microRNA在乳腺癌耐药中的作用

乳腺癌是危害全球女性健康的主要疾病,而乳腺癌患者对现有治疗方法产生获得性耐药成为目前乳腺癌临床治疗所面临的难题.微小RNA (miRNA)是一种内源性的非编码RNA,它参与调控多种生物学过程,包括细胞增殖、侵袭、转移、上皮间质转化和耐药等.获得性耐药包含多种复杂机制,可通过特定miRNA的异常表达影响细胞相关蛋白的表达、抗肿瘤药物与相应靶点的结合以及凋亡相关途径引起乳腺癌耐药.本文将重点关注在乳腺癌内分泌治疗、化疗、分子靶向治疗发生获得性耐药中表达异常的miRNA.相信miRNA能够成为乳腺癌临床诊断与治疗以及对抗获得性耐药的生物标志物和新的治疗靶点.     

Inherited polymorphisms in the RNA-mediated interference machinery affect microRNA expression and lung cancer survival

Background:

MicroRNAs (miRs) have an important role in lung carcinogenesis and progression. Single-nucleotide polymorphisms (SNPs) in genes involved in miR biogenesis may affect miR expression in lung tissue and be associated with lung carcinogenesis and progression.

Methods:

We analysed 12 SNPs in POLR2A, RNASEN and DICER1 genes in 1984 cases and 2073 controls from the Environment And Genetics in Lung cancer Etiology (EAGLE) study. We investigated miR expression profiles in 165 lung adenocarcinoma (AD) and 125 squamous cell carcinoma tissue samples from the same population. We used logistic and Cox regression models to examine the association of individual genotypes and haplotypes with lung cancer risk and with lung cancer-specific survival, respectively. SNPs-miR expression associations in cases were assessed using two-sample t-tests and global permutation tests.

Results:

A haplotype in RNASEN (Drosha) was significantly associated with shorter lung cancer survival (hazard ratio=1.86, 95% CI=1.19–2.92, P=0.007). In AD cases, a SNP within the same haplotype was associated with reduced RNASEN mRNA expression (P=0.013) and with miR expression changes (global P=0.007) of miRs known to be associated with cancer (e.g., let-7 family, miR-21, miR-25, miR-126 and miR15a).

Conclusion:

Inherited variation in the miR-processing machinery can affect miR expression levels and lung cancer-specific survival.     

MicroRNA调控胃癌多药耐药的研究进展

晚期胃癌最常用的治疗方法是化疗,但患者存在对化疗药物原发或继发的多药耐药(multidrug resistance,MDR)现象,使患者很难获得长期生存.大量研究证实,microRNA是转录后基因表达调节的关键分子,在肿瘤的多种生物学行为中起着关键性作用,本文就microRNA调控胃癌多药耐药的相关研究进展做一综述.     

Single-nucleotide polymorphism associations for colorectal cancer in southern Chinese population

Objective:Genome-wide association studies(GWAS) have identified 11 loci that influence the risk of developing colorectal cancer(CRC).Given that these studies were conducted in European Caucasian populations,it is not clear whether the results are relevant for populations with different ethnicities.The aim of this study was to examine these associations in a southern Chinese population.Methods:Eleven single-nucleotide polymorphisms(SNPs),rs12701937,rs16892766,rs7014346,rs6983267,rs719725,rs10795668,rs3802842,rs4444235,rs9929218,rs10411210,and rs961253,were genotyped in 229 CRC patients and 267 controls using the MassArray SNP genotyping system.Results:Evidence of an association with CRC was found for four of the 11 loci.The strongest associations were with rs4444235 and rs961253,with significant odds ratios close to those reported in previous GWAS.Among these four loci,rs719725 and rs4444235 were significantly associated with female gender,rs3802842,rs961253,and rs4444235 with early disease onset,and rs3802842 with later disease onset.However,no associations with CRC risk were detected for six other loci(rs9929218,rs10411210,rs12701937,rs7014346,rs6983267,and rs10795668),and one SNP,rs16892766,was not polymorphic in any of the study participants.Conclusion: The rs4444235 and rs961253 loci are strongly associated with the risk of CRC in southern Chinese.     

