MicroRNAs

This section is being extended during 2015.

MicroRNAs involved in Cancer

NameAliasesLocationTarget(s)Main EffectPublicationsDetail
miR-21MIRN21, miR-21, miRNA21, hsa-mir-2117q23.1PDCD4,  PTEN,  RECK,  TIMP3,  and 34 other genesoncogenic 789View
miR-126MIRN126, miRNA1269q34.3VEGFA,  PIK3R2,  CXCL2,  SOX2,  and 5 other genestumor-suppressive 132View
miR-122MIR122A, MIRN122, MIRN122A, miRNA122, miRNA122A, hsa-mir-12218q21.31IGF1R,  PTTG1IP,  CDK4,  ADAM10,  and 7 other genestumor-suppressive 96View
let-7cLET7C, let-7c, MIRNLET7C, hsa-let-7c21q21.15088,  BCL2L1,  CASP3,  SOCS1tumor-suppressive 69View
let-7bLET7B, let-7b, MIRNLET7B, hsa-let-7b22q13.31CYP2J2,  CCND1,  PRDM1tumor-suppressive 66View
miR-107MIRN107, miR-10710q23.31DICER1,  SUZ12,  KLF4,  NFIA,  and 6 other genestumor-suppressive 45View
let-7gLET7G, MIRNLET7G, hsa-let-7g3p21.1GAB2,  COL1A2,  BCL2L1,  FN1,  and 1 other genestumor-suppressive 42View
miR-10aMIRN10A, mir-10a, miRNA10A, hsa-mir-10a17q21.32DDX11,  RB1CC1,  SRSF1,  KLF4,  and 4 other genesoncogenic 41View
let-7iLET7I, MIRNLET7I, hsa-let-7i12q14.1PGRMC1tumor-suppressive 34View
miR-127MIRN127, miRNA12714q32.2CXCL12tumor-suppressive 26View
let-7dLET7D, let-7d, MIRNLET7D, hsa-let-7d9q22.32PBX3tumor-suppressive 26View
miR-127-3pMIRN127, miRNA12714q32.226View
let-7eLET7E, let-7e, MIRNLET7E, hsa-let-7e19q13.41CCND1,  MYCNtumor-suppressive 25View
miR-124aMIR124A, MIR124A1, MIRN124-1, MIRN124A18p23.1CDK6tumor-suppressive 21View
miR-1290MIRN1290, hsa-mir-12901KIF13B10View
miR-1301MIRN1301, hsa-mir-13012tumor-suppressive 5View
miR-1297MIRN1297, hsa-mir-129713TRIB2,  PTENtumor-suppressive 5View
miR-1271MIRN1271, hsa-mir-12715q35GPC3tumor-suppressive 5View
miR-1258MIRN1258, hsa-mir-12582q31.3HPSEtumor-suppressive 4View
miR-1256MIRN1256, hsa-mir-12561TRIM68tumor-suppressive 2View
miR-1226MIRN1226, hsa-mir-12263p21.31MUC1tumor-suppressive 1View

Latest Publications

Sun X, Luo S, He Y, et al.
Screening of the miRNAs related to breast cancer and identification of its target genes.
Eur J Gynaecol Oncol. 2014; 35(6):696-700 [PubMed] Related Publications
OBJECTIVE: To predict and verify the target genes of the miRNAs related to breast cancer beginning from the miRNA expression profile of human breast cancer.
MATERIALS AND METHODS: The total RNA was extracted from cancer tissues and the corresponding paracancerous tissues of eight breast cancer patients, and then miRNAs were separated. Human breast cancer cell line MDA-MB-231 and the normal mammary epithelial cell line HBL-100 were cultured, and the total RNA was extracted, respectively, with separation of miRNAs. The gene chip technology was used to analyze and detect the miRNAs differentially expressed in tissues and cancer cells. The miRNA expression profile of human breast cancer was obtained through chip scanning and data analysis.
RESULTS: Through dual-luciferase method, it was verified that PDCD4 and PDCD10 were real target genes of miR-21 and miR-200c, respectively.
CONCLUSION: miR-21 and miR-200c are related miRNAs to breast cancer, and they are associated with the occurrence and development of breast cancer.

Su Z, Hou XK, Wen QP
Propofol induces apoptosis of epithelial ovarian cancer cells by upregulation of microRNA let-7i expression.
Eur J Gynaecol Oncol. 2014; 35(6):688-91 [PubMed] Related Publications
OBJECTIVE: Propofol is one of the extensively and commonly used intravenous anaesthetic agents. The aims of the current study were to evaluate effects of propofol on the behavior of human epithelial ovarian cancer (EOC) cells and role of miR-let-7i in these effects.
MATERIALS AND METHODS: The effects of propofol on cell proliferation and apoptosis were detected by MTT assays and flow cytometry. Real-time polymerase chain reaction (PCR) was used to assess miR-let-7i expression in human EOC cells OVCAR-3 with or without propofol treatment. Finally, the authors evaluated the effect ofmiR-let-7i on propofol-induced anti-tumor activity using anti-miR-let-7i.
RESULTS: Propofol inhibited the proliferation of OVCAR-3 cells in a dose- and time-dependent manner. After exposure to propofol for 24 hours, OVCAR-3 cells showed increased apoptosis and increased expression of miR-let-7i. Finally, anti-miR-let-7i reversed the effect of propofol on cell proliferation and apoptosis.
CONCLUSIONS: Propofol can effectively inhibit proliferation and induce apoptosis of EOC cells and modulation of miR-let-7i possibly contributes to the anti-tumor action of propofol.

