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1.  Molecular profiling uncovers a p53-associated role for microRNA-31 in inhibiting the proliferation of serous ovarian carcinomas and other cancers 
Cancer research  2010;70(5):1906-1915.
MicroRNAs (miRNAs) regulate complex patterns of gene expression, and the relevance of altered miRNA expression to ovarian cancer remains to be elucidated. By comprehensively profiling expression of miRNAs and mRNAs in serous ovarian tumors and cell lines and normal ovarian surface epithelium, we identified hundreds of potential miRNA-mRNA targeting associations underlying cancer. Functional overexpression of miR-31, the most underexpressed miRNA in serous ovarian cancer, repressed predicted miR-31 gene targets including cell cycle regulator E2F2. MIR31 and CDKN2A, which encodes p14ARF and p16INK4A, are located at 9p21.3, a genomic region commonly deleted in ovarian and other cancers. p14ARF promotes p53 activity, and E2F2 overexpression in p53 wild-type cells normally leads via p14ARF to an induction of p53-dependent apoptosis. In a number of serous cancer cell lines with a dysfunctional p53 pathway (i.e., OVCAR8, OVCA433, and SKOV3), miR-31 overexpression inhibited proliferation and induced apoptosis; however, in other lines (i.e., HEY and OVSAYO) with functional p53, miR-31 had no effect. Additionally, the osteosarcoma cell line U2OS and the prostate cancer cell line PC3 (p14ARF-deficient and p53-deficient, respectively) were also sensitive to miR-31. Furthermore, miR-31 overexpression induced a global gene expression pattern in OVCAR8 associated with better prognosis in tumors from patients with advanced stage serous ovarian cancer, potentially impacting many genes underlying disease progression. Our findings reveal that loss of miR-31 is associated with defects in the p53 pathway and functions in serous ovarian cancer and other cancers, suggesting that patients with cancers deficient in p53 activity might benefit from therapeutic delivery of miR-31.
doi:10.1158/0008-5472.CAN-09-3875
PMCID: PMC2831102  PMID: 20179198
microRNA; serous ovarian carcinoma; cancer therapy; miR31; TP53
2.  Expression of miRNAs in Papillary Thyroid Carcinomas Is Associated with BRAF Mutation and Clinicopathological Features in Chinese Patients 
MicroRNAs (miRNAs) dysregulation has been shown to play a critical regulatory role in papillary thyroid carcinomas (PTCs). BRAF mutation is associated with poor clinicopathological outcomes in PTC. In order to identify a possible association between dysregulated miRNA expression and BRAF mutation as well as clinicopathological features in Chinese patients with PTC, we examined the expression levels of five reported dysregulated miRNAs (miRNA-221, miRNA-222, miRNA-146b, miRNA-181, and miRNA-21) and determined BRAF mutation status in 52 patients with PTC and 52 patients with benign thyroid nodules (BTNs). The expression levels of all five miRNAs were significantly increased in PTC when compared to BTN. The BRAF mutation occurred more frequently in PTC cases with advanced TNM stage. Importantly, miRNA-221, miRNA-222, miRNA-146b, and miRNA-181 expression levels were significantly higher in PTC patients with BRAF mutation. In addition, enhanced expression of miRNA-221 and miRNA-222 was found in patients with cervical lymph node metastasis and advanced TNM stage. Increased expression of miRNA-221 and miR-181 was evidenced in patients with larger tumors. These findings showed a potential role of this distinct profile of miRNAs in differentiating PTC from BTN. BRAF mutation might regulate or interact with miRNA in the pathogenesis and progression of PTC.
doi:10.1155/2013/128735
PMCID: PMC3639632  PMID: 23690767
3.  MicroRNAs in ovarian carcinomas 
Endocrine-related cancer  2010;17(1):F77-F89.
The molecular mechanisms involved in epithelial ovarian cancer initiation and progression are just beginning to be elucidated. In particular, it has become evident that microRNAs (miRNAs), a class of molecules that post-trancriptionally regulates gene expression, play a major role in ovarian tumorigenesis. Several miRNA profiling studies have identified changes in miRNA patterns that take place during ovarian cancer development. While most deregulated miRNAs are down-regulated in cancer, and may therefore act as tumor suppressors, others are elevated and may represent novel oncogenes in this disease. A number of miRNAs identified as aberrantly expressed in ovarian carcinoma have been shown to have important functional roles in cancer development and may therefore represent targets for therapy. In addition, some of the miRNA patterns may have prognostic significance. The identification of functional targets represents a major hurdle in our understanding of miRNA function in ovarian carcinoma, but significant progress is being made. It is hoped that a better understanding of the miRNA expression and roles in ovarian cancer may provide new avenues for the detection, diagnosis, and therapy of this deadly disease.
doi:10.1677/ERC-09-0203
PMCID: PMC2856347  PMID: 19903743
4.  ADAR2-Mediated Editing of miR-214 and miR-122 Precursor and Antisense RNA Transcripts in Liver Cancers 
PLoS ONE  2013;8(12):e81922.
