, mainly located in cytoplasm (200×). 2: in normal pancreas tissues (400×). 3: in pancreatic cancer with high and middle differentiation degree, stronger than that in normal pancreatic tissue, and was located in cytoplasm and nucleus (200×). 4: in pancreatic cancer with high and middle differentiation degree (400×). 5: in pancreatic cancer with low differentiation degree was stronger than that of high and middle differentiation degree, and was located in cytoplasm and nucleus (200×). 6: in pancreatic cancer with low differentiation degree (400×). (B) The relative expression of YAP mRNA in PDAC elevated, which was 9.4 times compared to that in the normal tissues (0.3685 ± 0.029 vs 0.03908 ± 0.0024, p < 0.001). (C) Kaplan–Meier analysis showing that with high YAP level had shorter lifetime than those with low YAP level (p < 0.05). (D) SJAMP inhibits SW1990 cell proliferation gradually with the increase of effect dose and the prolong of effect time. (p < 0.05). (E) After successfully knocked-down by YAP siRNA, the inhibition of proliferation of SJAMP to cancer cells was attenuated (p < 0.05).
Figure 2. Downregulation of YAP by SJAMP contributes to inhibition pancreatic cancer cells growth(A) With the prolong of effect time of 8 mg/ml SJAMP on the pancreatic cancer cells, the expression level of YAP, TEAD1, survivin mRNA decreased significantly, and the expression level of Caspase-9, MST1 mRNA increased significantly. (B) The same tendency was observed when effected by SJAMP in different dose. (C) and (D) After affected by SJAMP, the protein level of YAP decreased and the protein level of pYAP increased obviously. *p < 0.05, **p < 0.01.
Figure 3. SJAMP improved the phosphorylation of YAP to inhibit the proliferation of pancreatic cancer cells(A) The result of immunofluorescence analysis also indicated that after effected by SJAMP, there is a nuclear-to-cytoplasmic translocation of YAP. (B) A downstream target gene, TEAD, is downregulated with YAP silencing. (C–D) YAP silencing also resulted in a decrease in TEAD, with SJAMP 4 mg/ml, 8 mg/ml for 24 h (*p < 0.05,**p < 0.01). (E–F) YAP silencing also resulted in a decrease in TEAD, with 8 mg/ml SJAMP for 24 h, 48 h (**p < 0.01). These results might mean that the SJAMP has other targets, not only YAP, to downregulate TEAD.
Bai,
Expression of Yes-associated protein modulates Survivin expression in primary liver malignancies.
2012, Pubmed
Bai,
Expression of Yes-associated protein modulates Survivin expression in primary liver malignancies.
2012,
Pubmed
Basso,
Cytotoxic effects of zoledronic acid on human epithelial cells and gingival fibroblasts.
2013,
Pubmed
Basu,
Akt phosphorylates the Yes-associated protein, YAP, to induce interaction with 14-3-3 and attenuation of p73-mediated apoptosis.
2003,
Pubmed
Blanpain,
Tracing the cellular origin of cancer.
2013,
Pubmed
Cabrera,
Phenocopies induced with antisense RNA identify the wingless gene.
1987,
Pubmed
Chen,
Serum CA242, CA199, CA125, CEA, and TSGF are Biomarkers for the Efficacy and Prognosis of Cryoablation in Pancreatic Cancer Patients.
2015,
Pubmed
Chen,
Cancer statistics in China, 2015.
2016,
Pubmed
Collins,
Kras as a key oncogene and therapeutic target in pancreatic cancer.
2013,
Pubmed
Craven,
A decade of tyrosine kinases: from gene discovery to therapeutics.
2003,
Pubmed
Fernandez-L,
Oncogenic YAP promotes radioresistance and genomic instability in medulloblastoma through IGF2-mediated Akt activation.
2012,
Pubmed
Ferretti,
[TNM classification of malignant tumours, VII edition 2009. Changes and practical effects on cancer epidemiology].
2010,
Pubmed
Fitamant,
YAP Inhibition Restores Hepatocyte Differentiation in Advanced HCC, Leading to Tumor Regression.
