CXCR2 promotes ovarian cancer growth through dysregulated cell cycle, diminished apoptosis, and enhanced angiogenesis.
Abstract | PURPOSE: EXPERIMENTAL DESIGN: CXCR2 expression was silenced by stable small hairpin RNA in ovarian cancer cell lines T29Gro-1, T29H, and SKOV3. Western blotting, immunofluorescence, enzyme-linked immunosorbent assay, flow cytometry, electrophoretic mobility shift assay, and mouse assay were used to detect CXCR2, interleukin-8, Gro-1, cell cycle, apoptosis, DNA binding of NF-kappaB, and tumor growth. Immunohistochemical staining of CXCR2 was done in 240 high-grade serous ovarian carcinoma samples. RESULTS: Knockdown of CXCR2 expression by small hairpin RNA reduced tumorigenesis of ovarian cancer cells in nude mice. CXCR2 promoted cell cycle progression by modulating cell cycle regulatory proteins, including p21 (waf1/cip1), cyclin D1, CDK6, CDK4, cyclin A, and cyclin B1. CXCR2 inhibited cellular apoptosis by suppressing phosphorylated p53, Puma, and Bcl-xS; suppressing poly(ADP-ribose) polymerase cleavage; and activating Bcl-xL and Bcl-2. CXCR2 stimulated angiogenesis by increasing levels of vascular endothelial growth factor and decreasing levels of thrombospondin-1, a process likely involving mitogen-activated protein kinase, and NF-kappaB. Overexpression of CXCR2 in high-grade serous ovarian carcinomas was an independent prognostic factor of poor overall survival (P < 0.001) and of early relapse (P = 0.003) in the univariate analysis. CONCLUSIONS:
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Authors | Gong Yang, Daniel G Rosen, Guangzhi Liu, Fan Yang, Xiaoqing Guo, Xue Xiao, Fengxia Xue, Imelda Mercado-Uribe, Jiaoti Huang, Sue-Hwa Lin, Gordon B Mills, Jinsong Liu |
Journal | Clinical cancer research : an official journal of the American Association for Cancer Research
(Clin Cancer Res)
Vol. 16
Issue 15
Pg. 3875-86
(Aug 01 2010)
ISSN: 1557-3265 [Electronic] United States |
PMID | 20505188
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
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Copyright | (c) 2010 AACR. |
Chemical References |
- Biomarkers, Tumor
- Receptors, Interleukin-8B
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Topics |
- Animals
- Apoptosis
(genetics)
- Biomarkers, Tumor
(analysis)
- Blotting, Western
- Cell Cycle
(genetics)
- Cell Line, Tumor
- Cell Separation
- Cystadenocarcinoma, Serous
(genetics, metabolism, pathology)
- Electrophoretic Mobility Shift Assay
- Enzyme-Linked Immunosorbent Assay
- Female
- Flow Cytometry
- Fluorescent Antibody Technique
- Humans
- Immunohistochemistry
- Kaplan-Meier Estimate
- Mice
- Mice, Nude
- Neovascularization, Pathologic
(genetics, metabolism, pathology)
- Ovarian Neoplasms
(blood supply, genetics, metabolism, pathology)
- Prognosis
- Receptors, Interleukin-8B
(genetics, metabolism)
- Signal Transduction
(physiology)
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