A growing list of microRNAs (miRNAs) show aberrant expression patterns in hepatocellular carcinoma (HCC), but the regulatory mechanisms largely remain unclear. RNA editing catalyzed by members of the adenosine deaminase acting on the RNA (ADAR) family could target the miRNA precursors and affect the biogenesis process. Therefore, we investigate whether RNA editing could be one mechanism contributing to the deregulation of specific miRNAs in HCC. By overexpression of individual ADARs in hepatoma cells, RNA editing on the precursors of 16 miRNAs frequently deregulated in HCC was screened by a sensitive high-resolution melting platform. The results identified RNA precursors of miR-214 and miR-122 as potential targets edited by ADAR2. A subset of HCC showing elevated ADAR2 verified the major editings identified in ARAR2 overexpressed hepatoma cells, either with A-to-I or U-to-C changes. The unusual U-to-C editing at specific residues was demonstrated as being attributed to the A-to-I editing on the RNA transcripts complementary to the pri-miRNAs. The editing event caused a decrease of the RNA transcript complementary to pri-miR-214, which led to the decrease of pri-miR-214 and miR-214 and resulted in the increased protein level of its novel target gene Rab15. In conclusion, the current study discovered ADAR2-mediated editing of the complementary antisense transcripts as a novel mechanism for regulating the biogenesis of specific miRNAs during hepatocarcinogenesis.
doi:10.1371/journal.pone.0081922
PMCID: PMC3873926  PMID: 24386085
5.  The role of microRNA deregulation in the pathogenesis of adrenocortical carcinoma 
Endocrine-Related Cancer  2011;18(6):643-655.
Adrenocortical carcinoma (ACC) is an aggressive tumor showing frequent metastatic spread and poor survival. Although recent genome-wide studies of ACC have contributed to our understanding of the disease, major challenges remain for both diagnostic and prognostic assessments. The aim of this study was to identify specific microRNAs (miRNAs) associated with malignancy and survival of ACC patients. miRNA expression profiles were determined in a series of ACC, adenoma, and normal cortices using microarray. A subset of miRNAs showed distinct expression patterns in the ACC compared with adrenal cortices and adenomas. Among others, miR-483-3p, miR-483-5p, miR-210, and miR-21 were found overexpressed, while miR-195, miR-497, and miR-1974 were underexpressed in ACC. Inhibition of miR-483-3p or miR-483-5p and overexpression of miR-195 or miR-497 reduced cell proliferation in human NCI-H295R ACC cells. In addition, downregulation of miR-483-3p, but not miR-483-5p, and increased expression of miR-195 or miR-497 led to significant induction of cell death. Protein expression of p53 upregulated modulator of apoptosis (PUMA), a potential target of miR-483-3p, was significantly decreased in ACC, and inversely correlated with miR-483-3p expression. In addition, high expression of miR-503, miR-1202, and miR-1275 were found significantly associated with shorter overall survival among patients with ACC (P values: 0.006, 0.005, and 0.042 respectively). In summary, we identified additional miRNAs associated with ACC, elucidated the functional role of four miRNAs in the pathogenesis of ACC cells, demonstrated the potential involvement of the pro-apoptotic factor PUMA (a miR-483-3p target) in adrenocortical tumors, and found novel miRNAs associated with survival in ACC.
doi:10.1530/ERC-11-0082
PMCID: PMC3201061  PMID: 21859927
6.  Integrated Analyses of microRNAs Demonstrate Their Widespread Influence on Gene Expression in High-Grade Serous Ovarian Carcinoma 
PLoS ONE  2012;7(3):e34546.
Background
The Cancer Genome Atlas (TCGA) Network recently comprehensively catalogued the molecular aberrations in 487 high-grade serous ovarian cancers, with much remaining to be elucidated regarding the microRNAs (miRNAs). Here, using TCGA ovarian data, we surveyed the miRNAs, in the context of their predicted gene targets.
Methods and Results
Integration of miRNA and gene patterns yielded evidence that proximal pairs of miRNAs are processed from polycistronic primary transcripts, and that intronic miRNAs and their host gene mRNAs derive from common transcripts. Patterns of miRNA expression revealed multiple tumor subtypes and a set of 34 miRNAs predictive of overall patient survival. In a global analysis, miRNA:mRNA pairs anti-correlated in expression across tumors showed a higher frequency of in silico predicted target sites in the mRNA 3′-untranslated region (with less frequency observed for coding sequence and 5′-untranslated regions). The miR-29 family and predicted target genes were among the most strongly anti-correlated miRNA:mRNA pairs; over-expression of miR-29a in vitro repressed several anti-correlated genes (including DNMT3A and DNMT3B) and substantially decreased ovarian cancer cell viability.
Conclusions
This study establishes miRNAs as having a widespread impact on gene expression programs in ovarian cancer, further strengthening our understanding of miRNA biology as it applies to human cancer. As with gene transcripts, miRNAs exhibit high diversity reflecting the genomic heterogeneity within a clinically homogeneous disease population. Putative miRNA:mRNA interactions, as identified using integrative analysis, can be validated. TCGA data are a valuable resource for the identification of novel tumor suppressive miRNAs in ovarian as well as other cancers.
doi:10.1371/journal.pone.0034546
PMCID: PMC3315571  PMID: 22479643
7.  MiR-155 is a liposarcoma oncogene that targets casein kinase-1α and enhances β-catenin signaling 
Cancer Research  2012;72(7):1751-1762.
