Locus Summary

Gene:MIR34A; microRNA 34a
Aliases: mir-34, MIRN34A, mir-34a, miRNA34A
Summary:microRNAs (miRNAs) are short (20-24 nt) non-coding RNAs that are involved in post-transcriptional regulation of gene expression in multicellular organisms by affecting both the stability and translation of mRNAs. miRNAs are transcribed by RNA polymerase II as part of capped and polyadenylated primary transcripts (pri-miRNAs) that can be either protein-coding or non-coding. The primary transcript is cleaved by the Drosha ribonuclease III enzyme to produce an approximately 70-nt stem-loop precursor miRNA (pre-miRNA), which is further cleaved by the cytoplasmic Dicer ribonuclease to generate the mature miRNA and antisense miRNA star (miRNA*) products. The mature miRNA is incorporated into a RNA-induced silencing complex (RISC), which recognizes target mRNAs through imperfect base pairing with the miRNA and most commonly results in translational inhibition or destabilization of the target mRNA. The RefSeq represents the predicted microRNA stem-loop. [provided by RefSeq, Sep 2009]
Databases:miRBase, OMIM, HGNC, Ensembl, GeneCard, Gene
Source:NCBIAccessed: 17 August, 2015

Cancer Overview

Research Indicators

Publications Per Year (1990-2015)
Graph generated 17 August 2015 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

Tag cloud generated 17 August, 2015 using data from PubMed, MeSH and CancerIndex

Specific Cancers (6)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

MicroRNA Function

Numbers shown below represent number of publications held in OncomiRDB database for Oncogenic and Tumor-Suppressive MicroRNAs.

