Abstract
The cell adhesion molecule with homology to L1CAM (close homolog of L1) (CHL1) is a member of the cell adhesion molecule L1 (L1CAM) gene family. Although CHL1 expression and function have been reported in several tumors, the roles of CHL1 in the development of glioma remain unclear. In the present study, we investigated the effects of CHL1 on proliferation indexes and activation of Akt1 and Erk signaling by siRNA in U-87 MG human glioblastoma and human U251 and SHG-44 glioma cells. We found that siRNA targeting CHL1 significantly down-regulated the expression of CHL1 mRNA and protein accompanied by reduced cell proliferation and transmigration invasion in all three cell lines. Down-regulating CHL1 expression also reduced cell survival, as measured by the Bax/Bcl-2 ratio, and increased activation of caspase-3. In subcutaneous U-87 MG cell xenograft tumors in nude mice, intratumoral administration of siRNA targeting CHL1 treatment significantly down-regulated CHL1 expression in vivo, accompanied by increased levels of activated caspase-3. Our combined results confirmed for the first time that in contrast to findings about CHL1 in most other cancer types, CHL1 functions in promoting cell proliferation, metastasis and migration in human glioma cells both in vitro and in vivo. These results indicate that CHL1 is a therapeutic target in the clinical management of glioma/glioblastoma.
Highlights
Gliomas are a set of highly invasive glial cell-derived tumors that originate in the central nervous system, and they account for 40% to 50% of all intracranial tumors (Gabriel et al, 2014)
We found that 48 h post transfection, pAkt/AKT levels were significantly decreased in three cell adhesion molecule L1 (CHL1) siRNA-transfected human glioma cell lines compared with cells transfected with negative control siRNA (p < 0.05 for both comparisons in both SHG44 and U-87 MG cells and p < 0.01 for both comparisons in U251 cells (Figure 8)
Inhibition of L1 expression by siRNA and administration of L1 ectodomain-binding antibodies reduced the migration of glioblastoma cells in vitro (Izumoto et al, 1996) and disrupted glioma stem cell proliferation, leading to apoptosis (Bao et al, 2008)
Summary
Gliomas are a set of highly invasive glial cell-derived tumors that originate in the central nervous system, and they account for 40% to 50% of all intracranial tumors (Gabriel et al, 2014). Patients with lowly differentiated astroglioma and glioblastoma exhibit high recurrence, high mortality and low cure rates, and the 5-year survival rate remains less than 5% (Sathornsumetee et al, 2007; Nakazato, 2008; Jemal et al, 2010). All these clinical data suggest that the development of glioma is a multifactor-based process in which a series of molecules are involved. The close homolog of cell adhesion molecule L1 (CHL1) belongs to the transmembrane adhesion molecule
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