Wen Z, Lei Z, Jin-An M, et al.
The inhibitory role of miR-214 in cervical cancer cells through directly targeting mitochondrial transcription factor A (TFAM).
Eur J Gynaecol Oncol. 2014; 35(6):676-82 [PubMed] Related Publications
Mitochondrial transcription factor A (TFAM) is a high-mobility group (HMG) protein and acts as a key regulator in mitochondrial DNA (mtDNA) replication, transcription, and inheritance. Accumulating evidence has demonstrated that TFAM plays an important role in tumorigenesis; however, the regulatory mechanism of TFAM in cervical cancer has not been revealed. In the current study, the au- thors found that with malignancy of cervical cancer, the protein expression of TFAM was gradually increased, while the expression of miRNA-214 was gradually downregulated. They further identified that TFAM is a target of miR-214. Forced overexpression of miRNA-214 significantly suppressed cell proliferation, cell cycle progression, colony-formation, and migration of cervical cancer Hela and Caski cells; however, upregulation of TFAM notably promoted cell proliferation, cell cycle progression, colony-formation, and migration of Hela and Caski cells. The authors further showed that miR-214 enhanced the susceptibility of Hela and Caski cells to the chemotherapy drug cisplatin. In conclusion, the current study provides a new sight for the regulatory pattern of miRNA-214 and TFAM in cervical cancer in vitro, indicating that miRNA-214 and MTFA may become important candidates for developing promising therapeutic strategies for the treatment of cervical cancer.

Wang L, Wang B, Fang M, et al.
Identification of microRNAs and target genes involved in serous ovarian carcinoma and their influence on survival.
Eur J Gynaecol Oncol. 2014; 35(6):655-61 [PubMed] Related Publications
AIMS: To identify the expression of key microRNAs and their predicted target genes involved in serous ovarian carcinoma (SOC) and correlation between miRNAs and prognosis.
MATERIALS AND METHODS: The authors used quantitative polymerase chain reaction (qPCR) to detect the expression of miR-145, miR-143, miR-146a, miR-93, miR-29a, miR-18a, and miR-200a in tissues of 56 primary SOC patients and 30 benign lesion patients. Four protein (MUC1, FAP, MMP2, MMP9) expressions were identified by western blotting and immunohistochemical stain. The Kaplan-Meier method was used to estimate the relationship of these miRNAs with overall survival rate.
RESULTS: In SOC tissue, expression of miR-200a, miR-93, miR-146a, and miR-18a were up-regulated, while miR-145, miR-143, miR-29a were down-regulated. MUC1, FAP, MMP2, and MMP9 were overexpressed in SOC. MiR-143 or miR-145 higher expressed patients had significantly higher overall survival (OS) rates, while miR-93 or miR-200a lower expressed patients also had higher OS rates.
DISCUSSION: These results suggested that several miRNAs and their regulated target transcripts may have important roles in the initiation and development of SOC. MiR-145/miR-143, miR-200a, and miR-93 could be used as prognostic biomarkers.

Hall DP, Cost NG, Hegde S, et al.
TRPM3 and miR-204 establish a regulatory circuit that controls oncogenic autophagy in clear cell renal cell carcinoma.
Cancer Cell. 2014; 26(5):738-53 [PubMed] Article available free on PMC after 10/11/2015 Related Publications
Autophagy promotes tumor growth by generating nutrients from the degradation of intracellular structures. Here we establish, using shRNAs, a dominant-negative mutant, and a pharmacologic inhibitor, mefenamic acid (MFA), that the Transient Receptor Potential Melastatin 3 (TRPM3) channel promotes the growth of clear cell renal cell carcinoma (ccRCC) and stimulates MAP1LC3A (LC3A) and MAP1LC3B (LC3B) autophagy. Increased expression of TRPM3 in RCC leads to Ca(2+) influx, activation of CAMKK2, AMPK, and ULK1, and phagophore formation. In addition, TRPM3 Ca(2+) and Zn(2+) fluxes inhibit miR-214, which directly targets LC3A and LC3B. The von Hippel-Lindau tumor suppressor (VHL) represses TRPM3 directly through miR-204 and indirectly through another miR-204 target, Caveolin 1 (CAV1).

Cecconi F, Jäättelä M
Targeting ions-induced autophagy in cancer.
Cancer Cell. 2014; 26(5):599-600 [PubMed] Related Publications
Autophagy is an important cellular homeostasis pathway, but its role in cancer remains to be fully elucidated. In this issue of Cancer Cell, Hall and colleagues describe a TRPM3-dependent autophagy pathway that is selectively important for clear cell renal cell carcinoma and can be effectively inhibited.

Chaluvally-Raghavan P, Zhang F, Pradeep S, et al.
Copy number gain of hsa-miR-569 at 3q26.2 leads to loss of TP53INP1 and aggressiveness of epithelial cancers.
Cancer Cell. 2014; 26(6):863-79 [PubMed] Article available free on PMC after 08/12/2015 Related Publications
Small noncoding miRNAs represent underexplored targets of genomic aberrations and emerging therapeutic targets. The 3q26.2 amplicon is among the most frequent genomic aberrations in multiple cancer lineages including ovarian and breast cancers. We demonstrate that hsa-miR-569 (hereafter designated as miR569), which is overexpressed in a subset of ovarian and breast cancers, at least in part due to the 3q26.2 amplicon, alters cell survival and proliferation. Downregulation of TP53INP1 expression by miR569 is required for the effects of miR569 on survival and proliferation. Targeting miR569 sensitizes ovarian and breast cancer cells overexpressing miR569 to cisplatin by increasing cell death both in vitro and in vivo. Thus targeting miR569 could potentially benefit patients with the 3q26.2 amplicon and subsequent miR569 elevation.