TissueTarget Gene(s)Regulator(s)MIR34A Function in CancerEffect
brain (8)
-medulloblastoma (2)
-proneural subtype glioblastoma (1)
-glioma CD133+ cancer stem cells (1)
-proneural malignant glioma (1)
-glioblastoma multiforme (1)
-glioma (1)
-glioblastoma (1)
NOTCH1 (2)
MAGEA12 (1)
NOTCH2 (1)
MAGEA6 (1)
MET (1)
DLL1 (1)
MAGEA3 (1)
SIRT1 (1)
PDGF (1)
induce apoptosis (5)
inhibit cell proliferation (4)
inhibit cell growth (2)
inhibit cell survival (1)
inhibit cell cycle progression (1)
reduce cell invasion (1)
reduce cell migration (1)
induce cell cycle G0/G1 arrest (1)
increase chemosensitivity (1)
induce senescence (1)
induce cell cycle G2 arrest (1)
induce neural differentiation (1)
inhibit cell invasion (1)
tumor-suppressive (7)
nerve (8)
-neuroblastoma (5)
-malignant peripheral nerve sheath tumor (1)
-neuroblastoma with 1p36 deletion (1)
-neuroblastoma with MYCN amplification (1)
MYCN (3)
E2F3 (1)
BCL2 (1)
YY1 (1)
CDK1 (1)
TP53 (1)
induce apoptosis (4)
induce cell cycle arrest (2)
inhibit cell growth (2)
reduce cell growth (1)
repress tumor growth (1)
promote apoptosis (1)
decrease DNA synthesis (1)
inhibit cell proliferation (1)
tumor-suppressive (6)
prostate (7)
-prostate cancer (5)
-CD44+ prostate cancer stem cells (1)
-p53-defective prostate cancer (1)
AR (2)
SIRT1 (2)
CD44 (1)
MYC (1)
NOTCH1 (1)
inhibit cell growth (2)
induce cell cycle arrest (1)
reduce paclitaxel resistance (1)
inhibit metastasis (1)
inhibit tumor regeneration (1)
inhibit clonogenic expansion (1)
reduce AR-induced cell proliferation (1)
inhibit tumor growth (1)
promote apoptosis (1)
inhibit cell invasion (1)
inhibit cell proliferation (1)
induce senescencee (1)
induce cell cycle G1 arrest (1)
decrease self-renewal capacity (1)
induce apoptosis (1)
tumor-suppressive (6)
liver (4)
-hepatocellular carcinoma (2)
-hepatocellular cancer (1)
-HBV+ hepatocellular carcinoma (1)
CCL22 (1)
MET (1)
TGFB1 (1)
inhibit cell migration (2)
inhibit cell invasion (2)
inhibit tumor growth (1)
inhibit portal vein tumor thrombus (PVTT) (1)
inhibit cell proliferation (1)
tumor-suppressive (3)
colorectum (4)
-colon cancer (3)
-p53+ colon cancer (1)
SIRT1 (1)
TP53 (1)
inhibit cell proliferation (2)
inhibit cell growth (1)
reduce 5-FU resistance (1)
induce senescence-like phenotypes (1)
induce apoptosis (1)
induce senescence-like phenotype (1)
tumor-suppressive (4)
breast (4)
-breast cancer (3)
-breast cancer metastasis (1)
NOTCH1 (1)
SIRT1 (1)
BCL2 (1)
FOSL1 (1)
AXL (1)
inhibit cell invasion (2)
increase adriamycin sensitivity (1)
inhibit cell migration (1)
inhibit cell proliferation (1)
induce apoptosis (1)
tumor-suppressive (2)
blood (3)
-diffuse large B-cell lymphoma (1)
-lymphoma (1)
-acute myeloid leukemia (1)
FOXP1 (1)
E2F3 (1)
MYC (1)
MYC (1)
inhibit cell proliferation (2)
induce apoptosis (1)
reprogram granulocytic differentiation (1)
tumor-suppressive (3)
lung (3)
-lung cancer (2)
-non-small cell lung cancer (1)
NOTCH1 (1)
inhibit cell proliferation (1)
induce cell cycle G1 arrest (1)
inhibit cell growth (1)
inhibit cell invasiveness (1)
induce apoptosis (1)
synergisticly induce cell cycle arrest (1)
tumor-suppressive (3)
pancreas (3)
-pancreatic cancer (2)
-pancreatic cancer stem cells (1)
inhibit cell growth (2)
induce apoptosis (2)
inhibit cell invasion (2)
inhibit cell proliferation (1)
inhibit cell cycle progression (1)
inhibit self-renewal (1)
inhibit epithelial-mesenchymal transition (1)
induce cell cycle arrest (1)
reduce the population of CD44+/CD133+ pancreatic cancer tumor-initiating cells (1)
tumor-suppressive (3)
bone and muscle (2)
-osteosarcoma (1)
-Ewing's sarcoma (1)
MET (1)
inhibit cell proliferation (2)
inhibit cell migration (1)
inhibit cell invasion (1)
inhibit tumor growth (1)
inhibit pulmonary metastasis (1)
reduce malignancy (1)
increase chemo-sensitivity (1)
tumor-suppressive (2)
bladder (2)
-invasive urothelial bladder carcinoma (1)
-bladder cancer (1)
NOTCH1 (1)
SIRT1 (1)
CDK6 (1)
inhibit cell migration (1)
inhibit cell invasion (1)
increase cisplatin sensitivity (1)
tumor-suppressive (1)
skin (2)
-melanoma (1)
-uveal melanoma (1)
MET (1)
inhibit cell proliferation (1)
inhibit cell invasion (1)
inhibit tumor formation (1)
inhibit cell growth (1)
inhibit cell migration (1)
tumor-suppressive (2)
head and neck (2)
-head and neck squamous cell carcinoma (1)
-laryngeal squamous cell carcinoma (1)
inhibit cell proliferation (2)
inhibit colony formation (1)
inhibit cell migration (1)
inhibit tumor growth (1)
inhibit angiogenesis (1)
ihibit cell cycle G0/G1 transition (1)
tumor-suppressive (2)
stomach (1)
-gastric cancer (1)
reduce cell viability (1)
inhibit cell proliferation (1)
induce apoptosis (1)
inhibit cell migration (1)
tumor-suppressive (1)
esophagus (1)
-esophageal squamous cancer (1)
RELA (1)
TP53 (1)
ovary (1)
-ovarian cancer (1)
NOTCH1 (1)
JAG1 (1)
suppress cell invasion (1)
tumor-suppressive (1)
kidney (1)
-renal cell carcinoma (1)
MYC (1)
inhibit cell invasion (1)
tumor-suppressive (1)

Source: OncomiRDB Wang D. et al. Bioinformatics 2014, 30(15):2237-2238.

Latest Publications: MIR34A (cancer-related)

Kara M, Yumrutas O, Ozcan O, et al.
Differential expressions of cancer-associated genes and their regulatory miRNAs in colorectal carcinoma.
Gene. 2015; 567(1):81-6 [PubMed] Related Publications
Colorectal cancer is one of the frequently seen malignancies in the world. To date, several oncogenes and tumor suppressor genes have been identified and linked to colorectal cancer pathogenesis. Although recent advances in the diagnosis and therapy of colorectal cancer are promising, identifying novel genetic contributors is still high priority. In the present study, expression profile of some cancer-related genes and their regulatory miRNA molecules were evaluated by using a high-throughput real-time PCR method. For the study, a total of 54 patients diagnosed with CRC and normal colon tissue samples of 42 healthy controls were included. For the expression analysis, total RNA was extracted from FFPE tissue samples and converted to cDNA. All expression analyses were assessed by using Fluidigm Microfluidic Dynamic Array chips for 96 samples and the reactions were held in Fluidigm BioMark™ HD System Real-Time PCR. As a result of the study, expression of the ADAMTS1, FHIT, RUNX1, RUNX3 and WWOX genes was shown to be significantly altered in CRC tissues in contrast to normal tissue samples. Moreover, miR-378a-3p, miR-155-5p, miR-193b-3p, miR-96-5p, miR-17-5p, miR-27a-3p, miR-133b, miR-203a, miR-205-5p, miR-34c-5p, miR-130a-3p, miR-301a-3p, miR-132-3p, miR-222-3p, miR-34a-5p, miR-21-5p, miR-29a-3p and miR-29b-3p were found to be significantly deregulated in CRC. Consequently, results of the current study strongly suggest the involvement of novel cancer-related genes and their regulatory miRNAs in CRC physiopathology.