Liposarcoma can be an aggressive, debilitating and fatal malignancy. In this study, we identifed microRNAs (miRNAs) associated with the differentiation status of liposarcoma to gain insight into the basis for its progression. miRNA expression profiles determined in human tumors and normal fat specimens identified a de-differentiated tumor expression signature consisting of 35 miRNAs. Deregulated miRNA expression was confirmed in a second independent sample cohort. The miR-155 was the most overexpressed miRNA and functional investigations assigned an important role in the growth of de-differentiated liposarcoma cell lines. Transient or stable knockdown of miR-155 retarded tumor cell growth, decreased colony formation and induced G1-S cell cycle arrest in vitro and blocked tumor growth in murine xenografts in vivo. We identified casein kinase 1α (CK1α) as a direct target of miR-155 control which enhanced β-catenin signaling and cyclin D1 expression, promoting tumor cell growth. In summary, our results point to important functions for miR-155 and β-catenin signaling in progression of liposarcoma, revealing mechanistic vulnerabilities that might be exploited for both prognostic and therapeutic purposes.
doi:10.1158/0008-5472.CAN-11-3027
PMCID: PMC3319789  PMID: 22350414
Liposarcoma; miRNA; CK1α; β-catenin; cyclin D1
8.  Dysregulation of miR-15a and miR-214 in human pancreatic cancer 
Background
Recent reports indicate that microRNAs (miRNAs) play a critical role in malignancies. However, the role that miRNAs play in pancreatic cancer remains to be determined. The purpose of this study was to investigate aberrantly expressed miRNAs in pancreatic cancer tissues and demonstrate their roles in disease progression.
Results
We detected the expression patterns of miRNAs in 10 pancreatic cancer tissues and their adjacent benign tissues by quantitative real time-PCR (qRT-PCR) and found that miR-15a and miR-214 were dysregulated in the tumor samples. This is the first time that miR-214 has been identified as aberrantly expressed in pancreatic cancer. In vitro experiments showed that overexpression of miR-15a inhibited the viability of pancreatic cancer cells, whereas overexpression of miR-214 decreased the sensitivity of the cells to gemcitabine (GEM). Furthermore, we identified WNT3A and FGF7 as potential targets of miR-15a and ING4 as a target of miR-214.
Conclusions
Aberrant expression of miRNAs such as miR-15a and miR-214 results in different cellular effects in pancreatic cancer. Downregulation of miR-15a might contribute to proliferation of pancreatic cancer cells, whereas upregulation of miR-214 in pancreatic cancer specimens might be related to the poor response of pancreatic cancer cells to chemotherapy. MiR-15a directly targets multiple genes relevant in pancreatic cancer, suggesting that it may serve as a novel therapeutic target for treatment of the disease.
doi:10.1186/1756-8722-3-46
PMCID: PMC3002909  PMID: 21106054
9.  Analysis of serum exosomal microRNAs and clinicopathologic features of patients with pancreatic adenocarcinoma 
Background
Altered expression of serum microRNAs (miRNAs) have been reported to correlate with carcinogenesis and progression of pancreatic adenocarcinoma (PC), but descriptions of serum exosomal miRNAs in PC are still lacking. This study was designed to evaluate serum exosomal miRNA levels in PC patients and to investigate their relationships with clinicopathologic features and prognosis.
Methods
Four miRNAs (miR-17-5p, miR-21, miR-155 and miR-196a) related to PC were selected for examination in our research. Serum miRNA was examined by RT-PCR in a group of 49 patients, including 22 with PCs, 6 with benign pancreatic tumors, 7 with ampullary carcinomas, 6 with chronic pancreatitis and 8 healthy participants. The clinicopathologic data were also collected, and PC patients were classified according to the presence of metastasis, tumor differentiation and advanced stage.
Results
There were low expressions of exosomal miR-155 and miR-196a in serum samples of PC patients when U-6 was used as a control. Serum exosomal miR-17-5p was higher in PC patients than in non–PC patients and healthy participants. High levels of miR-17-5p were significantly correlated with metastasis and advanced stage of PC. The serum exosomal miR-21 level in PC was higher than that in the normal and chronic pancreatitis groups, but was not significantly correlated with PC differentiation and tumor stage.
Conclusions
There were high expressions of serum exosomal miR-17-5p and miR-21 in PC patients. Examination of serum exosomal microRNA is a useful serum biomarker for PC diagnosis other than serum-free microRNA. It is postulated that exosomal miR-17-5p participates in the progression of PC.
doi:10.1186/1477-7819-11-219
PMCID: PMC3766671  PMID: 24007214
Blood; microRNA; miR-17-5p; miR-21; Pancreatic adenocarcinoma
10.  Prognostic implications of microRNA-100 and its functional roles in human epithelial ovarian cancer 
Oncology Reports  2012;27(4):1238-1244.
