CD151-α3β1 integrin complexes are prognostic markers of glioblastoma and cooperate with EGFR to drive tumor cell motility and invasion
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Pengcheng Zhou1,*, Sonia Erfani2,*, Zeyi Liu2,3,*, Changhe Jia2,4,*, Yecang Chen5,*, Bingwei Xu2, Xinyu Deng2, Jose E. Alfáro1, Li Chen2, Dana Napier6, Michael Lu8, Jian-An Huang3, Chunming Liu7, Olivier Thibault2, Rosalind Segal1, Binhua P. Zhou7, Natasha Kyprianou9, Craig Horbinski6,#, Xiuwei H. Yang2,#
1Department of Cancer Biology and Pediatric Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA
2Department of Pharmacology and Nutritional Sciences, Markey Cancer Center and University of Kentucky, Lexington, KY, USA
3Department of Respiratory Medicine, First Affiliated Hospital of Soochow University, Suzhou, Jiangsu Province, P. R. China
4Department of Gastroenterology, Provincial People's Hospital, Zhengzhou, Henan Province, P. R. China
5Department of Chemistry, University of Kentucky, Lexington, KY, USA
6Department of Pathology and Laboratory Medicine, Markey Cancer Center and University of Kentucky, Lexington, KY, USA
7Department of Molecular and Cellular Biochemistry, Markey Cancer Center and University of Kentucky, Lexington, KY, USA
8Department of Biomedical Science, Florida Atlantic University, Boca Raton, FL, USA
9Department of Urology, Markey Cancer Center and University of Kentucky, Lexington, KY, USA
*These authors have contributed equally to this study
Xiuwei H. Yang, email: email@example.com
Craig Horbinski, email: firstname.lastname@example.org
Keywords: glioblastoma, CD151, α3 integrin, EGFR, cell invasion and motility
Received: May 23, 2015 Accepted: August 03, 2015 Published: August 13, 2015
Glioblastoma, one of the most aggressive forms of brain cancer, is featured by high tumor cell motility and invasiveness, which not only fuel tumor infiltration, but also enable escape from surgical or other clinical interventions. Thus, better understanding of how these malignant traits are controlled will be key to the discovery of novel biomarkers and therapies against this deadly disease. Tetraspanin CD151 and its associated α3β1 integrin have been implicated in facilitating tumor progression across multiple cancer types. How these adhesion molecules are involved in the progression of glioblastoma, however, remains largely unclear. Here, we examined an in-house tissue microarray-based cohort of 96 patient biopsies and TCGA dataset to evaluate the clinical significance of CD151 and α3β1 integrin. Functional and signaling analyses were also conducted to understand how these molecules promote the aggressiveness of glioblastoma at molecular and cellular levels. Results from our analyses showed that CD151 and α3 integrin were significantly elevated in glioblastomas at both protein and mRNA levels, and exhibited strong inverse correlation with patient survival (p < 0.006). These adhesion molecules also formed tight protein complexes and synergized with EGF/EGFR to accelerate tumor cell motility and invasion. Furthermore, disruption of such complexes enhanced the survival of tumor-bearing mice in a xenograft model, and impaired activation of FAK and small GTPases. Also, knockdown- or pharmacological agent-based attenuation of EGFR, FAK or Graf (ARHGAP26)/small GTPase-mediated pathways markedly mitigated the aggressiveness of glioblastoma cells. Collectively, our findings provide clinical, molecular and cellular evidence of CD151-α3β1 integrin complexes as promising prognostic biomarkers and therapeutic targets for glioblastoma.
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