Xu M, Qiang F, Gao Y, et al.
Evaluation of a novel functional single-nucleotide polymorphism (rs35010275 G>C) in MIR196A2 promoter region as a risk factor of gastric cancer in a Chinese population.
Medicine (Baltimore). 2014; 93(26):e173 [PubMed] Related Publications
Single-nucleotide polymorphisms (SNPs) in microRNAs (miRNAs) have been suggested to influence the occurrence and progression of cancer through altering the expression and biological function of miRNAs. The aim of this study was to investigate whether the potential functional SNPs in MIR196A2 promoter had effect on the susceptibility to gastric cancer (GC) in a Chinese population.We conducted a 2-stage case-control study (753 cases and 854 controls in testing set; 940 cases and 1061 controls in validation set) to evaluate the association between 2 potential functional SNPs in MIR196A2 promoter (rs12304647 A>C and rs35010275 G>C) and GC risk. The luciferase reporter assay and electrophoretic mobility shift assay were used to examine the functionality of the important polymorphism.We found that the rs35010275 C allele was significantly associated with the decreased risk of GC (adjusted odds ratio = 0.85, 95% confidence interval = 0.77-0.94) in the combined case-control studies. The miR-196a expression levels in GC tissues were significantly higher than that in corresponding adjacent normal tissues (P < 0.001). Besides, each allele of rs35010275 displayed completely opposite effects to influence the transcription activity of MIR196A2 promoter via recruiting different transcription factors or complexes.The functional rs35010275 G>C polymorphism in MIR196A2 promoter was significantly associated with miR-196a expression and influenced the genetic susceptibility to GC.

Xu Z, Zeng X, Tian D, et al.
MicroRNA-383 inhibits anchorage-independent growth and induces cell cycle arrest of glioma cells by targeting CCND1.
Biochem Biophys Res Commun. 2014; 453(4):833-8 [PubMed] Related Publications
In recent years, microRNAs (miRNAs) have been proved to be closely related to the tumorigenesis and progression. An increasing number of researches have shown that microRNAs function as oncogenes or tumor suppressor genes in human malignant tumors. This study aims to explore the effects of microRNA-383 (miR-383) on malignant biological function of human gliomas. We detected the expression of miR-383 in glioma tissues and normal brain tissues by quantitative real-time PCR. Anchorage-independent growth assays, and flow cytometry were used to evaluate the functions of miR-383 that involves in cell growth and cell cycle. Western blotting assay was used to examine protein expression levels of Cyclin D1 (CCND1), a cell cycle-associated oncogene which has a predicted binding site of miR-383 within its 3'-untranslated region (3'-UTR), and luciferase activity assay was used to evaluate the 3'-UTR activity of CCND1. In this study, we found that miR-383 expression level was lower in gliomas than normal brain tissues. Overexpression of miR-383 in U251 and U87 cells showed a significant inhibitory effect on cell growth, which accompanied with cell cycle G0/G1 arrest as well as downregulation of CCND1 expression. Moreover, CCND1 was verified to be one of the direct targets of miR-383. In summary, this study suggested that miR-383 plays the role of tumor suppressor by targeting CCND1 in glioma cells, and may be useful for developing a new therapeutic strategy for gliomas.

Wang R, Tian S, Wang HB, et al.
MiR-185 is involved in human breast carcinogenesis by targeting Vegfa.
FEBS Lett. 2014; 588(23):4438-47 [PubMed] Related Publications
MiR-185 expression has been associated with many cancers. However, the roles of miR-185 in human breast cancer remain elusive. Here, we found that miR-185 expression was decreased in human breast cancer tissues compared with healthy tissue controls. Up-regulation of miR-185 inhibited breast cancer cell proliferation and invasion and vice versa. MiR-185 was shown to bind to the 3′-untranslated region (UTR) of vascular endothelial growth factor a (Vegfa), and a significant inverse correlation was found between miR-185 and Vegfa. Vegfa overexpression partially restored the inhibition of cell proliferation and invasion that was induced by miR-185, and vice versa. Additionally, Vegfa expression was found to be high in human breast cancer tissues. Thus, miR-185-mediated Vegfa targeting may be involved in breast cancer formation.

Wang Z, Ma X, Cai Q, et al.
MiR-199a-3p promotes gastric cancer progression by targeting ZHX1.
FEBS Lett. 2014; 588(23):4504-12 [PubMed] Related Publications
Accumulating evidence has indicated that microRNAs (miRNAs) act as critical epigenetic regulators in tumor carcinogenesis. Here, we report that miR-199a-3p was significantly upregulated in gastric cancer (GC) cell lines and tissues. Functional studies demonstrated that miR-199a-3p dramatically increased cell proliferation and suppressed cell apoptosis both in vitro and in vivo. Furthermore, the transcriptional regulator zinc fingers and homeoboxes 1 (ZHX1) was identified as one of the direct downstream targets of miR-199a-3p, miR-199a-3p bound to the ZHX1 3′ untranslated region (3′UTR) to regulate ZHX1 protein expression. In addition, the expression of miR-199a-3p was inversely associated with that of ZHX1 in GC cell lines. Overexpression of miR-199a-3p in SGC-7901 cells inhibited ZHX1 expression, while reduction in miR-199a-3p by inhibitors in NCI-N87 cells enhanced ZHX1 expression. Moreover, restoring ZHX1 expression in SGC-7901/miR-199a-3p cells inhibited the cell proliferation induced by miR-199a-3p. Taken together, these findings suggest that miR-199a-3p may function as a novel tumor promoter in GC and its oncogenic activity may involve the direct targeting and inhibition of ZHX1.

Wang X, He H, Lu Y, et al.
Indole-3-carbinol inhibits tumorigenicity of hepatocellular carcinoma cells via suppression of microRNA-21 and upregulation of phosphatase and tensin homolog.
Biochim Biophys Acta. 2015; 1853(1):244-53 [PubMed] Article available free on PMC after 08/12/2015 Related Publications
A major obstacle to successful treatment of hepatocellular carcinoma (HCC) is its high resistance to cytotoxic chemotherapy due to overexpression of multidrug resistance genes. Activation of the AKT pathway is known to be involved in chemoresistance in HCC; however, the underlying mechanisms modulating the AKT pathway by chemopreventive agents remain unclear. In the present study, we found that indole-3-carbinol (I3C) treatment for tumor cells repressed the AKT pathway by increasing the expression of phosphatase and tensin homolog (PTEN) in HCC xenograft tumor and HCC cell lines. qRT-PCR data showed that the expression of miR-21 and miR-221&222 was significantly reduced by I3C in HCC cells in vitro and in vivo. Reactivation of the AKT pathway via restoration of miR-21 was reversed by I3C. Ectopic expression of miR-21 mediated-accelerated wound healing was abrogated by I3C. Moreover, reducing the expression of miR-21 by anti-miR decreased the resistance of HCC cells to I3C. These results provide experimental evidences that I3C could function as a miR-21 regulator, leading to repression of the PTEN/AKT pathway and opening a new avenue for eradication of drug-resistant cells, thus potentially helping to improve the therapeutic outcome in patients diagnosed with HCC.