Dysregulation of microRNAs (miRNAs) has been found to be associated with a variety of diseases, including epithelial ovarian cancer (EOC). Recently, miR-100 was reported to be downregulated in human ovarian carcinoma, however, the clinical significance and functional roles of miR-100 expression in human EOC are unclear. TaqMan real-time quantitative RT-PCR assay was performed to detect the expression of miR-100 in 98 EOC tissues and 15 adjacent normal epithelial tissues. The relationship between miR-100 expression and clinicopathological factors in 98 EOC patients was statistically analyzed. The effect of miR-100 expression on patient survival was determined. Finally, the role of miR-100 in EOC cell growth and its possible mechanisms were analyzed with miR-100 precursor or inhibitor-transfected cells. We showed that the level of miR-100 was significantly lower in EOC tissues compared to adjacent normal tissues. Low miR-100 expression was found to be closely correlated with advanced FIGO stage, higher serum CA125 expression level and lymph node involvement. Also, low miR-100 expression was correlated with shorter overall survival of EOC patients, and multivariate analysis showed that the status of miR-100 expression was an independent predictor of overall survival in EOC. Additionally, miR-100 could affect the growth of EOC cells by post-transcriptionally regulating polo-like kinase 1 (PLK1) expression. Together, these results suggest that low miR-100 expression may be an independent poor prognostic factor and miR-100 can function as a tumor suppressor by targeting PLK1 in human EOCs.
doi:10.3892/or.2012.1625
PMCID: PMC3583406  PMID: 22246341
epithelial ovarian carcinoma; microRNA-100; TaqMan real-time RT-PCR; prognosis; overall survival; polo-like kinase 1
11.  MicroRNA Expression Aids the Preoperative Diagnosis of Pancreatic Ductal Adenocarcinoma 
Pancreas  2012;41(5):685-690.
Objectives
To evaluate microRNA (miRNA) expression in pancreatic resection specimens and fine needle aspiration (FNA) biopsies and determine which, if any, miRNAs aid the distinction between benign and malignant pancreatic tumors in limited cytology material.
Methods
Resection specimens containing adenocarcinoma (n=17), intraductal papillary mucinous neoplasms (IPMN, n=11), and non-neoplastic tissues (n=15) were evaluated for miR-21, -221, -100, -155, and -181b expression by qRT-PCR, and a subset of carcinomas and IPMNs were analyzed with miRNA microarrays. Cellblocks containing carcinoma (n=26) or benign pancreatic lesions (n=11) from FNA biopsies were subjected to qRT-PCR for miR-21, miR-221, miR-181b, miR-196a and miR-217.
Results
Carcinomas showed higher expression of miR-21, -221, -155, -100, and -181b than benign lesions by qRT-PCR and overexpression of miR-21, -221, and-181b was confirmed by microarray analysis. Cellblocks containing carcinoma showed higher expression of miR-21, -221, and -196a than those from benign lesions (p<0.001, p=0.009, p<0.001, respectively).
Conclusions
Pancreatic ductal adenocarcinomas show differential expression of miRNAs compared to benign pancreatic lesions. A select panel of miRNAs aids the distinction between pancreatic lesions in cytology specimens.
doi:10.1097/MPA.0b013e318243a905
PMCID: PMC3375342  PMID: 22466166
Intraductal papillary mucinous neoplasm; Pancreas; Cytology; Fine needle aspiration; Molecular
12.  The Role of microRNAs in the Tumorigenesis of Ovarian Cancer 
Frontiers in Oncology  2013;3:153.
Epithelial ovarian cancer (EOC) is a complex disease, with multiple histological subtypes recognized. There have been major advances in the understanding of the cellular and molecular biology of this human malignancy, however the survival rate of women with EOC has changed little since platinum-based-treatment was introduced more than 30 years ago. Since 2006, an increasing number of studies have indicated an essential role for microRNAs (miRNAs) in ovarian-cancer tumorigenesis. Several miRNA profiling studies have shown that they associate with different aspects of ovarian cancer (tumor subtype, stage, histological grade, prognosis, and therapy resistance) and pointed to a critical role for miRNAs in the pathogenesis and progression of EOC. In this review, we discuss the current data concerning the accumulating evidence of the modulated expression of miRNAs in EOC, their role in diagnosis, prognosis, and prediction of response to therapy. Given the heterogeneity of this disease, it is likely that increases in long-term survival might be also achieved by translating the recent insights of miRNAs involvement in EOC into novel targeted therapies that will have a major impact on the management of ovarian cancer.
doi:10.3389/fonc.2013.00153
PMCID: PMC3682193  PMID: 23785667
microRNA; ovarian cancer; noncoding RNA; miRNA profiling; miRNA profiles
13.  The Tumor-Suppressive miR-497-195 Cluster Targets Multiple Cell-Cycle Regulators in Hepatocellular Carcinoma 
PLoS ONE  2013;8(3):e60155.