Ge YZ, Xu LW, Xu Z, et al.
Expression Profiles and Clinical Significance of MicroRNAs in Papillary Renal Cell Carcinoma: A STROBE-Compliant Observational Study.
Medicine (Baltimore). 2015; 94(16):e767 [PubMed] Related Publications
Papillary renal cell carcinoma (pRCC) is the second most prevalent subtype of kidney cancers. In the current study, we analyzed the global microRNA (miRNA) expression profiles in pRCC, with the aim to evaluate the relationship of miRNA expression with the progression and prognosis of pRCC.A total of 163 treatment-naïve primary pRCC patients were identified from the Cancer Genome Atlas dataset and included in this retrospective observational study. The miRNA expression profiles were graded by tumor-node-metastasis information, and compared between histologic subtypes. Furthermore, the training-validation approach was applied to identify miRNAs of prognostic values, with the aid of Kaplan-Meier survival, and univariate and multivariate Cox regression analyses. Finally, the online DAVID (Database for Annotation, Visualization, and Integrated Discover) program was applied for the pathway enrichment analysis with the target genes of prognosis-associated miRNAs, which were predicted by 3 computational algorithms (PicTar, TargetScan, and Miranda).In the progression-related miRNA profiles, 26 miRNAs were selected for pathologic stage, 28 for pathologic T, 16 for lymph node status, 3 for metastasis status, and 32 for histologic types, respectively. In the training stage, the expression levels of 12 miRNAs (mir-134, mir-379, mir-127, mir-452, mir-199a, mir-200c, mir-141, mir-3074, mir-1468, mir-181c, mir-1180, and mir-34a) were significantly associated with patient survival, whereas mir-200c, mir-127, mir-34a, and mir-181c were identified by multivariate Cox regression analyses as potential independent prognostic factors in pRCC. Subsequently, mir-200c, mir-127, and mir-34a were confirmed to be significantly correlated with patient survival in the validation stage. Finally, target gene prediction analysis identified a total of 113 target genes for mir-200c, 37 for mir-127, and 180 for mir-34a, which further generated 15 molecular pathways.Our results identified the specific miRNAs associated with the progression and aggressiveness of pRCC, and 3 miRNAs (mir-200c, mir-127, and mir-34a) as promising prognostic factors of pRCC.

Gocze K, Gombos K, Kovacs K, et al.
MicroRNA expressions in HPV-induced cervical dysplasia and cancer.
Anticancer Res. 2015; 35(1):523-30 [PubMed] Related Publications
BACKGROUND/AIM: The role of oncogenic or high-risk human papillomavirus (HPV) in cervical carcinogenesis is inevitable, yet not fully understood. Detailed analysis of microRNA (miRNA) alterations occurring during high-risk HPV transformation will increase our current understanding over cervical carcinogenesis. The two main aims of the study were: (i) finding association between HPV infection characteristics and socio-demographic variables, (ii) finding an predictors of clinical outcome.
MATERIALS AND METHODS: The expression levels of different microRNAs (miR-21, miR-27a, miR-34a, miR-155, miR-196a, miR-203) were determined in formalin-fixed paraffin-embedded (FFPE) human HPV-positive cervical dysplastic and tumorous tissue samples using quantitative real-time PCR (qPCR). Sociodemographic and life-style factors were also analyzed.
RESULTS: The expression of miR-27a was significantly higher in cervical intraepithelial neoplasia (CIN)2-3 compared to CIN1 (p=0.023) and in squamous cell carcinoma (SCC) compared to CIN2-3 (p=0.033). Moreover, significantly lower levels of miR-34a were detected in CIN2-3 than in CIN1 (p=0.041) and in SCC than in CIN2-3 (p=0.021). Furthermore, we found significant differences in subjects with multiple HPV in miR-27a (p=0.015) and miR-203 (p=0.025) in CIN2-3 compared to CIN1 and miR-21 (p=0.002), mir-27a (p=0.001) and miR-34a (p=0.001) in SCC/CIN2-3. Expression of miR-27a, showing up-regulation in CIN2-3 compared to CIN1 (p=0.028) and miR-34a (down-regulated), correlated with HPV 16 positivity (CIN2-3/CIN1: p=0.027 and SCC/CIN2-3: p=0.036). MiR-34a expression was also significantly altered in connection to smoking status and presence of HPV 16.
CONCLUSION: The demand for additional, alternative molecular biomarkers with prognostic potential is strong. Evaluation of miRNA expression might be helpful to distinguish different cervical lesions and might be able to help in the prediction of HPV infection outcome.

