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LRRC4 inhibits human glioblastoma cells proliferation, invasion, and proMMP‐2 activation by reducing SDF‐1α/CXCR4‐mediated ERK1/2 and Akt signaling pathways
Author(s) -
Wu Minghua,
Chen Qiong,
Li Dan,
Li Xiaoling,
Li Xiayu,
Huang Chen,
Tang Yunlian,
Zhou Yanhong,
Wang Di,
Tang Ke,
Cao Li,
Shen Shourong,
Li Guiyuan
Publication year - 2007
Publication title -
journal of cellular biochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.028
H-Index - 165
eISSN - 1097-4644
pISSN - 0730-2312
DOI - 10.1002/jcb.21400
Subject(s) - protein kinase b , signal transduction , cancer research , cxcl14 , microbiology and biotechnology , pi3k/akt/mtor pathway , biology , cell growth , mapk/erk pathway , cxcr4 , chemokine receptor , chemokine , receptor , biochemistry
Gliomas take a number of different genetic routes in the progression to glioblastoma multiforme, a highly invasive variant that is mostly unresponsive to current therapies. The α‐chemokine stromal cell‐derived factor (SDF)‐1α binds to the seven transmembrane G‐protein‐coupled CXCR‐4 receptor and acts to modulate cell migration and proliferation by activating multiple signal transduction pathways. Leucine‐rich repeats containing 4 (LRRC4), a putative glioma suppressive gene, inhibits glioblastoma cells tumorigenesis in vivo and cell proliferation and invasion in vitro. We also previously demonstrated that LRRC4 controlled glioblastoma cells proliferation by ERK/AKT/NF‐κB signaling pathway. In the present study, we demonstrate that CXC chemokine receptor 4 (CXCR4) is expressed in human glioblastoma U251 cell line, and that SDF‐1α increases the proliferation, chemotaxis, and invasion in CXCR4 + glioblastoma U251 cells through the activation of ERK1/2 and Akt. The reintroduction of LRRC4 in U251 cells inhibits the expression of CXCR4 and SDF‐1α/CXCR4 axis‐mediated downstream intracellular pathways such as ERK1/2 and Akt leading to proliferate, chemotactic and invasive effects. Furthermore, we provide evidence for proMMP‐2 activation involvement in the SDF‐1α/CXCR4 axis‐mediated signaling pathway. LRRC4 significantly inhibits proMMP‐2 activation by SDF‐1α/CXCR4 axis‐mediated ERK1/2 and Akt signaling pathway. Collectively, these results suggest a possible important “cross‐talk” between LRRC4 and SDF‐1α/CXCR4 axis‐mediated intracellular pathways that can link signals of cell proliferation, chemotaxis and invasion in glioblastoma, and may represent a new target for development of new therapeutic strategies in glioma. J. Cell. Biochem. 103: 245–255, 2008. © 2007 Wiley‐Liss, Inc.