Melo SA, Sugimoto H, O'Connell JT, et al.
Cancer exosomes perform cell-independent microRNA biogenesis and promote tumorigenesis.
Cancer Cell. 2014; 26(5):707-21 [PubMed] Article available free on PMC after 10/11/2015 Related Publications
Exosomes are secreted by all cell types and contain proteins and nucleic acids. Here, we report that breast cancer associated exosomes contain microRNAs (miRNAs) associated with the RISC-Loading Complex (RLC) and display cell-independent capacity to process precursor microRNAs (pre-miRNAs) into mature miRNAs. Pre-miRNAs, along with Dicer, AGO2, and TRBP, are present in exosomes of cancer cells. CD43 mediates the accumulation of Dicer specifically in cancer exosomes. Cancer exosomes mediate an efficient and rapid silencing of mRNAs to reprogram the target cell transcriptome. Exosomes derived from cells and sera of patients with breast cancer instigate nontumorigenic epithelial cells to form tumors in a Dicer-dependent manner. These findings offer opportunities for the development of exosomes based biomarkers and therapies.

Yunqiao L, Vanke H, Jun X, Tangmeng G
MicroRNA-206, down-regulated in hepatocellular carcinoma, suppresses cell proliferation and promotes apoptosis.
Hepatogastroenterology. 2014 Jul-Aug; 61(133):1302-7 [PubMed] Related Publications
BACKGROUND/AIMS: MicroRNA-206 has been proven down-regulated in many human malignancies and correlated with tumor progression. However, the expression and functions of miR-206 in hepatocellular carcinoma (HCC) are still unclear. The aim of this study was to explore the effects of miR-206 in HCC tumorigenesis and development.
METHODOLOGY: The expression levels of miR-206 were quantified by qRT-PCR in 147 surgically resected HCC and matched adjacent non-cancerous tissues, and correlated with clinicopathological factors. MTT, flow cytometric assay, and Transwell invasion and migration assays were used to test the proliferation, apoptosis, invasion, and migration of HepG2 HCC cells transfected with miR-206 mimics or negative control (NC) RNA-oligonucleotides.
RESULTS: MiR-206 expression was significantly downregulated in HCC compared with matched non-cancerous liver tissues. Low level of miR-206 was associated with poor tumor differentiation, multiple tumor nodes, lymph node metastasis, and advanced TNM stage. In addition, transfection of miR-206 mimics in HepG2 cells was able to reduce cell proliferation, invasion, and migration, and promote cell apoptosis.
CONCLUSIONS: These findings demonstrate that miRNA-206 could not only be useful as a novel biomarker but also serve as a potential target for gene therapy of HCC.

Zhang L, Ge Y, Fuchs E
miR-125b can enhance skin tumor initiation and promote malignant progression by repressing differentiation and prolonging cell survival.
Genes Dev. 2014; 28(22):2532-46 [PubMed] Article available free on PMC after 15/05/2015 Related Publications
Previously, we identified miR-125b as a key regulator of the undifferentiated state of hair follicle stem cells. Here, we show that in both mice and humans, miR-125b is abundantly expressed, particularly at early stages of malignant progression to squamous cell carcinoma (SCC), the second most prevalent cancer worldwide. Moreover, when elevated in normal murine epidermis, miR-125b promotes tumor initiation and contributes to malignant progression. We further show that miR-125b can confer "oncomiR addiction" in early stage malignant progenitors by delaying their differentiation and favoring an SCC cancer stem cell (CSC)-like transcriptional program. To understand how, we systematically identified and validated miR125b targets that are specifically associated with tumors that are dependent on miR-125b. Through molecular and genetic analysis of these targets, we uncovered new insights underlying miR-125b's oncogenic function. Specifically, we show that, on the one hand, mir-125b directly represses stress-responsive MAP kinase genes and associated signaling. On the other hand, it indirectly prolongs activated (phosphorylated) EGFR signaling by repressing Vps4b (vacuolar protein-sorting 4 homolog B), encoding a protein implicated in negatively regulating the endosomal sorting complexes that are necessary for the recycling of active EGFR. Together, these findings illuminate miR-125b as an important microRNA regulator that is shared between normal skin progenitors and their early malignant counterparts.

Zeitels LR, Acharya A, Shi G, et al.
Tumor suppression by miR-26 overrides potential oncogenic activity in intestinal tumorigenesis.
Genes Dev. 2014; 28(23):2585-90 [PubMed] Article available free on PMC after 01/06/2015 Related Publications
Down-regulation of miR-26 family members has been implicated in the pathogenesis of multiple malignancies. In some settings, including glioma, however, miR-26-mediated repression of PTEN promotes tumorigenesis. To investigate the contexts in which the tumor suppressor versus oncogenic activity of miR-26 predominates in vivo, we generated miR-26a transgenic mice. Despite measureable repression of Pten, elevated miR-26a levels were not associated with malignancy in transgenic animals. We documented reduced miR-26 expression in human colorectal cancer and, accordingly, showed that miR-26a expression potently suppressed intestinal adenoma formation in Apc(min/+) mice, a model known to be sensitive to Pten dosage. These studies reveal a tumor suppressor role for miR-26 in intestinal cancer that overrides putative oncogenic activity, highlighting the therapeutic potential of miR-26 delivery to this tumor type.