Musilova K, Mraz M
MicroRNAs in B-cell lymphomas: how a complex biology gets more complex.
Leukemia. 2015; 29(5):1004-17 [PubMed] Related Publications
MicroRNAs (miRNAs) represent important regulators of gene expression besides transcriptional control. miRNA regulation can be involved in the cell developmental fate decisions, but can also have more subtle roles in buffering stochastic fluctuations in gene expression. They participate in pathways fundamental to B-cell development like B-cell receptor (BCR) signalling, B-cell migration/adhesion, cell-cell interactions in immune niches, and the production and class-switching of immunoglobulins. miRNAs influence B-cell maturation, generation of pre-, marginal zone, follicular, B1, plasma and memory B cells. In this review, we discuss miRNAs with essential functions in malignant B-cell development (such as miR-150, miR-155, miR-21, miR-34a, miR-17-92 and miR-15-16). We also put these miRNAs in the context of normal B-cell differentiation, as this is intimately connected to neoplastic B-cell development. We review miRNAs' role in the most common B-cell malignancies, including chronic lymphocytic leukaemia (CLL), diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL) and mantle cell lymphoma (MCL). We focus on miR-contribution to the regulation of important signalling pathways (such as NF-κB, PI3K/AKT and TGF-β), BCR signalling and its modulators (such as PTEN, SHIP-1, ZAP-70, GAB1 and BTK), anti- and pro-apoptotic proteins (such as BCL2, MCL1, TCL1, BIM, p53 and SIRT1) and transcription factors (such as MYC, MYB, PU.1, FOXP1 and BCL6). We also discuss the association of miRNAs' expression levels with the patients' survival and response to therapy, summarizing their potential use as predictive and prognostic markers. Importantly, the targeting of miRNAs (like use of anti-miR-155 or miR-34a mimic) could provide a novel therapeutic approach as evidenced by tumour regression in xenograft mouse models and initial promising data from clinical trials.

Ma ZL, Hou PP, Li YL, et al.
MicroRNA-34a inhibits the proliferation and promotes the apoptosis of non-small cell lung cancer H1299 cell line by targeting TGFβR2.
Tumour Biol. 2015; 36(4):2481-90 [PubMed] Related Publications
MicroRNAs (MiRNAs) are small non-coding RNA molecules which act as important regulators of post-transcriptional gene expression by binding 3'-untranslated region (3'-UTR) of target messenger RNA (mRNA). In this study, we analyzed miRNA-34a (miR-34a) as a tumor suppressor in non-small cell lung cancer (NSCLC) H1299 cell line. The expression level of miR-34a in four different NSCLC cell lines, H1299, A549, SPCA-1, and HCC827, was significantly lower than that in the non-tumorigenic bronchial epithelium cell line BEAS-2B. In human NSCLC tissues, miR-34a expression level was also significantly decreased in pT2-4 compared with the pT1 group. Moreover, miR-34a mimic could inhibit the proliferation and triggered apoptosis in H1299 cells. Luciferase assays revealed that miR-34a inhibited TGFβR2 expression by targeting one binding site in the 3'-UTR of TGFβR2 mRNA. Quantitative real-time PCR (qRT-PCR) and Western blot assays verified that miR-34a reduced TGFβR2 expression at both mRNA and protein levels. Furthermore, downregulation of TGFβR2 by siRNA showed the same effects on the proliferation and apoptosis as miR-34a mimic in H1299 cells. Our results demonstrated that miR-34a could inhibit the proliferation and promote the apoptosis of H1299 cells partially through the downregulation of its target gene TGFβR2.