MicroRNAs (miRNAs) are key post-transcriptional regulators of gene expression and commonly deregulated in carcinogenesis. To explore functionally crucial tumor-suppressive (TS)-miRNAs in hepatocellular carcinoma (HCC), we performed integrative function- and expression-based screenings of TS-miRNAs in six HCC cell lines. The screenings identified seven miRNAs, which showed growth-suppressive activities through the overexpression of each miRNA and were endogenously downregulated in HCC cell lines. Further expression analyses using a large panel of HCC cell lines and primary tumors demonstrated four miRNAs, miR-101, -195, -378 and -497, as candidate TS-miRNAs frequently silenced in HCCs. Among them, two clustered miRNAs miR-195 and miR-497 showed significant growth-suppressive activity with induction of G1 arrest. Comprehensive exploration of their targets using Argonute2-immunoprecipitation-deep-sequencing (Ago2-IP-seq) and genome-wide expression profiling after their overexpression followed by pathway analysis, revealed a significant enrichment of cell cycle regulators. Among the candidates, we successfully identified CCNE1, CDC25A, CCND3, CDK4, and BTRC as direct targets for miR-497 and miR-195. Moreover, target genes frequently upregulated in HCC in a tumor-specific manner, such as CDK6, CCNE1, CDC25A and CDK4, showed an inverse correlation in the expression of miR-195 and miR-497, and their targets. These results suggest the molecular pathway regulating cell cycle progression to be integrally altered by downregulation of miR-195 and miR-497 expression, leading to the aberrant cell proliferation in hepatocarcinogenesis.
doi:10.1371/journal.pone.0060155
PMCID: PMC3609788  PMID: 23544130
14.  MicroRNA profiling of adrenocortical tumors reveals miR-483 as a marker of malignancy 
Cancer  2010;117(8):1630-1639.
Background
We are interested in identifying molecular markers that can aid in the diagnosis of adrenocortical carcinoma (ACC). The aim of this study was to identify microRNAs (miRNAs or miRs) that are differentially expressed in malignant adrenocortical tumors as compared to benign tumors and assess their potential as diagnostic predictors.
Methods
Differentially expressed miRNAs were identified using microarray profiling of adrenocortical tumors and validated by quantitative real-time RT-PCR.
Results
Microarray profiling in benign and primary malignant adrenocortical tumors revealed a number of significant differences between these histological groups. Using directed quantitative RT-PCR analysis on a subset of these differentially expressed miRNAs, we determined that miRs −100, −125b, and −195 were significantly downregulated and miR-483-5p was significantly upregulated in malignant as compared to benign tumors. Furthermore, our work shows that miR-483-5p expression can accurately categorize tumors as benign or malignant.
Conclusions
We identified four miRNAs that are dysregulated in adrenocortical carcinoma. The high expression of one of these, miR-483-5p, appears to be a defining characteristic of adrenocortical malignancies and can be used to accurately distinguish between benign and malignant adrenocortical tumors.
doi:10.1002/cncr.25724
PMCID: PMC3051015  PMID: 21472710
adrenocortical carcinoma; adrenal; microRNA; diagnostic marker
15.  MiR-124 Suppresses Growth of Human Colorectal Cancer by Inhibiting STAT3 
PLoS ONE  2013;8(8):e70300.
Emerging evidence indicate that microRNAs (miRNAs) may play important roles in cancer. Aberrant expression of miRNAs has been frequently identified in different human malignancies, including colorectal cancer (CRC). However, the mechanism by which deregulated miRNAs impact the development of CRC remains largely elusive. In this study, we show that miR-124 is significantly down-regulated in CRC compared to adjacent non-tumor colorectal tissues. MiR-124 suppresses the expression of STAT3 by directly binding to its 3′-untranslated region (3′-UTR). Overexpression of miR-124 led to increased apoptosis of CRC cells and reduced tumor growth in vitro and in vivo. Knocking down STAT3 expression by specific siRNA suppressed the growth of CRC cells in vitro and in vivo, resembling that of miR-124 overexpression. Moreover, overexpression of STAT3 in miR-124-transfected CRC cells effectively rescued the inhibition of cell proliferation caused by miR-124. These data suggest that miR-124 serves as a tumor suppressor by targeting STAT3, and call for the use of miR-124 as a potential therapeutic tool for CRC, where STAT3 is often hyper-activated.
doi:10.1371/journal.pone.0070300
PMCID: PMC3734178  PMID: 23940556
16.  Methylation-mediated transcriptional repression of microRNAs during cervical carcinogenesis 
Epigenetics  2013;8(2):220-228.
Deregulated expression of microRNAs (miRNAs) is common and biologically relevant in cervical carcinogenesis and appears only partly related to chromosomal changes. We recently identified 32 miRNAs showing decreased expression in high-grade cervical intraepithelial neoplasia (CIN) and carcinomas not associated with a chromosomal loss, 6 of which were located within a CpG island. This study aimed to investigate to what extent these miRNAs are subject to DNA methylation-mediated transcriptional repression in cervical carcinogenesis.
