Cyr61 Mediates Hepatocyte Growth Factor–Dependent Tumor Cell Growth, Migration, and Akt Activation
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Abstract
Certain tumor cell responses to the growth factor–inducible early response gene product CCN1/Cyr61 overlap with those induced by the hepatocyte growth factor (HGF)/c-Met signaling pathway. In this study, we investigate if Cyr61 is a downstream effector of HGF/c-Met pathway activation in human glioma cells. A semiquantitative immunohistochemical analysis of 112 human glioma and normal brain specimens showed that levels of tumor-associated Cyr61 protein correlate with tumor grade (P < 0.001) and with c-Met protein expression (r2 = 0.4791, P < 0.0001). Purified HGF rapidly upregulated Cyr61 mRNA (peak at 30 minutes) and protein expression (peak at 2 hours) in HGF−/c-Met+ human glioma cell lines via a transcription- and translation-dependent mechanism. Conversely, HGF/c-Met pathway inhibitors reduced Cyr61 expression in HGF+/c-Met+ human glioma cell lines in vitro and in HGF+/c-Met+ glioma xenografts. Targeting Cyr61 expression with small interfering RNA (siRNA) inhibited HGF-induced cell migration (P < 0.01) and cell growth (P < 0.001) in vitro. The effect of Cyr61 on HGF-induced Akt pathway activation was also examined. Cyr61 siRNA had no effect on the early phase of HGF-induced Akt phosphorylation (Ser473) 30 minutes after stimulation with HGF. Cyr61 siRNA inhibited a second phase of Akt phosphorylation measured 12 hours after cell stimulation with HGF and also inhibited HGF-induced phosphorylation of the Akt target glycogen synthase kinase 3α. We treated preestablished subcutaneous glioma xenografts with Cyr61 siRNA or control siRNA by direct intratumoral delivery. Cyr61 siRNA inhibited Cyr61 expression and glioma xenograft growth by up to 40% in a dose-dependent manner (P < 0.05). These results identify a Cyr61-dependent pathway by which c-Met activation mediates cell growth, cell migration, and long-lasting signaling events in glioma cell lines and possibly astroglial malignancies. Cancer Res; 70(7); 2932–41
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CCN1 expression significantly correlates with stage, tumor size, lymph node positivity, and poor prognosis in several cancers, including breast cancer, prostate cancer, glioma, gastric adenocarcinoma, and squamous cell carcinoma.
“The clinical relevance of these observations is supported by the finding of a significant correlation between CCN1 expression and the stage, tumor size, lymph node positivity, and poor prognosis in several cancers, including breast cancer [142,145–148], prostate cancer [149], glioma [150], gastric adenocarcinoma [151], and squamous cell carcinoma [143].”
From CCN1/CYR61: the very model of a modern matricellular protein (2011) · cites this paper as [150]
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References 43 · Cited by 48
- Authors
- Goodwin, C. R., Lal, B., Zhou, X., Ho, S., Xia, S., Taeger, A., Murray, J., & Laterra, J.
- Affiliations
- Kennedy Krieger Institute (US)
- Corresponding author
- Laterra, John
- Venue
- Cancer Research
- Published
- 2010-03-31
- Volume
- 70
- Issue
- 7
- Pages
- 2932-2941
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- PMC
- PMC2848876
- OpenAlex
- W2083239458
- Cited by
- 48
- References
- 43
- Citations by year
- 2026: 1 · 2022: 1 · 2021: 3 · 2020: 3 · 2019: 2 · 2018: 6 · 2017: 3 · 2016: 5 · 2015: 3 · 2014: 7 · 2013: 3 · 2012: 5
- FWCI
- 1.83
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health
- National Cancer Institute (R01CA129192)
- National Institute of Neurological Disorders and Stroke (NS32148, R01NS043987, R01NS032148)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Connective Tissue Growth Factor Research
- Health Sciences › Medicine › Pathology and Forensic Medicine › Cancer Mechanisms and Therapy
- Health Sciences › Medicine › Genetics › Glioma Diagnosis and Treatment
- Keywords
- CYR61, hepatocyte growth factor, C-MET signaling, glioma, Akt phosphorylation, glycogen synthase kinase-3α, tumor cell migration, tumor cell proliferation, siRNA knockdown, glioma xenografts, tumor grade
- MeSH terms
- Animals, Antibodies, Monoclonal, Cell Movement, Enzyme Activation, Female, Glioma, Humans, Mice, Nude, Transfection, Signal Transduction, Hepatocyte Growth Factor, Proto-Oncogene Proteins c-met, Xenograft Model Antitumor Assays, RNA, Small Interfering, Cell Line, Tumor, Cell Growth Processes, Oncogene Protein v-akt, Mice, Cysteine-Rich Protein 61, Gene Knockdown Techniques
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