Veija T, Sahi H, Koljonen V, et al.
miRNA-34a underexpressed in Merkel cell polyomavirus-negative Merkel cell carcinoma.
Virchows Arch. 2015; 466(3):289-95 [PubMed] Related Publications
Merkel cell polyomavirus (MCV) is frequently detectable in Merkel cell carcinoma (MCC) tumors, but the significance of MCV infection is not yet totally understood. Thus far, no key regulatory miRNA has been identified for MCC tumorigenesis. However, distinct miRNA expression profiles have been suggested for MCV-positive and MCV-negative tumors. We used microarray hybridization to identify miRNA expression differences in MCC tumor samples according to MCV status and further validated these results by quantitative reverse transcription polymerase chain reaction (qRT-PCR). When compared with MCV-negative tumors, we detected overexpression of miR-34a, miR-30a, miR-142-3p, and miR-1539 in those MCV positives. In addition, slight underexpression was detectable in MCV-positive tumors of miR-181d. We confirmed the distinct expression of miRNAs in MCV-positive and MCV-negative tumors and confirmed statistically significant underexpression of miR-34a in MCV-negative tumors by both array analysis and qRT-PCR. Neither tumor location nor development of metastases affected miRNA expression.

Barzon L, Cappellesso R, Peta E, et al.
Profiling of expression of human papillomavirus-related cancer miRNAs in penile squamous cell carcinomas.
Am J Pathol. 2014; 184(12):3376-83 [PubMed] Related Publications
Penile squamous cell carcinoma (PSCC) is a rare tumor associated with high-risk human papillomavirus (HR-HPV) infection in 30% to 60% of cases. Altered expression of miRNAs has been reported in HPV-related cervical and head and neck cancers, but such data have not been available for PSCC. We analyzed a series of 59 PSCCs and 8 condylomata for presence of HPV infection, for p16(INK4a), Ki-67, and p53 immunohistochemical expression, and for expression of a panel of cellular miRNAs (let-7c, miR-23b, miR-34a, miR-145, miR-146a, miR-196a, and miR-218) involved in HPV-related cancer. HR-HPV DNA (HPV16 in most cases) was detected in 17/59 (29%) PSCCs; all penile condylomata (8/8) were positive for low-risk HPV6 or HPV11. HR-HPV(+) PSCCs overexpressed p16(INK4a) in 88% cases and p53 in 35% of cases, whereas HR-HPV(-) PSCCs were positive for p16(INK4a) and p53 immunostaining in 9% and 44% of cases, respectively. Among the miRNAs investigated, expression of miR-218 was lower in PSCCs with HR-HPV infection and in p53(-) cancers. Hypermethylation of the promoter of the SLIT2 gene, which contains miR-218-1 in its intronic region, was frequently observed in PSCCs, mainly in those with low miR-218 expression. Epigenetic silencing of miR-218 is a common feature in HR-HPV(+) PSCCs and in HR-HPV(-) PSCCs without immunohistochemical detection of p53.

Wang L, Yu J, Xu J, et al.
The analysis of microRNA-34 family expression in human cancer studies comparing cancer tissues with corresponding pericarcinous tissues.
Gene. 2015; 554(1):1-8 [PubMed] Related Publications
Recently many studies have focused on the microRNA-34 (miR-34) family expression in various cancers; nevertheless, the controversial results of these studies still exist in identifying miR-34 members as new biomarkers of cancers. Therefore, we carried out this comprehensive meta-analysis of published studies that compared the miR-34 family expression profiles between cancer tissues and paired neighboring noncancerous tissues to systemically evaluate the findings globally and address the inconsistencies of pertinent literatures. The data included in this article were collected from Embase, PubMed and Web of Science up to December 2013. To overcome the difficulties that many raw data were unavailable and study methods were different, a vote-counting strategy was adopted to identify consistent markers in our analysis. Ultimately, a total of 23 cancers were reported in the 61 eligible studies, of which 46 studies provided fold-change value information. In the consistently reported cancer types, non-small cell lung cancer (NSCLC), glioma and nasopharyngeal carcinoma (NPC) ranked at the top with down-regulated feature. Cervical neoplasm was consistently reported to be over-expressed in the panel of each member of miR-34s. Subgroup analysis of miR-34 family expression demonstrated that colorectal cancer (CRC), gastric cancer (GC), hepatocellular carcinoma (HCC) and prostate cancer (PCa) were most frequently reported with inconsistent regulations. Our meta-analysis showed that miR-34 family members could be expected to become potential diagnostic and prognostic biomarkers in some types of human cancers. Further well-designed and larger sample studies are surely warranted to identify the role of the miR-34 family in the occurrence and development of tumors.

