Cell context-dependent dual effects of EFEMP1 stabilizes subpopulation equilibrium in responding to changes of in vivo growth environment
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Yuanjie Hu1,*, Chao Ke2,3,*, Ning Ru2, Yumay Chen4, Liping Yu5, Eric R. Siegel6, Mark E. Linskey2, Ping Wang4 and Yi-Hong Zhou1,2
1 Department of Biological Chemistry, University of California Irvine, Irvine, CA, USA
2 Department of Surgery, University of California Irvine, Irvine, CA, USA
3 State Key Laboratory of Oncology in South China and Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, China
4 UC Irvine Diabetes Center and Department of Medicine, University of California Irvine, Irvine, CA, USA
5 Ziren Research LLC, Irvine, CA, USA
6 Department of Biostatistics, University of Arkansas for Medical Sciences, Little Rock, AR, USA
* These authors have contributed equaly to this work
Yi-Hong Zhou, email:
Keywords: EFEMP1, glioma, tumor cell subpopulations, cell invasiveness, mitochondria respiration, tumor subpopulation equilibrium
Received: May 01, 2015 Accepted: August 08, 2015 Published: August 19, 2015
Conflicting functions of EFEMP1 in cancer have been reported. Using two syngeneic glioma cell lines (U251 and U251-NS) carrying two different principal cell subpopulations that express high or low EGFR, and that are able to interconvert via mis-segregation of chromosome 7 (Chr7), we studied EFEMP1’s cell-context-dependent functions in regulating subpopulation equilibrium, here defined by the percentage of cells carrying different copies of Chr7. We found that EFEMP1 attenuated levels of EGFR and cellular respiration in high-EGFR-expressing cells, but increased levels of NOTCH1, MMP2, cell invasiveness, and both oxidative phosphorylation and glycolytic respiration in low-EGFR-expressing cells. Consistently, EFEMP1 suppressed intracranial xenograft formation in U251 and promoted its formation in U251-NS. Interestingly, subpopulation equilibria in xenografts of U251-NS without EFEMP1 overexpression were responsive to inoculum size (1, 10 and 100 thousand cells), which may change the tumor-onset environment. It was not observed in xenografts of U251-NS with EFEMP1 overexpression. The anti-EGFR function of EFEMP1 suppressed acceleration of growth of U251-NS, but not the subpopulation equilibrium, when serially passed under a different (serum-containing adherent) culture condition. Overall, the data suggest that the orthotopic environment of the brain tumor supports EFEMP1 in carrying out both its anti-EGFR and pro-invasive/cancer stem cell-transforming functions in the two glioma cell subpopulations during formation of a single tumor, where EFEMP1 stabilizes the subpopulation equilibrium in response to alterations of the growth environment. This finding implies that EFEMP1 may restrain cancer plasticity in coping with ever-changing tumor microenvironments and/or therapeutic-intervention stresses.
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