microRNA在恶性肿瘤临床应用中的研究进展

microRNA作为一种高效、稳定的非编码调控基因,参与了多种恶性肿瘤发生及发展。针对其机制的研究已取得重大进展,在此基础上,其临床应用也已成为当前肿瘤研究热点之一。研究显示,microR-NA具有作为恶性肿瘤早期诊断、治疗及预后标志物的潜力,这为其临床应用打下了坚实的基础。     

microRNA与肺癌发生发展关系的研究进展

微小核糖核酸(microRNA,miRNA）是一类由大小为19~24个核苷酸(nucleotide,nt)构成的非编码小分子RNA,广泛存在于真核生物中。研究发现,miRNA通过调控相应靶基因的表达等多种途径参与癌症的发生发展等一系列过程,其中部分miRNA的靶基因已经成为治疗癌症的靶向基因。肺癌是世界范围内发病率与病死率均居首位的恶性肿瘤,目前缺乏理想的早期诊断手段及有效的治疗方法。目前大量研究表明,miRNA表达异常与肺癌的发生发展密切相关。本文就miRNA与肺癌发生发展关系的研究新进展作一综述。     

microRNA 在浆液性卵巢癌中的研究进展

卵巢癌是女性生殖系统最致命的恶性肿瘤,尽管在临床和基础研究中做了很多的努力,但是卵巢癌的整体存活率并无明显的改善。近年来,越来越多的研究表明,microRNA 的异常表达与上皮性卵巢癌的发生发展有着密切联系,很多的 microRNA 被证实可预测卵巢癌的预后和转移,因此 microRNA 可能成为诊断卵巢癌的新的肿瘤标记物,这将会给卵巢癌的诊治开辟新的途径,为卵巢癌患者带来一片曙光。     

Analysis of polymorphisms in the circadian-related genes and breast cancer risk in Norwegian nurses working night shifts

Introduction

Some studies have suggested that night work may be associated with an increased risk of breast cancer in nurses. We aimed to explore the role of circadian gene polymorphisms in the susceptibility to night work-related breast cancer risk.

Methods

We conducted a nested case-control study of Norwegian nurses comprising 563 breast cancer cases and 619 controls within a cohort of 49,402 Norwegian nurses ages 35 to 74 years. We studied 60 single-nucleotide polymorphisms (SNPs) in 17 genes involved in the regulation of the circadian rhythm in cases and controls. The data were analyzed in relation to the two exposure variables "maximum number of consecutive night shifts ever worked" and "maximum number of consecutive night shifts worked for at least 5 years." The odds of breast cancer associated with each SNP was calculated in the main effects analysis and in relation to night shift work. The statistically significant odds ratios were tested for noteworthiness using two Bayesian tests: false positive report probability (FPRP) and Bayesian false discovery probability (BFDP).

Results

In the main effects analysis, CC carriers of rs4238989 and GG carriers of rs3760138 in the AANAT gene had increased risk of breast cancer, whereas TT carriers of BMAL1 rs2278749 and TT carriers of CLOCK rs3749474 had reduced risk. The associations were found to be noteworthy using both the FPRP and BFDP tests. With regard to the effect of polymorphisms and night work, several significant associations were observed. After applying FPRP and BFDP in women with at least four night shifts, an increased risk of breast cancer was associated with variant alleles of SNPs in the genes AANAT (rs3760138, rs4238989), BMAL1 (rs2290035, rs2278749, rs969485) and ROR-b (rs3750420). In women with three consecutive night shifts, a reduced risk of breast cancer was associated with carriage of variant alleles of SNPs in CLOCK (rs3749474), BMAL1 (rs2278749), BMAL2 (rs2306074), CSNK1E (rs5757037), NPAS2 (rs17024926), ROR-b (rs3903529, rs3750420), MTNR1A (rs131113549) and PER3 (rs1012477).