Park EY, Chang E, Lee EJ, et al.
Targeting of miR34a-NOTCH1 axis reduced breast cancer stemness and chemoresistance.
Cancer Res. 2014; 74(24):7573-82 [PubMed] Related Publications
Human breast cancers include cancer stem cell populations as well as nontumorigenic cancer cells. Breast cancer stem cells have self-renewal capability and are resistant to conventional chemotherapy. miRNAs regulate the expression of many target genes; therefore, dysregulation of miRNAs has been associated with the pathogenesis of human diseases, including cancer. However, a role for miRNA dysregulation in stemness and drug resistance has yet to be identified. Members of the miR34 family are reportedly tumor-suppressor miRNAs and are associated with various human cancers. Our results confirm that miR34a expression was downregulated in MCF7/ADR cells compared with MCF7 cells. We hypothesized that this reduction was due to the p53 (TP53) mutation in MCF7/ADR cells. In this study, we found that primary and mature miR34a were suppressed by treatment with p53 RNAi or the dominant-negative p53 mutant in MCF7 cells. Ectopic miR34a expression reduced cancer stem cell properties and increased sensitivity to doxorubicin treatment by directly targeting NOTCH1. Furthermore, tumors from nude mice treated with miR34a were significantly smaller compared with those of mice treated with control lentivirus. Our research suggests that the ectopic expression of miR34a represents a novel therapeutic approach in chemoresistant breast cancer treatment.

Shiah SG, Hsiao JR, Chang WM, et al.
Downregulated miR329 and miR410 promote the proliferation and invasion of oral squamous cell carcinoma by targeting Wnt-7b.
Cancer Res. 2014; 74(24):7560-72 [PubMed] Related Publications
microRNA (miRNA) dysregulation contributes widely to human cancer but has not been fully assessed in oral cancers. In this study, we conducted a global microarray analysis of miRNA expression in 40 pairs of betel quid-associated oral squamous cell carcinoma (OSCC) specimens and their matched nontumorous epithelial counterparts. Eighty-four miRNAs were differentially expressed in the OSCC specimens compared with the matched tissue. Among these downregulated miRNAs, 19 miRNAs were found and mapped to the chromosome 14q32.2 miRNA cluster region, which resides within a parentally imprinted region designated as Dlk-Dio3 and known to be important in development and growth. Bioinformatic analysis predicted two miRNAs from the cluster region, miR329 and miR410, which could potentially target Wnt-7b, an activator of the Wnt-β-catenin pathway, thereby attenuating the Wnt-β-catenin signaling pathway in OSCC. Stable ectopic expression of Wnt-7b in OSCC cells overexpressing miR329 or miR410 restored proliferation and invasion capabilities abolished by these miRNA. Combining a demethylation agent and a histone deacetylase inhibitor was sufficient to reexpress miR329, miR410, and Meg3, consistent with epigenetic regulation of these miRNA in human OSCC. Specifically, arecoline, a major betel nut alkaloid, reduced miR329, miR410, and Meg3 gene expression. Overall, our results provide novel molecular insights into how betel quid contributes to oral carcinogenesis through epigenetic silencing of tumor-suppressor miRNA that targets Wnt-β-catenin signaling.

Cote GA, Gore AJ, McElyea SD, et al.
A pilot study to develop a diagnostic test for pancreatic ductal adenocarcinoma based on differential expression of select miRNA in plasma and bile.
Am J Gastroenterol. 2014; 109(12):1942-52 [PubMed] Article available free on PMC after 01/06/2015 Related Publications
OBJECTIVES: Accurate peripheral markers for the diagnosis of pancreatic ductal adenocarcinoma (PDAC) are lacking. We measured the differential expression of select microRNAs (miRNAs) in plasma and bile among patients with PDAC, chronic pancreatitis (CP), and controls.
METHODS: We identified patients (n=215) with treatment-naive PDAC (n=77), CP with bile/pancreatic duct pathology (n=67), and controls (n=71) who had been prospectively enrolled in a Pancreatobiliary Biorepository at the time of endoscopic retrograde cholangiopancreatography or endoscopic ultrasound. Controls were patients with choledocholithiasis but normal pancreata. The sample was separated into training (n=95) and validation (n=120) cohorts to establish and then test the performance of PDAC Signature Panels in diagnosing PDAC. The training cohort (n=95) included age-matched patients with PDAC, CP, and controls. Panels were derived from the differential expression of 10 candidate miRNAs in plasma or bile. We selected miRNAs having excellent accuracy for inclusion in regression models.
RESULTS: Using the training cohort, we confirmed the differential expression of 9/10 miRNAs in plasma (miR-10b, -30c, -106b, -132, -155, -181a, -181b, -196a, and -212) and 7/10 in bile (excluding miR-21, -132, and -181b). Of these, five (miR-10b, -155, -106b, -30c, and -212) had excellent accuracy for distinguishing PDAC. In the training and validation cohorts, the sensitivity/specificity for a PDAC Panel derived from plasma was 95/100% and 100/100%, respectively; in bile, these were 96/100% and 100/100%.
CONCLUSIONS: Increased expression of miRNA-10b, -155, and -106b in plasma appears highly accurate in diagnosing PDAC. Additional studies are needed to confirm this Panel and explore its value as a prognostic test.

Akçakaya P, Caramuta S, Åhlen J, et al.
microRNA expression signatures of gastrointestinal stromal tumours: associations with imatinib resistance and patient outcome.
Br J Cancer. 2014; 111(11):2091-102 [PubMed] Article available free on PMC after 01/06/2015 Related Publications
BACKGROUND: Gastrointestinal stromal tumour (GIST) is mainly initialised by receptor tyrosine kinase gene mutations. Although the tyrosine kinase inhibitor imatinib mesylate considerably improved the outcome of patients, imatinib resistance still remains a major therapeutic challenge in GIST therapy. Herein we evaluated the clinical impact of microRNAs in imatinib-treated GISTs.
METHODS: The expression levels of microRNAs were quantified using microarray and RT-qPCR in GIST specimens from patients treated with neoadjuvant imatinib. The functional roles of miR-125a-5p and PTPN18 were evaluated in GIST cells. PTPN18 expression was quantified by western blotting in GIST samples.
RESULTS: We showed that overexpression levels of miR-125a-5p and miR-107 were associated with imatinib resistance in GIST specimens. Functionally, miR-125a-5p expression modulated imatinib sensitivity in GIST882 cells with a homozygous KIT mutation but not in GIST48 cells with double KIT mutations. Overexpression of miR-125a-5p suppressed PTPN18 expression, and silencing of PTPN18 expression increased cell viability in GIST882 cells upon imatinib treatment. PTPN18 protein levels were significantly lower in the imatinib-resistant GISTs and inversely correlated with miR-125a-5p. Furthermore, several microRNAs were significantly associated with metastasis, KIT mutational status and survival.
CONCLUSIONS: Our findings highlight a novel functional role of miR-125a-5p on imatinib response through PTPN18 regulation in GIST.

