LARG at chromosome 11q23 has functional characteristics of a tumor suppressor in human breast and colorectal cancer

Abstract

Deletion of 11q23-q24 is frequent in a diverse variety of malignancies, including breast and colorectal carcinoma, implicating the presence of a tumor suppressor gene at that chromosomal region. We examined a 6-Mb region on 11q23 by high-resolution deletion mapping, using both loss of heterozygosity analysis and customized microarray comparative genomic hybridization. LARG (leukemiaassociated Rho guanine-nucleotide exchange factor) (also called ARHGEF12), identified from the analysed region, is frequently underexpressed in breast and colorectal carcinomas with a reduced expression observed in all breast cancer cell lines (n ¼ 11), in 12 of 38 (32%) primary breast cancers, 5 of 10 (50%) colorectal cell lines and in 20 of 37 (54%) primary colorectal cancers. Underexpression of the LARG transcript was significantly associated with genomic loss (P ¼ 0.00334). Hypermethylation of the LARG promoter was not detected in either breast or colorectal cancer, and treatment of four breast and four colorectal cancer cell lines with 5-aza-2 0 -deoxycytidine and/or trichostatin A did not result in a reactivation of LARG. Enforced expression of LARG in breast and colorectal cancer cells by stable transfection resulted in reduced cell proliferation and colony formation, as well as in a markedly slower cell migration rate in colorectal cancer cells, providing functional evidence for LARG as a candidate tumor suppressor gene.

Gα13/PDZ-RhoGEF/RhoA Signaling Is Essential for Gastrin-Releasing Peptide Receptor–Mediated Colon Cancer Cell Migration

“…In contrast to elevated expression of p115 in prostate cancer, LARG expression in breast and colon cancers is reported to be decreased. In these cancers, LARG has been reported to act as a tumor suppressor (Ong et al, 2009). Loss of LARG expression in breast and colon cancer is also supported by data that shows that there is loss of gene copy number of LARG in these solid tumors.…”

γH2AX as a molecular marker of aging and disease

“…[33][34][35][36][37] H2AX has tumor-suppressor capabilities and deficiency of the H2AFX gene promotes tumor growth and development. 38,39 This is consistent with the fact that numerous other DDR genes are located at the distal q arm including, ATM and meiotic recombination 11 (MRE11). 40 Therefore, loss of the region severely compromises the DDR, resulting in chromosomal instability and carcinogenesis.…”

Endomembrane control of cell polarity: Relevance to cancer

“…Therefore, the mechanism by which they regulate the Golgi pool of Cdc42 must be a different one that still needs to be resolved. ARHGEF12 (also known as LARG) was previously reported to act as a tumor suppressor in human breast and colorectal cancer (22). Testing the role of these GEFs in cancer, in the context of spatial Cdc42 signaling represents and exciting future research area.…”