Conclusions

Significant and noteworthy associations between several polymorphisms in circadian genes, night work and breast cancer risk were found among nurses who had worked at least three consecutive night shifts.     

DNA-repair genetic polymorphisms and risk of breast cancer in Cyprus

The DNA repair pathway is known to play a role in the etiology of breast cancer. A number of studies have demonstrated that common germline variants in genes involved in the DNA repair pathway influence breast cancer risk. To assess whether alterations in DNA repair genes contribute to breast cancer, we genotyped 12 single nucleotide polymorphisms (SNPs) in 1,109 Cypriot women with breast cancer and 1,177 age-matched healthy controls. We found significant associations with breast cancer for SNPs in the BRCA2 and MRE11A genes. Carriers of the BRCA2 rs1799944 variant (991 Asp) were found to have an increased risk of breast cancer (OR = 1.41, 95% CI 1.08–1.83, P = 0.01) with P _trend = 0.0076. Homozygous carriers of the MRE11A rs601341 A allele had an increased risk of breast cancer (OR = 1.36, 95% CI 1.08–1.71, P = 0.009) with P _trend = 0.0087. This study suggests that genetic variants in BRCA2 and MRE11A are associated with breast cancer risk.     

Candidate microRNA biomarkers in human colorectal cancer: systematic review profiling studies and experimental validation

Colorectal cancer (CRC) is a major cause of cancer mortality worldwide. There is an urgent need to search for specific and sensitive biomarkers for early diagnosis of CRC. We carried out a comprehensive systematic review of published studies that compared the miRNA expression profiles between CRC tissue and paired neighboring noncancerous colorectal tissue to determine candidate miRNA biomarkers for CRC. A miRNA ranking system that takes the number of comparisons in agreement, total study sizes and direction of differential expression into the consideration was devised and used. One of the most up-regulated miRNAs, miRNA-106a, was consistently reported to be differentially expressed in six studies and the five most down-regulated miRNAs, miR-30a-3p, miR-139, miR-145, miR-125a and miR-133a, were consistently reported to be differentially expressed in four studies. Moreover, we further validated five miRNAs in a clinical setting using qRT-PCR, which demonstrated that miR-106a expression was increased, whereas the expression of miR-30a-3p, miR-145, miR-125a and miR-133a was decreased in the CRC tissues. Therefore, these miRNAs may be the candidates to develop a panel of biomarkers with sufficient sensitivity and specificity for the diagnosis of CRC in a clinical setting.     

微小RNA多态性与肿瘤易感性的研究进展

 微小RNA（microRNA,简称miRNA）是一类生物体内源性的非编码小RNA,在转录后水平对基因的表达进行负调控,导致mRNA的降解或翻译抑制,与肿瘤发生密切相关。miRNA序列的单核苷酸多态性（miRSNP）影响成熟体miRNA的表达水平以及对靶标mRNA的选择,miRSNP介导的表观遗传学改变与肿瘤的发生机制相关,并可能成为恶性肿瘤的分子标志,文章就最近研究的热点miRSNP与肿瘤易感性作一综述。     

An evaluation of urinary microRNA reveals a high sensitivity for bladder cancer

Background:

Urinary biomarkers are needed to improve the care and reduce the cost of managing bladder cancer. Current biomarkers struggle to identify both high and low-grade cancers due to differing molecular pathways. Changes in microRNA (miR) expression are seen in urothelial carcinogenesis in a phenotype-specific manner. We hypothesised that urinary miRs reflecting low- and high-grade pathways could detect bladder cancers and overcome differences in genetic events seen within the disease.

Methods:

We investigated urinary samples (n=121) from patients with bladder cancer (n=68) and age-matched controls (n=53). Fifteen miRs were quantified using real-time PCR.

