title: CD151-α3β1 integrin complexes are prognostic markers of glioblastoma and cooperate with EGFR to drive tumor cell motility and invasion.
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.
authors.affiliation: Department of Cancer Biology and Pediatric Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA.
authors.forename: Pengcheng
authors.initials: P
authors.lastname: Zhou
authors.affiliation: Department of Pharmacology and Nutritional Sciences, Markey Cancer Center and University of Kentucky, Lexington, KY, USA.
authors.forename: Sonia
authors.initials: S
authors.lastname: Erfani
authors.affiliation: Department of Pharmacology and Nutritional Sciences, Markey Cancer Center and University of Kentucky, Lexington, KY, USA.|Department of Respiratory Medicine, First Affiliated Hospital of Soochow University, Suzhou, Jiangsu Province, P. R. China.
authors.forename: Zeyi
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Department of Pharmacology and Nutritional Sciences, Markey Cancer Center and University of Kentucky, Lexington, KY, USA.|Department of Gastroenterology, Provincial People's Hospital, Zhengzhou, Henan Province, P. R. China.
authors.forename: Changhe
authors.initials: C
authors.lastname: Jia
authors.affiliation: Department of Chemistry, University of Kentucky, Lexington, KY, USA.
authors.forename: Yecang
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Pharmacology and Nutritional Sciences, Markey Cancer Center and University of Kentucky, Lexington, KY, USA.
authors.forename: Bingwei
authors.initials: B
authors.lastname: Xu
authors.affiliation: Department of Pharmacology and Nutritional Sciences, Markey Cancer Center and University of Kentucky, Lexington, KY, USA.
authors.forename: Xinyu
authors.initials: X
authors.lastname: Deng
authors.affiliation: Department of Cancer Biology and Pediatric Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA.
authors.forename: Jose E
authors.initials: JE
authors.lastname: Alfáro
authors.affiliation: Department of Pharmacology and Nutritional Sciences, Markey Cancer Center and University of Kentucky, Lexington, KY, USA.
authors.forename: Li
authors.initials: L
authors.lastname: Chen
authors.affiliation: Department of Pathology and Laboratory Medicine, Markey Cancer Center and University of Kentucky, Lexington, KY, USA.
authors.forename: Dana
authors.initials: D
authors.lastname: Napier
authors.affiliation: Department of Biomedical Science, Florida Atlantic University, Boca Raton, FL, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Lu
authors.affiliation: Department of Respiratory Medicine, First Affiliated Hospital of Soochow University, Suzhou, Jiangsu Province, P. R. China.
authors.forename: Jian-An
authors.initials: JA
authors.lastname: Huang
authors.affiliation: Department of Molecular and Cellular Biochemistry, Markey Cancer Center and University of Kentucky, Lexington, KY, USA.
authors.forename: Chunming
authors.initials: C
authors.lastname: Liu
authors.affiliation: Department of Pharmacology and Nutritional Sciences, Markey Cancer Center and University of Kentucky, Lexington, KY, USA.
authors.forename: Olivier
authors.initials: O
authors.lastname: Thibault
authors.affiliation: Department of Cancer Biology and Pediatric Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA.
authors.forename: Rosalind
authors.initials: R
authors.lastname: Segal
authors.affiliation: Department of Molecular and Cellular Biochemistry, Markey Cancer Center and University of Kentucky, Lexington, KY, USA.
authors.forename: Binhua P
authors.initials: BP
authors.lastname: Zhou
authors.affiliation: Department of Urology, Markey Cancer Center and University of Kentucky, Lexington, KY, USA.
authors.forename: Natasha
authors.initials: N
authors.lastname: Kyprianou
authors.affiliation: Department of Pathology and Laboratory Medicine, Markey Cancer Center and University of Kentucky, Lexington, KY, USA.
authors.forename: Craig
authors.initials: C
authors.lastname: Horbinski
authors.affiliation: Department of Pharmacology and Nutritional Sciences, Markey Cancer Center and University of Kentucky, Lexington, KY, USA.
authors.forename: Xiuwei H
authors.initials: XH
authors.lastname: Yang
mesh_terms: D000818:Animals; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation / Q000235:genetics; D066246:ErbB Receptors / Q000378:metabolism*; D051417:Focal Adhesion Kinase 1 / Q000378:metabolism; D020690:GTPase-Activating Proteins / Q000378:metabolism; D005909:Glioblastoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D039201:Integrin alpha3beta1 / Q000235:genetics / Q000378:metabolism*; D007521:Isocitrate Dehydrogenase / Q000235:genetics; D008819:Mice, Nude; D009154:Mutation; D009361:Neoplasm Invasiveness; D011379:Prognosis; D034622:RNA Interference; D016019:Survival Analysis; D060185:Tetraspanin 24 / Q000235:genetics / Q000378:metabolism*; D046888:Tissue Array Analysis; D014183:Transplantation, Heterologous
chemical_list: C115971:ARHGAP26 protein, human; D014408:Biomarkers, Tumor; C554715:CD151 protein, human; D020690:GTPase-Activating Proteins; D039201:Integrin alpha3beta1; D060185:Tetraspanin 24; D007521:Isocitrate Dehydrogenase; C543588:IDH1 protein, human; D066246:ErbB Receptors; D051417:Focal Adhesion Kinase 1; C496050:PTK2 protein, human
keywords: CD151; EGFR; cell invasion and motility; glioblastoma; α3 integrin