 
Methylation-specific PCR (MSP) analysis on a cell line panel representing different stages of human papillomavirus (HPV) induced transformation revealed an increase in methylation of hsa-miR-149, -203 and -375 with progression to malignancy, whereas expression of these miRNAs was restored upon treatment with a demethylating agent. All three miRNAs showed significantly increased levels of methylation in cervical carcinomas, whereas methylation levels of hsa-miR-203 and -375 were also significantly increased in high-grade CIN. A pilot analysis showed that increased hsa-miR-203 methylation was also detectable in HPV-positive cervical scrapes of women with high-grade CIN compared with controls. Similar to recent findings on hsa-miR-375, ectopic expression of hsa-miR-203 in cervical cancer cells decreased both the proliferation rate and anchorage independent growth. We found evidence for methylation-mediated transcriptional repression of hsa-miR-149, -203 and -375 in cervical cancer. Methylation of the latter two was already apparent in precancerous lesions and represent functionally relevant events in HPV-mediated transformation. Increased hsa-miR-203 methylation was detectable in scrapes of women with high-grade CIN, indicating that methylated miRNAs may provide putative markers to assess the presence of (pre)cancerous lesions.
doi:10.4161/epi.23605
PMCID: PMC3592908  PMID: 23324622
microRNA; squamous cell carcinoma; DNA methylation; CIN lesion; HPV; MSP
17.  MicroRNA Profiling of BRCA1/2 Mutation-Carrying and Non-Mutation-Carrying High-Grade Serous Carcinomas of Ovary 
PLoS ONE  2009;4(10):e7314.
Background
MicroRNAs (miRNA) are 20∼25 nucleotide non-coding RNAs that inhibit the translation of targeted mRNA, and they have been implicated in the development of human malignancies. High grade serous ovarian carcinomas, the most common and lethal subtype of ovarian cancer, can occur sporadically or in the setting of BRCA1/2 syndromes. Little is known regarding the miRNA expression profiles of high grade serous carcinoma in relation to BRCA1/2 status, and compared to normal tubal epithelium, the putative tissue of origin for high grade serous carcinomas.
Methodology/Principal Findings
Global miRNA expression profiling was performed on a series of 33 high grade serous carcinomas, characterized with respect to BRCA1/2 status (mutation, epigenetic silencing with loss of expression or normal), and with clinical follow-up, together with 2 low grade serous carcinomas, 2 serous borderline tumors, and 3 normal fallopian tube samples, using miRNA microarrays (328 human miRNA). Unsupervised hierarchical clustering based on miRNA expression profiles showed no clear separation between the groups of carcinomas with different BRCA1/2 status. There were relatively few miRNAs that were differentially expressed between the genotypic subgroups. Comparison of 33 high grade serous carcinomas to 3 normal fallopian tube samples identified several dysregulated miRNAs (false discovery rate <5%), including miR-422b and miR-34c. Quantitative RT-PCR analysis performed on selected miRNAs confirmed the pattern of differential expression shown by microarray analysis. Prognostically, lower level miR-422b and miR-34c in high grade serous carcinomas were both associated with decreased disease-specific survival by Kaplan-Meier analysis (p<0.05).
Conclusions/Significance
High grade serous ovarian carcinomas with and without BRCA1/2 abnormalities demonstrate very similar miRNA expression profiles. High grade serous carcinomas as a group exhibit significant miRNA dysregulation in comparison to tubal epithelium and the levels of miR-34c and miR-422b appear to be prognostically important.
doi:10.1371/journal.pone.0007314
PMCID: PMC2749450  PMID: 19798417
18.  MiR-138 induces cell cycle arrest by targeting cyclin D3 in hepatocellular carcinoma 
Carcinogenesis  2012;33(5):1113-1120.
The deregulation of microRNA (miRNA) is frequently associated with a variety of cancers, including hepatocellular carcinoma (HCC). In this study, we identified 10 upregulated miRNAs (miR-217, miR-518b, miR-517c, miR-520g, miR-519a, miR-522, miR-518e, miR-525-3p, miR-512-3p and miR-518a-3p) and 10 downregulated miRNAs (miR-138, miR-214, miR-214#, miR-27a#, miR-199a-5p, miR-433, miR-511, miR-592, miR-483-5p and miR-483-3p) by Taqman miRNAs array and quantitative real-time PCR (qRT–PCR) confirmation. Additionally, we investigated the expression and possible role of miR-138 in HCC. qRT–PCR results showed that miR-138 was downregulated in 77.8%(14/18) of HCC tissues compared with adjacent non-tumor tissues. Overexpression of miR-138 reduced cell viability and colony formation by induction of cell arrest in HCC cell lines and inhibited tumor cell growth in xenograft nude mice. The use of miR-138 inhibitor increased cell viability and colony formation in HCC cell lines and tumor cell growth in xenograft nude mice. Using TargetScan predictions, CCND3 was defined as a potential direct target of miR-138. Furthermore, CCND3 protein expression was observed to be negatively correlated with miR-138 expression in HCC tissues. The dual-luciferase reporter gene assay results showed that CCND3 was a direct target of miR-138. The use of miR-138 mimic or inhibitor could decrease or increase CCND3 protein levels in HCC cell lines. We conclude that the frequently downregulated miR-138 can regulate CCND3 and function as a tumor suppressor in HCC. Therefore, miR-138 may serve as a useful therapeutic agent for miRNA-based HCC therapy.
doi:10.1093/carcin/bgs113
PMCID: PMC3334515  PMID: 22362728
19.  Roles and Mechanism of miR-199a and miR-125b in Tumor Angiogenesis 
PLoS ONE  2013;8(2):e56647.