Liu R, Xie H, Luo C, et al.
Identification of FLOT2 as a novel target for microRNA-34a in melanoma.
J Cancer Res Clin Oncol. 2015; 141(6):993-1006 [PubMed] Related Publications
PURPOSE: To confirm whether flotillin 2 (FLOT2) is a direct target of miR-34a and miR-34a/FLOT2 pathway plays a key role in melanoma proliferation and metastasis.
METHODS: First, miR-34a and FLOT2 expressions were both detected in human tissues and cell lines by qRT-PCR. Then, after transfection of mimics/inhibitor of miR-34a into melanoma cell lines, MTT, colony formation, scratch migration assays and transwell invasion assays were performed to evaluate the impact of miR-34a on cell proliferation and metastasis. Western blot, qRT-RCR and dual luciferase reporter gene assays were carried out to confirm whether FLOT2 is a direct target gene of miR-34a. In functional recovery experiments, proliferation and metastasis ability of WM35 and WM451 was tested after being co-transfected with miR-34a inhibitor/si-FLOT2 or miR-34a mimics/FLOT2 cDNA to confirm that FLOT2 is downregulated by miR-34a.
RESULTS: The miR-34a significantly lower-expressed in metastasis melanoma tissues compared to in situ melanoma, nevi and normal skin whereas FLOT2 has an opposite trend. The level of miR-34a and FLOT2 in different melanoma cell lines was also tested and found that metastatic melanoma cell lines has lower miR-34a expression and higher FLOT2 expression compare to in situ melanoma cell line. MiR-34a overexpression profoundly inhibits WM451 cell proliferation and metastasis, whereas miR-34a reduction had a promoting effect to proliferation and metastasis of WM35. Results of Western blot, qRT-RCR and dual luciferase reporter gene assays revealed that FLOT2 is a direct target gene of miR-34a. Furthermore, overexpression/blockage of FLOT2 could attenuate effect of miR-34a overexpression/inhibition which indicated miR-34a suppresses melanoma biological behavior partially through FLOT2 inhibition.
CONCLUSIONS: Our study confirmed that miR-34a is involved in the tumor inhibition of melanoma by directly targeting FLOT2 gene. This finding provides potential novel strategies for therapeutic interventions of melanoma.

Tafsiri E, Darbouy M, Shadmehr MB, et al.
Expression of miRNAs in non-small-cell lung carcinomas and their association with clinicopathological features.
Tumour Biol. 2015; 36(3):1603-12 [PubMed] Related Publications
Lung cancer is recognized as a leading cause of cancer-related deaths worldwide. Over the past several years, evidence emerged that microRNAs (miRNAs), a class of small non-coding RNA molecules regulating gene expression at posttranscriptional level, play an important role in cell functioning, as well as in human diseases. Here, we analyzed expression of miR-15a/16, miR-21, miR-34a, miR-126, miR-128, and miR-210 at transcriptional level in 30 non-small-cell lung carcinoma (NSCLC) tumor tissues compared to the matched adjacent normal tissues and their correlation with clinicopathological features of the patients. Samples were collected from the NSCLC patients undergoing surgery before radiotherapeutic or chemotherapeutic treatment. Expression levels of miRNAs were assessed by TaqMan RT-PCR assay. The data obtained in this study were processed using REST 2009 and SPSS statistical software. The graphs were designed by GraphPad prism 5.0. In tumor samples, we found downregulation of miR-15a/16 (50/83.3%), miR-34a (83.3%), miR-126 (70%), and miR-128 (63.3%). At the same time, miR-21 and miR-210 were upregulated by 53.3 and 66.6% in cancer tissue versus matched adjacent normal tissues, respectively. No significant correlation was found between the expression levels of miR-15a/16, miR-21, miR-34a, miR-126, miR-128, and miR-210 and lymph node, tumor size, sex, and smoking. However, the study demonstrated a correlation between a change in expression of miR-15, miR-16, miR-34a, miR-126, and miR-210 compared to normal tissues and TNM staging (P < 0.05). Furthermore, miR-126 expression level was different in adenocarcinomas and squamous cell carcinoma (SCC) subtype (P < 0.1). Detailed analysis revealed significant change in expression of miR-15a/16, miR-34a, miR-126, and miR-210 in NSCLC tumor samples indicating involvement of these miRNAs in lung cancer pathogenesis. miR-210 demonstrated the most consistent increase in tumor tissues between different patients, suggesting its potential significance for NSCLC.

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.

