LRRC4 Inhibits Glioma Cell Growth and Invasion Through a miR-185- Dependent Pathway

Abstract

Leucine-rich repeat (LRR) genes encode transmembrane proteins that are essential for normal brain development and are often dysregulated in central nervous system tumors. Leucine-rich repeat C4 (LRRC4) is a member of the LRR protein superfamily and specifically expressed in brain tissue. Importantly it acts as a tumor suppressor in the pathogenesis of malignant gliomas. However, the molecular mechanisms by which LRRC4 regulates glioma tumorigenesis are largely unknown. In this report, we found that miR-185 is markedly upregulated by LRRC4. We also found that miR-185 was downregulated in glioma, and overexpression of miR-185 inhibited glioma cell invasion. Low expressions of LRRC4 and miR-185 were associated with a poor outcome in glioma patients. Further investigation revealed that LRRC4 mediated its tumor suppressor function by regulating miR-185 targets CDC42 and RhoA. LRRC4 overexpression inhibited glioma cell invasion through miR-185-mediated CDC42 and RhoA direct regulation and VEGFA indirect regulation. Together, our findings suggest that the altered expression of the tumor suppressor LRRC4 may be an important event that leads to the dysregulation of miR-185 in human gliomas. LRRC4 and miR-185 may also be good prognostic markers and therapeutic targets in glioma.

Expression and clinical significance of LRRC4 in benign and malignant nasopharyngeal diseases

“…Our previous study showed methylation status before and after the development of a carcinoma in 3 cases of nasopharyngeal precancerous lesions; we found that there is substantial methylation of the LRRC4 gene promoter region after the development of nasopharyngeal carcinoma, and there is a large number of methylation peaks in the sequence. Studieson brain glioma also showed that aberrant methylation of the LRRC4 promoter is an important mechanism behind the lack of LRRC4 expression in glioma cells (Zhang et al, 2009;Tang et al, 2012). The present result suggests that the substantial methylation of the upstream region of the LRRC4 promoter abrogates the LRRC4 expression in nasopharyngeal carcinoma.…”

MicroRNA-185 suppresses growth and invasion of colon cancer cells through inhibition of the hypoxia-inducible factor-2α pathway in vitro and in vivo

“…Low expression of miR-185 is also associated with a poor outcome in glioma patients. miR-185 was found to suppress glioma cell invasion, indicating that it may be a potential prognostic marker and therapeutic target (16). Previous studies have revealed that miR-185 impedes anchorage-independent growth, cell migration and invasion, in addition to suppressing tumor growth in vivo and increasing cisplatin sensitivity by promoting apoptosis, implicating it as a potent tumor suppressor (17)(18)(19).…”

miR-200b and miR-200c as Prognostic Factors and Mediators of Gastric Cancer Cell Progression

“…ISH procedures were carried out as previously described (20). miR-200b and miR-200c miRCURY LNA custom detection probes (Exiqon) were used for ISH.…”

“…The cell invasion assay was conducted as described previously (20). Briefly, cells were seeded onto the basement membrane matrix present in the insert of a 24-well culture plate (EC matrix; Chemicon).…”