Study of a novel brain relatively specific gene LRRC4 involved in glioma tumorigenesis suppression using the Tet-on
Qiu-Hong Zhang1, Li-Li Wang, Li Cao
1Cancer Research Institute, Central South University, Changsha 410078, China.
Abstract:
LRRC4 is a novel relatively specific gene, which displays significant down-regulation in primary brain tumor biopsies and has the potential to suppress brain tumor growth. In this study, we investigated the growth inhibitory effect of LRRC4 on tumorigencity in vivo and on cell proliferation in vitro by a tetracycline-inducible expression system. Results showed that LRRC4 significantly reduced the growth and malignant grade of xenografts arising from glioblastoma U251MG cells. Cell proliferation was markedly inhibited after U251MG Tet-on-LRRC4 cell induction with doxycycline. Flow cytometry and Western blot analysis demonstrated that LRRC4 mediated a delay of the cell cycle in late G1, possibly through up-regulating the expressions of p21Waf1/cip1 and p27Kip1 and down-regulating the expressions of cyclin-dependent kinase 2, retinoblastoma protein and epidermal growth factor receptors. Together, these findings provide clues to the function of LRRC4 as a negative regulator of cell growth and underscore a link between the above-mentioned cyclins, cyclin-associated molecules and tumorigenicity.
Insights
Leucine-rich repeat-containing 4 (LRRC4) gene suppresses brain tumor growth. Inducing LRRC4 in glioblastoma cells inhibited proliferation and delayed the cell cycle, suggesting its potential as a tumor suppressor.
Area of Science:
- Neuro-oncology
- Molecular Biology
- Genetics
Background:
- LRRC4 is a novel gene significantly downregulated in primary brain tumors.
- LRRC4 shows potential for suppressing brain tumor growth.
Purpose of the Study:
- To investigate the in vivo and in vitro effects of LRRC4 on tumor growth and cell proliferation.
- To elucidate the molecular mechanisms underlying LRRC4's potential tumor-suppressive function.
Main Methods:
- Utilized a tetracycline-inducible expression system to control LRRC4 levels in glioblastoma U251MG cells.
- Assessed tumor xenograft growth and malignant grade in vivo.
- Analyzed cell proliferation, cell cycle progression (flow cytometry), and protein expression (Western blot) in vitro.
Main Results:
- LRRC4 induction significantly reduced the growth and malignant grade of glioblastoma xenografts.
- LRRC4 markedly inhibited U251MG cell proliferation.
- LRRC4 mediated a G1 cell cycle delay, potentially via altered expression of p21Waf1/cip1, p27Kip1, cyclin-dependent kinase 2, retinoblastoma protein, and epidermal growth factor receptors.
Conclusions:
- LRRC4 functions as a negative regulator of cell growth.
- LRRC4's tumor-suppressive activity is linked to its modulation of cell cycle regulators and growth factor receptors.
- These findings highlight LRRC4's potential therapeutic relevance in brain tumors.