Diao L, Su H, Wei G, et al.
Prognostic value of microRNA 502 binding site SNP in the 3'-untranslated region of the SET8 gene in patients with non-Hodgkin's lymphoma.
Tumori. 2014 Sep-Oct; 100(5):553-8 [PubMed] Related Publications
AIMS AND BACKGROUND: A number of important cancer-associated covalent modifications of histone genes can be regulated by microRNAs (miRNAs) that bind to their target sites in the 3'-untranslated regions. We evaluated the effect of single-nucleotide polymorphisms (SNPs) at the miR-502 binding site in the 3'-untranslated region of the SET8 gene on the clinical outcome of non-Hodgkin's lymphomas (NHL).
METHODS AND STUDY DESIGN: The miR-502 binding site SNP of rs16917496 in the 3'-untranslated region of SET8 was genotyped with the ligation detection reaction method. The association of rs16917496 with NHL survival was calculated with the log-rank test using the Kaplan-Meier method. Multivariate survival analysis was performed using a Cox proportional hazards model.
RESULTS: Patients carrying the rs16917496 CC genotype had a significantly longer survival time than patients carrying the CT genotype (P = 0.043) or TT genotype (P = 0.086). In addition, rs16917496 was associated independently with the survival of NHL patients in multivariate analysis (CC vs TT, 95% CI: 1.021-3.279, RR: 1.829, P = 0.043; CC vs CT, 95% CI: 1.026-3.339, RR: 1.851, P = 0.041). The association of rs16917496 with NHL survival was further identified in the peripheral T cell lymphoma (pTCL) subtype of NHL at borderline statistically significant levels (P = 0.069).
CONCLUSION: Our study provides evidence that the SNP in the miRNA binding site of the SET8 3'-untranslated region seems to influence survival of NHL. It may have possible prognostic and survival value in the clinic.

Sana J, Radova L, Lakomy R, et al.
Risk Score based on microRNA expression signature is independent prognostic classifier of glioblastoma patients.
Carcinogenesis. 2014; 35(12):2756-62 [PubMed] Related Publications
Glioblastoma multiforme (GBM) is the most malignant primary brain tumor. The prognosis of GBM patients varies considerably and the histopathological examination is not sufficient for individual risk estimation. MicroRNAs (miRNAs) are small, non-coding RNAs that function as post-transcriptional regulators of gene expression and were repeatedly proved to play important roles in pathogenesis of GBM. In our study, we performed global miRNA expression profiling of 58 glioblastoma tissue samples obtained during surgical resections and 10 non-tumor brain tissues. The subsequent analysis revealed 28 significantly deregulated miRNAs in GBM tissue, which were able to precisely classify all examined samples. Correlation with clinical data led to identification of six-miRNA signature significantly associated with progression free survival [hazard ratio (HR) 1.98, 95% confidence interval (CI) 1.33-2.94, P < 0.001] and overa+ll survival (HR 2.86, 95% CI 1.91-4.29, P < 0.001). O(6)-methylguanine-DNA methyltransferase methylation status was evaluated as reference method and Risk Score based on six-miRNA signature indicated significant superiority in prediction of clinical outcome in GBM patients. Multivariate Cox analysis indicated that the Risk Score based on six-miRNA signature is an independent prognostic classifier of GBM patients. We suggest that the Risk Score presents promising prognostic algorithm with potential for individualized treatment decisions in clinical management of GBM patients.

Pennelli G, Galuppini F, Barollo S, et al.
The PDCD4/miR-21 pathway in medullary thyroid carcinoma.
Hum Pathol. 2015; 46(1):50-7 [PubMed] Related Publications
Programmed cell death 4 (PDCD4) is a tumor suppressor gene involved in tumorogenesis. MicroRNA-21 (miR-21) specifically targets PDCD4, and recent studies suggest that PDCD4 is also regulated by Akt (antiapoptotic regulator within phosphatidylinositol 3-kinase). Medullary thyroid carcinoma (MTC) is a rare neuroendocrine cancer, and disease stage at diagnosis represents the main prognostic indicator. A consecutive series of 64 MTCs was considered. REarranged during Transfection (RET) and rat sarcoma (RAS) mutation status was assessed by direct sequencing. Quantitative real-time polymerase chain reaction was used to quantify mature hsa-miR-21. PDCD4 and Ki-67 immunostaining was performed with an automated platform. Immunoblot analysis of PI3K/Akt pathway was done on thyroid tissues. MTCs were consistently associated with miR-21 up-regulation (P < .0016) and featured significant PDCD4 nuclear down-regulation. An inverse correlation emerged between miR-21 overexpression and PDCD4 down-regulation (P = .0013). At enrollment, high miR-21 levels were associated with high calcitonin levels (P = .0003), lymph node metastases (P = .001), and advanced stages (P = .0003). At the end of follow-up, high miR-21 levels were associated with biochemically persistent disease (P = .0076). At enrollment, instead, PDCD4 nuclear down-regulation was associated with high calcitonin levels (P = .04), more advanced stages of disease (P < .01), and persistent disease after the follow-up (P = .02). p-Akt was more expressed in RAS-mutated MTC than in nonmutated cancers and normal tissue. This study showed, in MTCs, that miR-21 regulates PDCD4 expression and also that the miR-21/PDCD4 pathway correlates with clinicopathological variables and prognosis. Further studies should investigate the role of miR-21 as a prognostic biomarker and the feasibility of using PDCD4-restoring strategies as a therapeutic approach to MTC.

