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The MDA-9/Syntenin/IGF1R/STAT3 Axis Directs Prostate Cancer Invasion
- Source :
- Cancer Research. 78:2852-2863
- Publication Year :
- 2018
- Publisher :
- American Association for Cancer Research (AACR), 2018.
-
Abstract
- Although prostate cancer is clinically manageable during several stages of progression, survival is severely compromised once cells invade and metastasize to distant organs. Comprehending the pathobiology of invasion is required for developing efficacious targeted therapies against metastasis. Based on bioinformatics data, we predicted an association of melanoma differentiation-associated gene-9 [syntenin, or syndecan binding protein (SDCBP)] in prostate cancer progression. Using tissue samples from various Gleason stage prostate cancer patients with adjacent normal tissue, a series of normal prostate and prostate cancer cell lines (with differing tumorigenic/metastatic properties), mda-9/syntenin-manipulated variants (including loss-of-function and gain-of-function cell lines), and CRISPR/Cas9 stable MDA-9/Syntenin knockout cells, we now confirm the relevance of and dependence on MDA-9/syntenin in prostate cancer invasion. MDA-9/Syntenin physically interacted with insulin-like growth factor-1 receptor following treatment with insulin-like growth factor binding protein-2 (IGFBP2), regulating downstream signaling processes that enabled STAT3 phosphorylation. This activation enhanced expression of MMP2 and MMP9, two established enzymes that positively regulate invasion. In addition, MDA-9/syntenin-mediated upregulation of proangiogenic factors including IGFBP2, IL6, IL8, and VEGFA also facilitated migration of prostate cancer cells. Collectively, our results draw attention to MDA-9/Syntenin as a positive regulator of prostate cancer metastasis, and the potential application of targeting this molecule to inhibit invasion and metastasis in prostate cancer and potentially other cancers. Significance: This study provides new mechanistic insight into the proinvasive role of MDA-9/Syntenin in prostate cancer and has potential for therapeutic application to prevent prostate cancer metastasis. Cancer Res; 78(11); 2852–63. ©2018 AACR.
- Subjects :
- Male
STAT3 Transcription Factor
Vascular Endothelial Growth Factor A
0301 basic medicine
Cancer Research
MMP2
Carcinogenesis
Syntenins
Syndecan binding
Article
Receptor, IGF Type 1
Metastasis
03 medical and health sciences
Prostate cancer
0302 clinical medicine
Cell Movement
Prostate
Cell Line, Tumor
medicine
Animals
Humans
Neoplasm Invasiveness
Melanoma
Insulin-like growth factor 1 receptor
Interleukin-6
business.industry
Interleukin-8
Prostatic Neoplasms
Cancer
Cell Differentiation
Receptors, Somatomedin
medicine.disease
Gene Expression Regulation, Neoplastic
030104 developmental biology
medicine.anatomical_structure
Matrix Metalloproteinase 9
Oncology
030220 oncology & carcinogenesis
Cancer research
Matrix Metalloproteinase 2
business
Signal Transduction
Subjects
Details
- ISSN :
- 15387445 and 00085472
- Volume :
- 78
- Database :
- OpenAIRE
- Journal :
- Cancer Research
- Accession number :
- edsair.doi.dedup.....5ec5590926b7e8d863e57087b3ab0e25