2015,
Pubmed
Gao,
Hippo signaling regulates differentiation and maintenance in the exocrine pancreas.
2013,
Pubmed
Greaves,
Clonal evolution in cancer.
2012,
Pubmed
He,
Advances in pancreatic cancer research: moving towards early detection.
2014,
Pubmed
Hermeking,
The 14-3-3 cancer connection.
2003,
Pubmed
Huang,
YAP modifies cancer cell sensitivity to EGFR and survivin inhibitors and is negatively regulated by the non-receptor type protein tyrosine phosphatase 14.
2013,
Pubmed
Huang,
The Hippo signaling pathway coordinately regulates cell proliferation and apoptosis by inactivating Yorkie, the Drosophila Homolog of YAP.
2005,
Pubmed
Hwang,
Structural insight into dimeric interaction of the SARAH domains from Mst1 and RASSF family proteins in the apoptosis pathway.
2007,
Pubmed
Kohno,
Targeting the ERK signaling pathway in cancer therapy.
2006,
Pubmed
Long,
Cancer statistics: current diagnosis and treatment of pancreatic cancer in Shanghai, China.
2014,
Pubmed
Lu,
The effects of Stichopus japonicus acid mucopolysaccharide on the apoptosis of the human hepatocellular carcinoma cell line HepG2.
2010,
Pubmed
,
Echinobase
Merlo,
Cancer as an evolutionary and ecological process.
2006,
Pubmed
Momi,
Interplay between smoking-induced genotoxicity and altered signaling in pancreatic carcinogenesis.
2012,
Pubmed
Nusse,
Many tumors induced by the mouse mammary tumor virus contain a provirus integrated in the same region of the host genome.
1982,
Pubmed
Ota,
Mammalian Tead proteins regulate cell proliferation and contact inhibition as transcriptional mediators of Hippo signaling.
2008,
Pubmed
Pan,
The hippo signaling pathway in development and cancer.
2010,
Pubmed
Piagnerelli,
Clinical value and impact on prognosis of peri-operative CA 19-9 serum levels in stage I and II adenocarcinoma of the pancreas.
2016,
Pubmed
Romano,
Protein interaction switches coordinate Raf-1 and MST2/Hippo signalling.
2014,
Pubmed
Siegel,
Cancer statistics, 2015.
2015,
Pubmed
Song,
Hippo coactivator YAP1 upregulates SOX9 and endows esophageal cancer cells with stem-like properties.
2014,
Pubmed
Song,
Mammalian Mst1 and Mst2 kinases play essential roles in organ size control and tumor suppression.
2010,
Pubmed
Wang,
Yes-associated protein (YAP) expression is involved in epithelial-mesenchymal transition in hepatocellular carcinoma.
2016,
Pubmed
Yu,
Adhesion glycoprotein CD44 functions as an upstream regulator of a network connecting ERK, AKT and Hippo-YAP pathways in cancer progression.
2015,
Pubmed
Zeng,
The emerging role of the hippo pathway in cell contact inhibition, organ size control, and cancer development in mammals.
2008,
Pubmed
Zhang,
Meta-analysis of diagnostic value of serum Carbohydrate antigen 199 in pancreatic cancer.
2016,
Pubmed
Zhang,
YAP-dependent induction of amphiregulin identifies a non-cell-autonomous component of the Hippo pathway.
2009,
Pubmed
Zhang,
The Roles of ROS and Caspases in TRAIL-Induced Apoptosis and Necroptosis in Human Pancreatic Cancer Cells.
2015,
Pubmed
Zhao,
TEAD mediates YAP-dependent gene induction and growth control.
2008,
Pubmed
Zhao,
Cell detachment activates the Hippo pathway via cytoskeleton reorganization to induce anoikis.
2012,
Pubmed
Zhao,
The Hippo-YAP pathway: new connections between regulation of organ size and cancer.
2008,
Pubmed
Zhao,
Inactivation of YAP oncoprotein by the Hippo pathway is involved in cell contact inhibition and tissue growth control.
2007,
Pubmed