Results:

We found that miR is stable within urinary cells despite adverse handling and detected differential expression of 10 miRs from patients with cancer and controls (miRs−15a/15b/24-1/27b/100/135b/203/212/328/1224, ANOVA P<0.05). Individually, miR-1224-3p had the best individual performance with specificity, positive and negative predictive values and concordance of 83%, 83%, 75% and 77%, respectively. The combination of miRs-135b/15b/1224-3p detected bladder cancer with a high sensitivity (94.1%), sufficient specificity (51%) and was correct in 86% of patients (concordance).

Conclusion:

The use of this panel in patients with haematuria would have found 94% of urothelial cell carcinoma, while reducing cystoscopy rates by 26%. However, two invasive cancers (3%) would have been missed.     

Novel genetic variants in microRNA genes and familial breast cancer

MicroRNA (miRNA) plays an important role in tumorigenesis, but whether miRNA is a cancer predisposition factor or not is still unknown. Considering the fact that miRNA regulates a number of tumor suppressor genes (TSGs) and oncogenes, genetic variations in miRNA genes could affect the levels of expression of TSGs or oncogenes and, thereby, cancer risk. To test this hypothesis, we screened genetic variants in 17 selected miRNA genes, which are predicted to regulate key breast cancer genes, in 42 patients with familial breast cancer. Seven novel genetic variants were observed in 7 primary or precursor miRNA genes. Among them, 1 rare variant in the precursor of miR‐30c‐1 and 1 rare variant in the primary precursor of miR‐17 were only observed in noncarriers of BRCA1/2 mutations. In functional assays, these 2 variants resulted in conformational changes in the predicted secondary structures, and consequently altered the expression of mature miR‐30c‐1 and miR‐17. In the target in vitro assay, we observed that miR‐17 could bind to the 3′UTR of BRCA1 mRNAs, which is predicted to be a target for miR‐17. Our findings suggest that functional genetic variants in miRNA genes can potentially alter the regulation of key breast cancer genes. Whether they confer genetic susceptibility to breast cancer remains to be determined. © 2008 Wiley‐Liss, Inc.     

ｍｉＲＮＡ：新一代肿瘤生物标志

微小ＲＮＡ（ｍｉＲＮＡ）是一类小分子非编码ＲＮＡ,能够在转录后水平调控蛋白合成,几乎参与了调控细胞活动的各个环节。到目前为止,ｍｉＲＮＡ给予人们一个新的视野理解肿瘤的发生发展,展示了作为肿瘤标志物以及肿瘤治疗靶点的巨大潜能。作者从肿瘤标志物的角度,归纳了ｍｉＲＮＡ用于肿瘤诊断、药物疗效预测以及预后判断所获得的成就,并对其临床应用前景作了展望。     

Identification of serum microRNA profiles in colon cancer

Background:

microRNAs (miRNAs) exist in blood in an apparently stable form. We have explored whether serum miRNAs can be used as non-invasive early biomarkers of colon cancer.

Methods:

Serum samples from 30 patients with colon cancer stage IV and 10 healthy controls were examined for the expression of 375 cancer-relevant miRNAs. Based on the miRNA profile in this study, 34 selected miRNAs were measured in serum from 40 patients with stage I–II colon cancer and from 10 additional controls.

Results:

Twenty miRNAs were differentially expressed in serum from stage IV patients compared with controls (P<0.01). Unsupervised clustering revealed four subgroups; one corresponding mostly to the control group and the three others to the patient groups. Of the 34 miRNAs measured in the follow-up study of stage I–II patients, 21 showed concordant expression between stage IV and stage I–II patient. Based on the profiles of these 21 miRNAs, a supervised linear regression analysis (Partial Least Squares Regression) was performed. Using this model we correctly assigned stage I–II colon cancer patients based on miRNA profiles of stage IV patients.

Conclusion:

Serum miRNA expression profiling may be utilised in early detection of colon cancer.