Song B, Ji W, Guo S, et al.
miR-545 inhibited pancreatic ductal adenocarcinoma growth by targeting RIG-I.
FEBS Lett. 2014; 588(23):4375-81 [PubMed] Related Publications
Pancreatic ductal adenocarcinoma (PDAC) ranks fourth on the list of cancer-related causes of death. Deregulation or dysfunction of miRNAs contribute to cancer development. In this study, we found that low miR-545 level and high RIG-I protein in PDAC tissues were both correlated with low survival rate. MiR-545 up-regulation inhibited PDAC cell lines growth and vice versa. 3'UTR of RIG-I was targeted by miR-545. Thus we concluded that low miR-545 levels in PDAC promote tumor cells growth, and this is associated with reduced survival in PDAC patients. MiR-545 exerts its effects by directly targeting RIG-1.

Gibert B, Delloye-Bourgeois C, Gattolliat CH, et al.
Regulation by miR181 family of the dependence receptor CDON tumor suppressive activity in neuroblastoma.
J Natl Cancer Inst. 2014; 106(11) [PubMed] Related Publications
BACKGROUND: The Sonic Hedgehog (SHH) signaling pathway plays an important role in neural crest cell fate during embryonic development and has been implicated in the progression of multiple cancers that include neuroblastoma, a neural crest cell-derived disease. While most of the SHH signaling is mediated by the well-described canonical pathway leading to the activation of Smoothened and Gli, it has recently been shown that cell-adhesion molecule-related/downregulated by oncogenes (CDON) serves as a receptor for SHH and contributes to SHH-induced signaling. CDON has also been recently described as a dependence receptor, triggering apoptosis in the absence of SHH. This CDON proapoptotic activity has been suggested to constrain tumor progression.
METHODS: CDON expression was analyzed by quantitative-reverse transcription-polymerase chain reaction in a panel of 226 neuroblastoma patients and associated with stages, overall survival, and expression of miR181 family members using Kaplan Meier and Pearson correlation methods. Cell death assays were performed in neuroblastoma cell lines and tumor growth was investigated in the chick chorioallantoic model. All statistical tests were two-sided.
RESULTS: CDON expression was inversely associated with neuroblastoma aggressiveness (P < .001). Moreover, re-expression of CDON in neuroblastoma cell lines was associated with apoptosis in vitro and tumor growth inhibition in vivo. We show that CDON expression is regulated by the miR181 miRNA family, whose expression is directly associated with neuroblastoma aggressiveness (survival: high miR181-b 73.2% vs low miR181-b 54.6%; P = .03).
CONCLUSIONS: Together, these data support the view that CDON acts as a tumor suppressor in neuroblastomas, and that CDON is tightly regulated by miRNAs.

Dong W, Shen R, Cheng S
Reduction of TIP30 in esophageal squamous cell carcinoma cells involves promoter methylation and microRNA-10b.
Biochem Biophys Res Commun. 2014; 453(4):772-7 [PubMed] Related Publications
TIP30 is a putative tumor suppressor that can promote apoptosis and inhibit angiogenesis. However, the role of TIP30 in esophageal squamous cell carcinoma (ESCC) biology has not been investigated. Immunohistochemistry was used to investigate the expression of TIP30 in 70 ESCC. Hypermethylation of TIP30 was evaluated by the methylation specific PCR (MSP) method in ESCC (tumor and paired adjacent non-tumor tissues). Lost expression of TIP30 was observed in 50 of 70 (71.4%) ESCC. 61.4% (43 of 70) of primary tumors analyzed displayed TIP30 hypermethylation, indicating that this aberrant characteristic is common in ESCC. Moreover, a statistically significant inverse association was found between TIP30 methylation status and expression of the TIP30 protein in tumor tissues (p=0.001). We also found that microRNA-10b (miR-10b) targets a homologous DNA region in the 3'untranslated region of the TIP30 gene and represses its expression at the transcriptional level. Reporter assay with 3'UTR of TIP30 cloned downstream of the luciferase gene showed reduced luciferase activity in the presence of miR-10b, providing strong evidence that miR-10b is a direct regulator of TIP30. These results suggest that TIP30 expression is regulated by promoter methylation and miR-10b in ESCC.

Volinia S, Nuovo G, Drusco A, et al.
Pluripotent stem cell miRNAs and metastasis in invasive breast cancer.
J Natl Cancer Inst. 2014; 106(12) [PubMed] Related Publications
BACKGROUND: The purpose of this study is to determine whether microRNA for pluripotent stem cells are also expressed in breast cancer and are associated with metastasis and outcome.
METHODS: We studied global microRNA profiles during differentiation of human embryonic stem cells (n =26) and in breast cancer patients (n = 33) and human cell lines (n = 35). Using in situ hybridization, we then investigated MIR302 expression in 318 untreated breast cancer patients (test cohort, n = 22 and validation cohort, n = 296). In parallel, using next-generation sequencing data from breast cancer patients (n = 684), we assessed microRNA association with stem cell markers. All statistical tests were two-sided.
RESULTS: In healthy tissues, the MIR302 (high)/MIR203 (low) asymmetry was exclusive for pluripotent stem cells. MIR302 was expressed in a small population of cancer cells within invasive ductal carcinoma, but not in normal breast (P < .001). Furthermore, MIR302 was expressed in the tumor cells together with stem cell markers, such as CD44 and BMI1. Conversely, MIR203 expression in 684 breast tumors negatively correlated with CD44 (Spearman correlation, Rho = -0.08, P = .04) and BMI1 (Rho = -0.11, P = .004), but positively correlated with differentiation marker CD24 (Rho = 0.15, P < .001). Primary tumors with lymph node metastasis had cancer cells showing scattered expression of MIR302 and widespread repression of MIR203. Finally, overall survival was statistically significantly shorter in patients with MIR302-positive cancer cells (P = .03).
CONCLUSIONS: In healthy tissues the MIR302(high)/MIR203(low) asymmetry was characteristic of embryonic and induced pluripotency. In invasive ductal carcinoma, the MIR302/MIR203 asymmetry was associated with stem cell markers, metastasis, and shorter survival.