MicroRNAs (miRNAs) have been shown to be involved in different aspects of cancer biology including tumor angiogenesis. In this study, we identified that two miRNAs, miR-199a and miR-125b were downregulated in ovarian cancer tissues and cell lines. Overexpression of miR-199a and miR-125b inhibited tumor-induced angiogenesis associated with the decrease of HIF-1α and VEGF expression in ovarian cancer cells. Moreover, the levels of miR-199a and miR-125b were negatively correlated with VEGF mRNA levels in ovarian tissues. We further showed that direct targets of miR-199a and miR-125b HER2 and HER3 were functionally relevant. Forced expression of HER2 and HER3 rescued miR-199a- and miR-125b-inhibiting angiogenesis responses and Akt/p70S6K1/HIF-1α pathway. This study provides a rationale for new therapeutic approach to suppress tumor angiogenesis using miR-199a, miR-125b, or their mimics for ovarian cancer treatment in the future.
doi:10.1371/journal.pone.0056647
PMCID: PMC3577861  PMID: 23437196
20.  MicroRNA Expression Signatures of Bladder Cancer Revealed by Deep Sequencing 
PLoS ONE  2011;6(3):e18286.
Background
MicroRNAs (miRNAs) are a class of small noncoding RNAs that regulate gene expression. They are aberrantly expressed in many types of cancers. In this study, we determined the genome-wide miRNA profiles in bladder urothelial carcinoma by deep sequencing.
Methodology/Principal Findings
We detected 656 differentially expressed known human miRNAs and miRNA antisense sequences (miRNA*s) in nine bladder urothelial carcinoma patients by deep sequencing. Many miRNAs and miRNA*s were significantly upregulated or downregulated in bladder urothelial carcinoma compared to matched histologically normal urothelium. hsa-miR-96 was the most significantly upregulated miRNA and hsa-miR-490-5p was the most significantly downregulated one. Upregulated miRNAs were more common than downregulated ones. The hsa-miR-183, hsa-miR-200b∼429, hsa-miR-200c∼141 and hsa-miR-17∼92 clusters were significantly upregulated. The hsa-miR-143∼145 cluster was significantly downregulated. hsa-miR-182, hsa-miR-183, hsa-miR-200a, hsa-miR-143 and hsa-miR-195 were evaluated by Real-Time qPCR in a total of fifty-one bladder urothelial carcinoma patients. They were aberrantly expressed in bladder urothelial carcinoma compared to matched histologically normal urothelium (p<0.001 for each miRNA).
Conclusions/Significance
To date, this is the first study to determine genome-wide miRNA expression patterns in human bladder urothelial carcinoma by deep sequencing. We found that a collection of miRNAs were aberrantly expressed in bladder urothelial carcinoma compared to matched histologically normal urothelium, suggesting that they might play roles as oncogenes or tumor suppressors in the development and/or progression of this cancer. Our data provide novel insights into cancer biology.
doi:10.1371/journal.pone.0018286
PMCID: PMC3065473  PMID: 21464941
21.  MiR-221 and MiR-222 Alterations in Sporadic Ovarian Carcinoma: Relationship to CDKN1B, CDKNIC and Overall Survival 
Genes, chromosomes & cancer  2010;49(7):577-584.
MicroRNAs are often aberrantly expressed in human neoplasms and are postulated to play a role in neoplastic initiation and progression. miR-221 and miR-222 negatively regulate expression of CDKN1B (p27)and CDKN1C (p57), two cell cycle regulators expressed in ovarian surface epithelium and down-regulated in ovarian carcinomas. We characterized miR-221 and miR-222 expression in 49 sporadic high grade ovarian carcinomas and determined whether somatic mutation or epigenetic alterations explained the differences in expression of these miRNAs. We correlated these findings with protein expression of CDKN1B and CDKN1C as assessed by immunohistochemistry. Expression of miR-221 and miR-222 were closely correlated with each other (P=0.0001). Interestingly, a lower ratio of miR-221 to miR-222 expression was significantly correlated with worse overall survival (P=0.01) and remained a significant predictor of overall survival in multivariate analysis using the co-variate adequacy of surgical cytoreduction (P=0.03). Higher miR-222 and miR-221 expression were significantly associated with decreased CDKN1C expression (P=0.009 and 0.01). In contrast, CDKN1B expression was not associated with miR-221 or miR-222 expression. Neither somatic mutations nor methylation of the studied region explained the alterations in miR-221 and miR-222 expression in most carcinomas.
doi:10.1002/gcc.20768
PMCID: PMC2869465  PMID: 20461750
22.  Phospho-ΔNp63α is a key regulator of the cisplatin-induced microRNAome in cancer cells 
Cell Death and Differentiation  2011;18(7):1220-1230.