Thor T, Künkele A, Pajtler KW, et al.
MiR-34a deficiency accelerates medulloblastoma formation in vivo.
Int J Cancer. 2015; 136(10):2293-303 [PubMed] Related Publications
Previous studies have evaluated the role of miRNAs in cancer initiation and progression. MiR-34a was found to be downregulated in several tumors, including medulloblastomas. Here we employed targeted transgenesis to analyze the function of miR-34a in vivo. We generated mice with a constitutive deletion of the miR-34a gene. These mice were devoid of mir-34a expression in all analyzed tissues, but were viable and fertile. A comprehensive standardized phenotypic analysis including more than 300 single parameters revealed no apparent phenotype. Analysis of miR-34a expression in human medulloblastomas and medulloblastoma cell lines revealed significantly lower levels than in normal human cerebellum. Re-expression of miR-34a in human medulloblastoma cells reduced cell viability and proliferation, induced apoptosis and downregulated the miR-34a target genes, MYCN and SIRT1. Activation of the Shh pathway by targeting SmoA1 transgene overexpression causes medulloblastoma in mice, which is dependent on the presence and upregulation of Mycn. Analysis of miR-34a in medulloblastomas derived from ND2:SmoA1(tg) mice revealed significant suppression of miR-34a compared to normal cerebellum. Tumor incidence was significantly increased and tumor formation was significantly accelerated in mice transgenic for SmoA1 and lacking miR-34a. Interestingly, Mycn and Sirt1 were strongly expressed in medulloblastomas derived from these mice. We here demonstrate that miR-34a is dispensable for normal development, but that its loss accelerates medulloblastomagenesis. Strategies aiming to re-express miR-34a in tumors could, therefore, represent an efficient therapeutic option.

Xiao F, Chen J, Lian C, et al.
Tumor necrosis factor-related apoptosis-inducing ligand induces cytotoxicity specific to osteosarcoma by microRNA response elements.
Mol Med Rep. 2015; 11(1):739-45 [PubMed] Related Publications
As the most common primary bone neoplasm, osteosarcoma is highly aggressive and represents a high risk to human health. Biological agents, including tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), are considered promising therapeutic strategies for osteosarcoma. The current issue limiting the application of TRAIL gene therapy is that normal cells are also affected due to the lack of tumor selectivity. The present study aimed to employ the miRNA response elements (MREs) of microRNA (miR)-34 and miR-122, which are tumor suppressors, to enable the selective expression of TRAIL by adenoviral vectors in osteosarcoma cells. The results revealed that miR-34 and miR-122 were underexpressed in osteosarcoma tissues, compared with normal tissues. The MREs of miR-34 and miR-122 ensured that the luciferase gene was expressed selectively in osteosarcoma cells. Adenovirus (Ad)-TRAIL-34-122, which expressed TRAIL in an miR-34 and miR-122-regulated manner, selectively expressed TRAIL in the osteosarcoma cells assessed, which was detected using reverse transcription quantitative polymerase chain reaction, immunoblotting and ELISA. Apoptosis and cytotoxicity were also detected in the osteosarcoma cells, compared with the normal cells. Animal experiments further indicated that Ad-TRAIL-34-122 was able to reduce the growth of osteosarcoma xenografts without toxicity to the liver. In conclusion, the present study identified a novel miRNA-regulated biological cancer therapy against osteosarcoma, which is tumor selective and may be promising for future clinical treatment.

Li X, Zhao H, Zhou X, Song L
Inhibition of lactate dehydrogenase A by microRNA-34a resensitizes colon cancer cells to 5-fluorouracil.
Mol Med Rep. 2015; 11(1):577-82 [PubMed] Related Publications
5-Fluorouracil (5-FU) chemotherapy is widely used in the treatment of advanced colon cancer. However, the development of resistance to 5-FU is a significant obstacle to successful treatment. MicroRNA-34a (miR-34a) has been reported to be downregulated in a number of tumor types and has also been shown to act as a tumor suppressor. However, the mechanisms underlying the biological effects of miR-34a in chemoresistance remain unclear. The present study showed that the expression of miR-34a is downregulated in 5-FU-resistant colon cancer cells. In addition, 5-FU-resistant colon cancer cells exhibited upregulation of lactate dehydrogenase A (LDHA) expression and activity compared with parental cells. Furthermore, LDHA was shown to be a direct target of miR-34a. Overexpression of miR-34a reduced the expression of LDHA, probably through binding to the 3' untranslated region, leading to the re-sensitization of 5-FU-resistant cancer cells to 5-FU. Additionally, overexpression of LDHA rendered colon cancer cells resistant to 5-FU, suggesting that the miR-34a-induced sensitization to 5-FU is mediated through the inhibition of LDHA. In conclusion, the current study showed that miR-34a is involved in sensitivity to 5-FU in part through its effects on LDHA expression. This indicates that miR-34a‑mediated inhibition of glucose metabolism may be a therapeutic target in patients with chemoresistant colon cancer.