Logan M, Hawkins SM
Role of microRNAs in cancers of the female reproductive tract: insights from recent clinical and experimental discovery studies.
Clin Sci (Lond). 2015; 128(3):153-80 [PubMed] Related Publications
microRNAs (miRNAs) are small RNA molecules that represent the top of the pyramid of many tumorigenesis cascade pathways as they have the ability to affect multiple, intricate, and still undiscovered downstream targets. Understanding how miRNA molecules serve as master regulators in these important networks involved in cancer initiation and progression open up significant innovative areas for therapy and diagnosis that have been sadly lacking for deadly female reproductive tract cancers. This review will highlight the recent advances in the field of miRNAs in epithelial ovarian cancer, endometrioid endometrial cancer and squamous-cell cervical carcinoma focusing on studies associated with actual clinical information in humans. Importantly, recent miRNA profiling studies have included well-characterized clinical specimens of female reproductive tract cancers, allowing for studies correlating miRNA expression with clinical outcomes. This review will summarize the current thoughts on the role of miRNA processing in unique miRNA species present in these cancers. In addition, this review will focus on current data regarding miRNA molecules as unique biomarkers associated with clinically significant outcomes such as overall survival and chemotherapy resistance. We will also discuss why specific miRNA molecules are not recapitulated across multiple studies of the same cancer type. Although the mechanistic contributions of miRNA molecules to these clinical phenomena have been confirmed using in vitro and pre-clinical mouse model systems, these studies are truly only the beginning of our understanding of the roles miRNAs play in cancers of the female reproductive tract. This review will also highlight useful areas for future research regarding miRNAs as therapeutic targets in cancers of the female reproductive tract.

Roncati L, Pignatti E, Vighi E, et al.
Pre-miR146a expression in follicular carcinomas of the thyroid.
Pathologica. 2014; 106(2):58-60 [PubMed] Related Publications
INTRODUCTION: Micro-RNA, a new class of small, non-coding RNAs, have been shown to be deregulated in several human carcinomas. In particular, SNP rs2910164 in pre-miR146a appears to be correlated with papillary thyroid carcinoma and may be involved in its genetic predisposition. Since data on follicular thyroid carcinomas (FTC) are lacking, we evaluated the involvement of SNP rs2910164 in FTC.
METHODS: Thirty-nine cases of FTC and 20 follicular adenomas, defined according to WHO criteria, were selected. DNA and RNA were extracted from formalin-fixed paraffin-embedded blocks of both neoplastic and non-neoplastic areas. The DNA region of pre-miR146a, containing SNP rs2910164, was sequenced. Total RNA including miRNAs was used for stem-loop RT reactions, and applying a standard TaqMan PCR kit protocol for real-time PCR. Wilcoxon signed-rank test and Friedman test were used for statistical analyses.
RESULTS: In 31% of FTC, the G allele was observed in neoplastic tissues, compared with the non-neoplastic areas (p < 0.05), whereas the CC phenotype was completely absent in tumours. Moreover, the expression of pre-miR146a was found to be significantly down-regulated in neoplastic tissues from FTC cases (p = 0.043), although no significant differences were seen in follicular thyroid adenomas.
DISCUSSION: The expression profile of pre-miR146a can be correlated with FTC tumourigenesis. The G allele in SNP rs2910164 appears to be correlated with the transition from normal to neoplastic tissue. The GG and GC alleles appear to be associated with an increased risk for FTC, while the CC allele seems to play a protective role.

Yu D, Shin HS, Lee YS, Lee YC
miR-106b modulates cancer stem cell characteristics through TGF-β/Smad signaling in CD44-positive gastric cancer cells.
Lab Invest. 2014; 94(12):1370-81 [PubMed] Related Publications
Cancer stem cells have the capacity to form new tumors and are thus considered to be a cause of metastasis and tumor recurrence. However, many of the mechanisms determining cancer stem cell characteristics are still unknown. MicroRNAs (miRNAs) are possible modulators of cancer stem cell generation and may be involved in the retention of cancer stem cell characteristics. The aim of this study was to examine the miRNA expression profiles regulating the cancer stem-like cell characteristics in gastric cancer. We sorted gastric cancer stem-like cells using the stem cell marker CD44 by fluorescence-activated cell sorting. CD44(+) cells formed more and larger spheres compared with CD44(-) cells. Cancer stem cell markers were overexpressed in CD44(+) cells. CD44(+) cells showed increased expression of mesenchymal cell markers, whereas epithelial markers were downregulated. In miRNA microarray, the miR-106b family comprising miR-106b, miR-93, and miR-25 was significantly upregulated in CD44(+) cells than in CD44(-) cells. Smad7, which inhibits transforming growth factor-β (TGF-β)/Smad signaling as a target of the miR-106b family, was downregulated in CD44(+) cells. Furthermore, expression of TGF-β/Smad signal molecules was activated in CD44(+) cells, in accordance with the action of the miR-106b family. Inhibition of miR-106b showed suppression of the TGF-β/Smad signaling pathway and decreased self-renewal capacity and cell invasiveness. Our study suggests that CD44(+) gastric cancer cells show cancer stem cell properties with epithelial-mesenchymal transition (EMT). Increased miR-106b family expression regulated cancer stem-like cell properties, particularly EMT characteristics, through the TGF-β/Smad signaling pathway in CD44(+) stem-like cells. Taken together, these results indicate that targeting miR-106b may be an effective form of cancer therapy in gastric cancer through the modulation of cancer stem cell characteristics.

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