MiR-378 as a biomarker for response to anti-angiogenic treatment in ovarian cancer

Objective

To determine the role of miR-378 as a biomarker for anti-angiogenic therapy response in ovarian cancer.

Methods

Expression of miR-378 was analyzed in ovarian cancer cell lines and human tumors vs. normal ovarian epithelial cells by qRT-PCR. After miR-378 transfection in SKOV3 cells, dysregulated genes were identified using microarray. Data from The Cancer Genome Atlas (TCGA) was utilized to correlate miR-378 expression with progression-free survival (PFS) among patients treated with anti-angiogenic therapy by using Kaplan–Meier and Cox proportional hazards.

Results

MiR-378 was overexpressed in ovarian cancer cells and tumors vs. normal ovarian epithelial cells. Overexpressing miR-378 in ovarian cancer cells altered expression of genes associated with angiogenesis (ALCAM, EHD1, ELK3, TLN1), apoptosis (RPN2, HIPK3), and cell cycle regulation (SWAP-70, LSM14A, RDX). In the TCGA dataset, low vs. high miR-378 expression was associated with longer PFS in a subset of patients with recurrent ovarian cancer treated with bevacizumab (9.2 vs. 4.2 months; p = 0.04). On multivariate analysis, miR-378 expression was an independent predictor for PFS after anti-angiogenic treatment (HR = 2.04, 95% CI: 1.12–3.72; p = 0.02). Furthermore, expression levels of two miR-378 targets (ALCAM and EHD1) were associated with PFS in this subgroup of patients who received anti-angiogenic therapy (9.4 vs. 4.2 months, p = 0.04 for high vs. low ALCAM; 7.9 vs. 2.3 months, p < 0.01 for low vs. high EHD1).

Conclusions

Our data suggest that miR-378 is overexpressed in ovarian cancer cells and tumors vs. normal ovarian epithelial cells. MiR-378 and its downstream targets may serve as markers for response to anti-angiogenic therapy.     

Differential Distribution of microRNAs in Breast Cancer Grouped by Clinicopathological Subtypes

Background: microRNAs (miRNAs) that regulate proliferation, invasion and metastasis are considered to bethe principal molecular basis of tumor heterogeneity. Breast cancer is not a homogeneous tissue. Thus, it is veryimportant to perform microarray-based miRNA screening of tumors at different sites. Methods: Breast tissuesamples from the centers and edges of tumors of 30 patients were classified into 5 clinicopathological subtypes.In each group, 6 specimens were examined by microRNA array. All differential miRNAs were analyzed betweenthe edges and centers of the tumors. Results: Seventeen kinds of miRNAs were heterogeneously distributedin the tumors from different clinicopathological subtypes that included 1 kind of miRNA in Luminal A andLuminal B Her2+ subtypes, 4 kinds in Luminal A and Her2 overexpression subtypes, 6 kinds in Luminal BKi67+ and Luminal B Her2+ subtypes, 2 kinds between Luminal B Ki67+ and triple-negative breast cancer(TNBC) subtypes, 2 kinds between Luminal B Her2+ and TNBC subtypes, and 2 kinds between Luminal BKi67+, Luminal B Her2+, and TNBC subtypes. Twenty kinds of miRNAs were homogenously distributed in thetumors from different clinicopathological subtypes that included 6 kinds of miRNAs in Luminal B Ki67+ andLuminal B Her2+ subtypes, 1 kind in Luminal B Ki67+ and Her2 overexpression subtypes, 10 kinds betweenLuminal B Ki67+ and TNBC subtypes, 2 kinds in Luminal B Her2+ and TNBC subtypes, and 1 kind betweenLuminal B Ki67+, Luminal B Her2+, and TNBC subtypes. Conclusions: A total of 37 miRNAs were significantlydistributed in tumors from the centers to edges, and in all clinicopathological subtypes.     