Head and neck squamous cell carcinoma (HNSCC) cells exposed to cisplatin (CIS) displayed a dramatic ATM-dependent phosphorylation of ΔNp63α that leads to the transcriptional regulation of downstream mRNAs. Here, we report that phospho (p)-ΔNp63α transcriptionally deregulates miRNA expression after CIS treatment. Several p-ΔNp63α-dependent microRNA species (miRNAs) were deregulated in HNSCC cells upon CIS exposure, including miR-181a, miR-519a, and miR-374a (downregulated) and miR-630 (upregulated). Deregulation of miRNA expression led to subsequent modulation of mRNA expression of several targets (TP53-S46, HIPK2, ATM, CDKN1A and 1B, CASP3, PARP1 and 2, DDIT1 and 4, BCL2 and BCL2L2, TP73, YES1, and YAP1) that are involved in the apoptotic process. Our data support the notion that miRNAs are critical downstream targets of p-ΔNp63α and mediate key pathways implicated in the response of cancer cells to chemotherapeutic drugs.
doi:10.1038/cdd.2010.188
PMCID: PMC3131951  PMID: 21274007
p63; cisplatin; squamous cell carcinomas; DICER1; microRNA
23.  Subsite-based alterations in miR-21, miR-125b, and miR-203 in squamous cell carcinoma of the oral cavity and correlation to important target proteins 
Background:
MicroRNAs (miRNAs) are small noncoding RNA molecules with an essential role in regulation of gene expression. miRNA expression profiles differ between tumor and normal control tissue in many types of cancers and miRNA profiling is seen as a promising field for finding new diagnostic and prognostic tools.
Materials and Methods:
In this study, we have analyzed expression of three miRNAs, miR-21, miR-125b, and miR-203, and their potential target proteins p53 and p63, known to be deregulated in squamous cell carcinoma of the head and neck (SCCHN), in two distinct and one mixed subsite in squamous cell carcinoma in the oral cavity.
Results:
We demonstrate that levels of miRNA differ between tumors of different subsites with tongue tumors showing significant deregulation of all three miRNAs, whereas gingival tumors only showed significant downregulation of miR-125b and the mixed group of tumors in tongue/floor of the mouth showed significant deregulation of miR-21 and miR-125b. In the whole group of oral squamous cell carcinoma (SCC), a significant negative correlation was seen between miR-125b and p53 as well as a significant correlation between TP53 mutation status and miR-125b.
Conclusion:
The present data once again emphasize the need to take subsite into consideration when analyzing oral SCC and clearly show that data from in vitro studies cannot be transferred directly to the in vivo situation.
doi:10.4103/1477-3163.104007
PMCID: PMC3515918  PMID: 23230394
MicroRNA; oral squamous cell carcinoma; p53; p63
24.  Transcriptome and Small RNA Deep Sequencing Reveals Deregulation of miRNA Biogenesis in Human Glioma 
The Journal of pathology  2013;229(3):10.1002/path.4109.
Altered expression of oncogenic and tumor-suppressing microRNAs (miRNAs) is widely associated with tumorigenesis. However, the regulatory mechanisms underlying these alterations are poorly understood. We sought to shed light on the deregulation of miRNA biogenesis promoting the aberrant miRNA expression profiles identified in these tumors. Using sequencing technology to perform both whole-transcriptome and small RNA sequencing of glioma patient samples, we examined precursor and mature miRNAs to directly evaluate the miRNA maturation process, and interrogated expression profiles for genes involved in the major steps of miRNA biogenesis. We found that ratios of mature to precursor forms of a large number of miRNAs increased with the progression from normal brain to low-grade and then to high-grade gliomas. The expression levels of genes involved in each of the three major steps of miRNA biogenesis (nuclear processing, nucleo-cytoplasmic transport, and cytoplasmic processing) were systematically altered in glioma tissues. Survival analysis of an independent data set demonstrated that the alteration of genes involved in miRNA maturation correlates with survival in glioma patients. Direct quantification of miRNA maturation with deep sequencing demonstrated that deregulation of the miRNA biogenesis pathway is a hallmark for glioma genesis and progression.
doi:10.1002/path.4109
PMCID: PMC3857031  PMID: 23007860
microRNA; biogenesis; glioma
25.  MiR-15a and MiR-16 control Bmi-1 expression in ovarian cancer 
Cancer research  2009;69(23):9090-9095.
Oncogenic activation of Bmi-1 is found in a wide variety of epithelial malignancies including ovarian cancer, yet a specific mechanism for over expression of Bmi-1 has not been determined. Thus realizing the immense pathological significance of Bmi-1 in cancer, we wanted to investigate if microRNA aberrations played a role in the regulation of Bmi-1 in ovarian cancer. In this report we identify two microRNAs, miR-15a and miR-16 that are under expressed in ovarian cell lines and in primary ovarian tissues. We demonstrate that these miRNAs directly target the Bmi-1 3’ UTR and significantly correlate with Bmi-1 protein levels in ovarian cancer patients and cell lines. Furthermore, Bmi-1 protein levels are down regulated in response to miR-15a or miR-16 expression and lead to significant reduction in ovarian cancer cell proliferation and clonal growth. These findings suggest the development of therapeutic strategies by restoring miR-15a and miR-16 expression in ovarian cancer and in other cancers that involve up regulation of Bmi-1.
doi:10.1158/0008-5472.CAN-09-2552
PMCID: PMC2859686  PMID: 19903841
MicroRNA; ovarian cancer; Bmi-1; clonal growth; proliferation

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