CD151-α3β1 integrin complexes are prognostic markers of glioblastoma and cooperate with EGFR to drive tumor cell motility and invasion

// Pengcheng Zhou 1, * , Sonia Erfani 2, * , Zeyi Liu 2, 3, * , Changhe Jia 2, 4, * , Yecang Chen 5, * , Bingwei Xu 2 , Xinyu Deng 2 , Jose E. Alfaro 1 , Li Chen 2 , Dana Napier 6 , Michael Lu 8 , Jian-An Huang 3 , Chunming Liu 7 , Olivier Thibault 2 , Rosalind Segal 1 , Binhua P. Zhou 7 , Natasha Kyprianou 9 , Craig Horbinski 6, # , Xiuwei H. Yang 2, # 1 Department of Cancer Biology and Pediatric Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA 2 Department of Pharmacology and Nutritional Sciences, Markey Cancer Center and University of Kentucky, Lexington, KY, USA 3 Department of Respiratory Medicine, First Affiliated Hospital of Soochow University, Suzhou, Jiangsu Province, P. R. China 4 Department of Gastroenterology, Provincial People's Hospital, Zhengzhou, Henan Province, P. R. China 5 Department of Chemistry, University of Kentucky, Lexington, KY, USA 6 Department of Pathology and Laboratory Medicine, Markey Cancer Center and University of Kentucky, Lexington, KY, USA 7 Department of Molecular and Cellular Biochemistry, Markey Cancer Center and University of Kentucky, Lexington, KY, USA 8 Department of Biomedical Science, Florida Atlantic University, Boca Raton, FL, USA 9 Department of Urology, Markey Cancer Center and University of Kentucky, Lexington, KY, USA * These authors have contributed equally to this study # Co-equal contribution Correspondence to: Xiuwei H. Yang, email: xiuwei-yang@uky.edu Craig Horbinski, email: craig.horbinski@uky.edu Keywords: glioblastoma, CD151, α3 integrin, EGFR, cell invasion and motility Received: May 23, 2015 Accepted: August 03, 2015 Published: August 13, 2015 ABSTRACT 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.