TY - JOUR
T1 - CD151-'3β1 integrin complexes are prognostic markers of glioblastoma and cooperate with EGFR to drive tumor cell motility and invasion
AU - Zhou, Pengcheng
AU - Erfani, Sonia
AU - Liu, Zeyi
AU - Jia, Changhe
AU - Chen, Yecang
AU - Xu, Bingwei
AU - Deng, Xinyu
AU - Alfáro, Jose E.
AU - Chen, Li
AU - Napier, Dana
AU - Lu, Michael
AU - Huang, Jian An
AU - Liu, Chunming
AU - Thibault, Olivier
AU - Segal, Rosalind
AU - Zhou, Binhua P.
AU - Kyprianou, Natasha
AU - Horbinski, Craig
AU - Yang, Xiuwei H.
PY - 2015
Y1 - 2015
N2 - 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 '3β1 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 '3β1 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 '3 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-'3β1 integrin complexes as promising prognostic biomarkers and therapeutic targets for glioblastoma.
AB - 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 '3β1 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 '3β1 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 '3 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-'3β1 integrin complexes as promising prognostic biomarkers and therapeutic targets for glioblastoma.
KW - A3 integrin
KW - CD151
KW - Cell invasion and motility
KW - EGFR
KW - Glioblastoma
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U2 - 10.18632/oncotarget.4896
DO - 10.18632/oncotarget.4896
M3 - Article
C2 - 26377974
AN - SCOPUS:84945143875
SN - 1949-2553
VL - 6
SP - 29675
EP - 29693
JO - Oncotarget
JF - Oncotarget
IS - 30
ER -