Reference - Detail
| RRC ID | 37545 |
|---|---|
| Author | Zhu S, Chen Z, Katsha A, Hong J, Belkhiri A, El-Rifai W. |
| Title | Regulation of CD44E by DARPP-32-dependent activation of SRp20 splicing factor in gastric tumorigenesis. |
| Journal | Oncogene |
| Abstract |
CD44E is a frequently overexpressed variant of CD44 in gastric cancer. Mechanisms that regulate CD44 splicing and expression in gastric cancer remain unknown. Herein, we investigated the role of DARPP-32 (dopamine and cyclic adenosine monophosphate-regulated phosphoprotein, Mr 32000) in promoting tumor growth through regulation of CD44 splicing. Using western blot and quantitative real-time PCR analysis, our results indicated that knockdown of endogenous DARPP-32 markedly reduces the expression of CD44 V8-V10 (CD44E). Using a quantitative splicing luciferase reporter system, we detected a significant increase in the reporter activity following DARPP-32 overexpression (P<0.001). Conversely, knocking down endogenous DARPP-32 significantly attenuated the splicing activity (P<0.001). Further experiments showed that DARPP-32 regulates the expression of SRp20 splicing factor and co-exists with it in the same protein complex. Inhibition of alternative splicing with digitoxin followed by immunoprecipitation and immunoblotting indicated that DARPP-32 has an important role in regulating SRp20 protein stability. The knockdown of endogenous DARPP-32 confirmed that DARPP-32 regulates the SRp20-dependent CD44E splicing. Using tumor xenograft mouse model, knocking down endogenous DARPP-32 markedly reduced SRp20 and CD44E protein levels with a decreased tumor growth. The reconstitution of SRp20 expression in these cells rescued tumor growth. In addition, we also demonstrated frequent co-overexpression and positive correlation of DARPP-32, SRp20 and CD44E expression levels in human gastric primary tumors. Our novel findings establish for the first time the role of DARPP-32 in regulating splicing factors in gastric cancer cells. The DARPP-32-SRp20 axis has a key role in regulating the CD44E splice variant that promotes gastric tumorigenesis. |
| Volume | 35(14) |
| Pages | 1847-56 |
| Published | 2016-4-7 |
| DOI | 10.1038/onc.2015.250 |
| PII | onc2015250 |
| PMID | 26119931 |
| PMC | PMC4486340 |
| MeSH | Alternative Splicing / genetics Animals Carcinogenesis / genetics* Cell Line, Tumor Cell Proliferation Dopamine and cAMP-Regulated Phosphoprotein 32 / genetics* Gene Expression Regulation, Neoplastic Humans Hyaluronan Receptors / biosynthesis Hyaluronan Receptors / genetics* Mice RNA-Binding Proteins / biosynthesis RNA-Binding Proteins / genetics* Serine-Arginine Splicing Factors Signal Transduction / genetics Stomach Neoplasms / genetics* Stomach Neoplasms / pathology Xenograft Model Antitumor Assays |
| IF | 7.971 |
| Times Cited | 10 |
| WOS Category | GENETICS & HEREDITY ONCOLOGY BIOCHEMISTRY & MOLECULAR BIOLOGY CELL BIOLOGY |
| Altmetric score |
オルトメトリクス指標項目
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| The most frequently cited source | X(Twitter) |
| Total number of mentions | 3 |
| Altmetric score changes over past 6months | 0.0 |
| Resource | |
| Human and Animal Cells | MKN45(RCB1001) |