Abstract Protein arginine methylation is a novel post‐translational modification regulating a diversity of cellular processes, including histone functions, but the roles of protein arginine methyltransferases (PRMTs) in human cancer are not well investigated. To address this issue, we first examined expression levels of genes belonging to the PRMT family and found significantly higher expression of PRMT1 and PRMT6 , both of which are Type I PRMTs, in cancer cells of various tissues than in non‐neoplastic cells. Abrogation of the expression of these genes with specific siRNAs significantly suppressed growth of bladder and lung cancer cells. Expression profile analysis using the cells transfected with the siRNAs indicated that PRMT1 and PRMT6 interplay in multiple pathways, supporting regulatory roles in the cell cycle, RNA processing and also DNA replication that are fundamentally important for cancer cell proliferation. Furthermore, we demonstrated that serum asymmetric dimethylarginine (ADMA) levels of a number of cancer cases are significantly higher than those of nontumor control cases. In summary, our results suggest that dysregulation of PRMT1 and PRMT6 can be involved in human carcinogenesis and that these Type I arginine methyltransferases are good therapeutic targets for various types of cancer.
<div>Abstract<p>To date, few association studies have been done to better understand the genetic basis for the development of sporadic medullary thyroid carcinoma (sMTC). To identify additional low-penetrance genes, we have done a two-stage case-control study in two European populations using high-throughput genotyping. We selected 417 single nucleotide polymorphisms (SNP) belonging to 69 genes either related to <i>RET</i> signaling pathway/functions or involved in key processes for cancer development. TagSNPs and functional variants were included where possible. These SNPs were initially studied in the largest known series of sMTC cases (<i>n</i> = 266) and controls (<i>n</i> = 422), all of Spanish origin. In stage II, an independent British series of 155 sMTC patients and 531 controls was included to validate the previous results. Associations were assessed by an exhaustive analysis of individual SNPs but also considering gene- and linkage disequilibrium–based haplotypes. This strategy allowed us to identify seven low-penetrance genes, six of them (<i>STAT1, AURKA, BCL2, CDKN2B, CDK6</i>, and <i>COMT</i>) consistently associated with sMTC risk in the two case-control series and a seventh (<i>HRAS</i>) with individual SNPs and haplotypes associated with sMTC in the Spanish data set. The potential role of <i>CDKN2B</i> was confirmed by a functional assay showing a role of a SNP (rs7044859) in the promoter region in altering the binding of the transcription factor HNF1. These results highlight the utility of association studies using homogeneous series of cases for better understanding complex diseases. [Cancer Res 2007;67(19):9561–7]</p></div>
The fibroblast growth factor receptor 2 (FGFR2) locus is consistently the top hit in genome-wide association studies for oestrogen receptor-positive (ER+) breast cancer. Yet, its mode of action continues to be controversial. Here, we employ a systems biology approach to demonstrate that signalling via FGFR2 counteracts cell activation by oestrogen. In the presence of oestrogen, the oestrogen receptor (ESR1) regulon (set of ESR1 target genes) is in an active state. However, signalling by FGFR2 is able to reverse the activity of the ESR1 regulon. This effect is seen in multiple distinct FGFR2 signalling model systems, across multiple cells lines and is dependent on the presence of FGFR2. Increased oestrogen exposure has long been associated with an increased risk of breast cancer. We therefore hypothesized that risk variants should reduce FGFR2 expression and subsequent signalling. Indeed, transient transfection experiments assaying the three independent variants of the FGFR2 risk locus (rs2981578, rs35054928 and rs45631563) in their normal chromosomal context show that these single-nucleotide polymorphisms (SNPs) map to transcriptional silencer elements and that, compared with wild type, the risk alleles augment silencer activity. The presence of risk variants results in lower FGFR2 expression and increased oestrogen responsiveness. We thus propose a molecular mechanism by which FGFR2 can confer increased breast cancer risk that is consistent with oestrogen exposure as a major driver of breast cancer risk. Our findings may have implications for the clinical use of FGFR2 inhibitors.
Abstract Background and Aim: Interstitial cells of Cajal (ICC) are pacemakers and mediators of neurotransmission in gastroenteric smooth muscles. Interstitial cells of Cajal require cellular signaling via KIT, a receptor tyrosine kinase, for development and maintenance of cellular phenotype. Much of the evidence demonstrating the functions of ICC comes from studies of W/W V mutant mice, which have reduced KIT function. The aim of the present study was to differentially examine gene expression in the small intestines of wild‐type and W/W V mice. Methods: RNA from the jejunum of wild‐type and W/W V mice was analyzed using a differential gene display method. Results: One candidate gene, encoding a novel small GTPase of the RAS superfamily, was significantly suppressed both in fed and starved W/W V mice. The full‐length clone of the murine gene and its human and xenopus counterparts were designated GTP‐binding protein, 28 kDa ( G28K ). Human G28K cDNA encodes a protein of 258 amino acids with homology to the human cell division cycle 42/ G25K protein. This gene is located at 1q42.11–q42.3. G28K was abundantly expressed in the human stomach and the small intestine. Semi‐quantitative reverse transcription–polymerase chain reaction analysis revealed expression of G28K mRNA within single isolated ICC. Conclusions: Gene analysis showed that G28K was differentially expressed in the small intestines of wild‐type and W/W V mice. Interstitial cells of Cajal within the small intestine expressed mRNA for G28K . The specific downregulation of G28K in the jejunum of W/W V mice, and high expression in human intestinal tissue suggest that the G28K gene might be associated with ICC function in mice and in humans.
We typed 247 cases of nasopharyngeal carcinoma (NPC), a disease predominantly of the southern Chinese, and 274 controls from the Chao Shan region of China's Guangdong province for HLA A and B. Besides confirming the established associations with A2, A33, B46 and B58 (positive associations) and A11 (negative association), the results demonstrated a number of rarer alleles with strong negative association with NPC. Our data, combined with those from the previous studies in Southern Chinese, displayed the protective effects for A31 (odds ratio (OR)=0.0; 95% confidence interval (CI)=0–0.11), B13 (OR=0.50; 95% CI=0.35–0.69), B27 (OR=0.49; 95% CI=0.25–0.92), B39 (OR=0.18; 95% CI=0.06–0.48) and B55 (OR=0.32; 95% CI=0.14–0.68), the ORs comparing individuals with or without each allele. Other ethnic groups do not display such large HLA-associated variation in NPC risk. We show that a linked NPC gene with dominant mode of action could not generate such large protective effects. The results provide strong supporting evidence for the existence of a southern Chinese specific, recessive NPC gene closely linked to the HLA region as a major determinant of the Chinese risk for the disease.
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