Associations Between Three Common MicroRNA Polymorphisms and Hepatocellular Carcinoma Risk in Chinese

Aim: Associations between polymorphisms in miR-146aG>C, miR-196a2C>T and miR-499A>G and riskof HCC, and interaction with HBV infection in a Chinese population, were the target of the present research.Methods: The duplex polymerase-chain-reaction with confronting-two-pair primers (PCR-RFLP) was performedto determine the genotypes of the miR-146aG>C, miR-196a2C>T and miR-499A>G genotypes. Associations ofpolymorphisms with the risk of HCC were estimated by conditional logistic regression analysis. Results: Drinking,family history of cancer, HBsAg and HCV were risk factors for HCC. Multivariate regression analyses showedthat subjects carrying the miR-196a2 CC genotype had significantly increased risk of HCC, with an adjustedOR (95% CI) of 2.18 (1.23-3.80). In addition, cases carrying the miR-196a2 C allele had a 1.64-fold increase inthe risk for HCC (95%CI=1.03-2.49). The miR-196a2 CT and TT genotypes greatly significantly increased therisk of HCC in subjects with HBV infection, with adjusted ORs (95% CI) of 2.02 (1.12-3.68) and 2.69 (1.28-5.71),respectively. Conclusion: Our results demonstrate that miR-196a2 CC genotype and C allele have an importantrole in HCC risk in Chinese, especially in patients with HBV infection.     

甲状腺乳头状癌组织中差异表达miRNA及其靶基因的筛选和预测

目的：分析甲状腺乳头状癌组织中差异表达小分子RNA（miRNAs）并预测其靶基因,寻找影响甲状腺乳头状癌（PTC）发生发展及可用于生物标志物的miRNAs。方法：选取经病理证实的甲状腺乳头状癌组织及配对正常组织切除标本,运用高通量基因芯片的方法对差异表达的基因和miRNAs进行筛选,采用KEGG通路分析差异表达基因的功能,通过预测网站对差异表达miRNA进行靶基因预测,并对分析结果进行qRT-PCR验证。结果：与同源正常组织比较,基因芯片检测出PTC组织有248个miRNAs（ P<0.01）和3 631个基因差异表达（P<0.05）。hsa-miR-101［靶基因：整合素3(ITGA3）］已验证,癌组织中hsa-miR-101表达(59.8%)低于正常甲状腺组织, ITGA3表达（100%）高于正常甲状腺组织,并且与正常组织比较,59.8%PTC组织hsa-miR -101表达下调,同时ITGA3表达上调。结论：hsa-miR-101的靶基因可能为ITGA3,两者在PTC的发生发展中可能发挥重要作用。     

Hepatitis C virus infection,microRNA and liver disease progression

Hepatitis C virus (HCV) is a global health problem with an estimated 170-200 million peoples (approximately 3% of world population) are chronically infected worldwide and new infections are predicted to be on rise in coming years. HCV infection remains categorized as a major risk factor for chronic hepatitis, liver cirrhosis and hepatocellular carcinoma worldwide. There has been considerable improvement in our understanding of virus life cycle since, the discovery of HCV two-decades ago. MicroRNAs (miRNAs) are important players in establishment of HCV infection and their propagation in infected hepatocytes. They target crucial host cellular factors needed for productive HCV replication and augmented cell growth. Very first anti-miRNA oligonucleotides, miravirsen has been tested in clinical trial and shown promising results as therapeutic agent in treatment against chronic HCV infection. Deregulated expression of miRNAs has been linked to the pathogenesis associated with HCV infection by controlling signaling pathways such as, proliferation, apoptosis and migration. Circulating miRNAs emerging as growing field in identification of biomarkers in disease progression and their potential as a means of communication between cells inside the liver is an exciting area of research in future. This review focuses on recent studies enforcing the contribution of miRNAs in HCV life cycle and coordinated regulation in HCV mediated liver disease progression.     

Circulating microparticles and microRNAs as players in atherosclerosis

Microparticles (MPs) are extracellular membrane vesicles released from normal, apoptotic and pathological cells following a process of detachment from cells of origin. MPs are typically defined by their size, exposure of phosphatidylserine, the expression of surface antigens, proteins and genetic material, originating from their donor cells, and as important vehicles of intercellular communication across numerous biological processes. MPs contain the major source of systemic RNA including microRNA (miRNA) of which aberrant expression appears to be associated with stage and progression of atherosclerosis. The involvement and influence of miRNA during the onset and progression of atherosclerotic disease have generated a lot of interest in assessing the feasibility of therapeutic regulation of miRNAs to manipulate them with a special focus on cardiovascular disease. We speculate on the future developments of MPs which contain miRNA as new therapeutic targets for proliferative vascular diseases such as atherosclerosis.