CpG island methylation of microRNAs is associated with tumor size and recurrence of non‐small‐cell lung cancer

Abstract

We investigated whether the CpG island methylation of certain microRNAs was associated with the clinicopathological features and the prognosis of non-small-cell lung cancer. The methylation of mir-152, -9-3, -124-1, -124-2, and -124-3 was analyzed in 96 nonsmall-cell lung cancer specimens using a combined bisulfite restriction analysis. The median observation period was 49.5 months. The methylation of mir-9-3, -124-2, and -124-3 was individually associated with an advanced T factor independent of age, sex, and smoking habit. Moreover, the methylation of multiple microRNA loci was associated with a poorer progression-free survival in a univariate analysis. Our result enlightens the accumulation of aberrant DNA methylation which occurs in concordance with the tumor progression. (Cancer Sci 2011; 102: 2126-2131 L ung cancer is the leading cause of cancer-related mortality in the world,(1) and non-small-cell lung cancer (NSCLC) is the most common type. Surgical resection remains the only curative treatment for NSCLC. Identifying factors that are associated with aggressive disease may lead to the development of novel biomarkers and the identification of therapeutic targets that can help reduce the burden of this disease.MicroRNAs (miRNAs) are a class of small non-coding RNAs that negatively regulate target gene expression by accelerating the degradation of mRNA and translational inhibition, with potentially hundreds of target mRNAs.(2) They influence a variety of cellular functions including proliferation, differentiation, and apoptosis.(3) Specific miRNAs can behave as either tumor suppressor genes or oncogenes, depending on the tissue type and the presence of specific targets. (4,5) More than 100 species of known miRNAs are embedded within or near the CpG islands of the human genome and are potentially subject to control by epigenetic alterations such as DNA methylation and histone modification. Systematic assessments of miRNA expression and epigenetic modifications among cell lines and primary tumor specimens have revealed the existence of the epigenetic regulation of miRNAs in multiple tumor types. (6)(7)(8)(9) The goals of this study were to explore possible relationships between the methylation profiles of miRNAs and the clinicopathological characteristics of NSCLC patients and to identify new specific methylation markers capable of detecting advanced pathological features.In the present study, the methylation status of five miRNA loci within five separate CpG islands was determined in 96 NSCLC tissue specimens. The choice of the miRNAs was based on our previous study (9) as well as other published reports. (10,11) Our data show that the CpG island methylation of miRNAs is common in NSCLC, and that the methylation of multiple miR-NA loci is associated with an advanced T status as well as the progression-free survival (PFS) of patients with NSCLC. Materials and MethodsPatients. We collected cancer tissues and normal lung tissues from NSCLC patients who underwent surgical resection at the University of Tokyo Hosp...

MicroRNA 9-3p Targets β1 Integrin To Sensitize Claudin-Low Breast Cancer Cells to MEK Inhibition

“…Following a bioinformatic search for candidate CpG islands 5= of miRNA genes, it was initially shown that the mir-9-1 gene was hypermethylated in primary invasive breast tumors (22). Additional studies have since shown that mir-9 loci are epigenetically silenced in gastric tumors (9), breast mammosphere models (23), oral squamous cell carcinoma (24), and non-small-cell lung cancers, where methylation of mir-9-3 can serve as a prognostic indicator (25,26). To see if methylation was a contributing silencing mechanism in our system, we first treated cells with the methyltransferase inhibitor 5-aza-2=-deoxycytidine (5AZA).…”

Genome-Wide miRNA Expression Profiling Identifies miR-9-3 and miR-193a as Targets for DNA Methylation in Non–Small Cell Lung Cancers

“…Methylation of certain miRNAs in NSCLCs was also investigated in the studies by Kitano and colleagues (44) and by Watanabe and colleagues (23). Kitano and colleagues (44) observed miR-9-3 methylation in 65% of primary NSCLCs.…”

A new insight on reciprocal relationship between microRNA expression and epigenetic modifications in human lung cancer

“…The methylation statuses of miR-124-2 and miR-124-3 were individually related to recurrence of NSCLC. 78 Tan et al 86 conducted research on the NSCLC tumor samples and found higher amount of methylated miR-124a, especially miR-124a-2 and 124a-3, in tumors compared with normal lung tissues.…”

“…In the human genome, miR-9 is located at three distinct loci: miR-9-1/2/3. So, except miR-9-2, all of them have CpG islands; 78 In all normal tissues, miR-9 family was always unmethylated. Lujambio et al 74 treated metastatic cancer cell lines with the DNMT inhibitor 5-aza-2′-deoxycytidine and measured the miRNA expression.…”

“…They found a similar proportion of methylated miR-9-3; however, they did not observe any correlation between the methylation status of miR-9-3 and lymph metastasis. 78 Heller et al 83 evaluated the miRNA expression profile in A549 cells, which had been treated with both the tricostatin A (TSA) and the 5-aza-2′-deoxycytidine. They found that miR-9-3 could be a target for DNA methylation in NSCLC.…”