Reduced Expression of <i>GNA11</i> and Silencing of <i>MCT1</i> in Human Breast Cancers

Abstract

Alteration in the methylation status of a gene is often associated with its altered expression. Based on a genome scanning technique for differences in CpG methylations, methylation-sensitive representational difference analysis, DNA fragments hypermethylated in a human breast cancer were isolated. A DNA fragment was isolated from intron 1 of guanine-nucleotide-binding protein α-11 (GNA11). mRNA expression of GNA11 was shown to be decreased in 10 of 16 breast cancers by RT-PCR analysis, and the immunoreactivity of the GNA11 product, Gα11 subunit of heterotrimeric G-protein, was observed to be reduced in 14 of the 16 cancers by immunohistochemistry. Methylation of a CpG island (CGI) in the 5′ region of GNA11 or that of intron 1 did not show a clear correlation with its decreased expression. Another DNA fragment was isolated from a CGI in the 5′ upstream region of monocarboxylate transporter 1 (MCT1), and was methylated in 4 of 20 breast cancers. The CGI was also methylated in a human breast cancer cell line, MDA-MB-231, and quantitative RT-PCR showed that its expression was almost lost in the cell line. By treatment of the cells with a demethylating agent, 5-aza-2′-deoxycytidine, the methylation was removed and the expression was restored. GNA11 is involved in signalling of gonadotropin-releasing hormone receptor, which negatively regulates cell growth. MCT1 is involved in cellular transportation of butyrate, which induces cellular differentiation. Downregulation of these two genes was suggested to be involved in human breast cancers.

Glucose deprivation increases monocarboxylate transporter 1 (MCT1) expression and MCT1-dependent tumor cell migration

“…11,12,14 This basic information, however, is essential for the prediction of treatment sensitivity and resistance as well as for the rational design of combination therapies. In this study, we report that mitochondria deprived from glycolytic fuels stabilize the expression of MCT1 and of its chaperone protein CD147/basigin in human TCs, thus providing a functional complex known to be involved in the transport of monocarboxylic acids (through MCT1) and in the activation of matrix metalloproteinases (through CD147).…”

“…11 In cancer cells, gene expression may further be regulated by promoter methylation/inactivation. 12 At the posttranslational level, the membrane expression and transport activities of MCT1 require its direct interaction with the scaffold protein CD147. [13][14][15] The assembly of the complex exerts a stabilizing effect, which is necessary for the trafficking, cell surface localization and function of both proteins.…”

Modulation of cell cycle and gene expression in pancreatic tumor cell lines by methionine deprivation (methionine stress): implications to the therapy of pancreatic adenocarcinoma

“…The cytostatic effect of methionine stress may be related to marked down-regulation of EGF, IGF, and AGT receptors and VEGF, M-CSF, and IGF-2 and the upregulation of GNA11, a gene involved in signaling of gonadotropin-releasing hormone receptor, which negatively regulates cell growth (43). The growth of some pancreatic tumors may also be stimulated by IL6, the synthesis of which is regulated by AREG (44).…”

Novel somatic mutations in heterotrimeric G proteins in melanoma

“…7 Although we only found one somatic mutation in GNA11, this gene is of great interest phenotypically as it has previously been shown to have reduced expression in breast cancer. 24 mRNA expression was found to be decreased in 62.5% (10/16) of human breast cancers by RT-PCR, and the immunoreactivity of the G-alpha 11 protein reduced in 14 of 16 cancers. 24 This study by Asada et al suggests that reduced G-alpha 11 levels are advantageous for the growth of breast cancer cells; functional work on GNA11 could help elucidate the mechanisms behind this phenotype.…”