Wang L, Che XJ, Wang N, et al.
Regulatory network analysis of microRNAs and genes in neuroblastoma.
Asian Pac J Cancer Prev. 2014; 15(18):7645-52 [PubMed] Related Publications
Neuroblastoma (NB), the most common extracranial solid tumor, accounts for 10% of childhood cancer. To date, scientists have gained quite a lot of knowledge about microRNAs (miRNAs) and their genes in NB. Discovering inner regulation networks, however, still presents problems. Our study was focused on determining differentially-expressed miRNAs, their target genes and transcription factors (TFs) which exert profound influence on the pathogenesis of NB. Here we constructed three regulatory networks: differentially-expressed, related and global. We compared and analyzed the differences between the three networks to distinguish key pathways and significant nodes. Certain pathways demonstrated specific features. The differentially-expressed network consists of already identified differentially-expressed genes, miRNAs and their host genes. With this network, we can clearly see how pathways of differentially expressed genes, differentially expressed miRNAs and TFs affect on the progression of NB. MYCN, for example, which is a mutated gene of NB, is targeted by hsa-miR-29a and hsa-miR-34a, and regulates another eight differentially-expressed miRNAs that target genes VEGFA, BCL2, REL2 and so on. Further related genes and miRNAs were obtained to construct the related network and it was observed that a miRNA and its target gene exhibit special features. Hsa-miR-34a, for example, targets gene MYC, which regulates hsa-miR-34a in turn. This forms a self-adaption association. TFs like MYC and PTEN having six types of adjacent nodes and other classes of TFs investigated really can help to demonstrate that TFs affect pathways through expressions of significant miRNAs involved in the pathogenesis of NB. The present study providing comprehensive data partially reveals the mechanism of NB and should facilitate future studies to gain more significant and related data results for NB.

Jia LF, Wei SB, Mitchelson K, et al.
miR-34a inhibits migration and invasion of tongue squamous cell carcinoma via targeting MMP9 and MMP14.
PLoS One. 2014; 9(9):e108435 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: miR-34a is an important tumor suppressor gene in various cancer types. But little is known about the dysregulation of miR-34a in tongue squamous cell carcinoma (TSCC). In this study, we investigate the expression and potential role of miR-34a in TSCC.
METHODS: We evaluated miR-34a expression and its relationship with clinicopathological characters in 75 pairs of TSCC samples, and confirmed the role of miR-34a for predicting lymph node metastases from a further 15 pairs of paraffin-embedded TSCC specimens with stringent clinicopathological recruitment criteria using quantitative reverse transcription polymerase chain reaction (qRT-PCR). The effects of miR-34a on cell proliferation, migration and invasion were examined in TSCC cell lines using Cell Counting Kit-8 assay, wound healing assay and transwell assay, respectively. The effects of miR-34a on the expression of matrix metalloproteinase (MMP) 9 and 14 were detected by luciferase reporter assays and Western blot analysis. The expression of miR-34a, MMP9 and MMP14 were also confirmed in TSCC samples by in situ hybridization and immunohistochemistry.
RESULTS: miR-34a expression in tumor tissues from TSCC patients with positive lymph node metastases was significantly lower than that with negative lymph node metastases. Overexpression of miR-34a significantly suppressed migration and invasion in TSCC cells and simultaneously inhibited the expression of MMP9 and MMP14 through targeting the coding region and the 3'untranslated region, respectively. Moreover, miR-34a expression in TSCC was inversely correlated with protein expression of MMP9 and MMP14 in the TSCC samples.
CONCLUSIONS: miR-34a plays an important role in lymph node metastases of TSCC through targeting MMP9 and MMP14 and may have potential applications in prognosis prediction and gene therapy for lymph node metastases of TSCC patients.

Lv H, Pei J, Liu H, et al.
A polymorphism site in the pre‑miR‑34a coding region reduces miR‑34a expression and promotes osteosarcoma cell proliferation and migration.
Mol Med Rep. 2014; 10(6):2912-6 [PubMed] Free Access to Full Article Related Publications
Osteosarcoma (OS) is the most prevalent primary malignant bone tumor in children and young adults, its complex etiology involving a combination of environmental and genetic factors. MicroRNA (miRNA) is a short, non‑coding regulatory RNA molecule that represses gene expression by imperfectly base‑pairing to the 3' untranslated region of target mRNAs. Evidence has shown that alterations in the expression of miRNA are involved in the initiation, progression, and metastasis of human cancers. It is believed that miRNAs function both as tumor suppressors and oncogenes during cancer development. In the present study, three tumor-associated miRNAs (miR‑21, miR‑34a and miR‑146a) coding regions were screened in Chinese‑Han OS patients. A G>A variation in the pre‑miR‑34a coding region was found to be associated with higher OS morbidity. By detecting the mature miR‑34a expression in cells transfected with pre‑miR‑34a expression vectors of different genotypes using quantitative polymerase chain reaction, it was demonstrated that the G>A variation reduced miR‑34a expression in vitro. This was in accordance with the data collected from tumor tissue and patient serum samples. Subsequently, a dual‑luciferase reporter assay and western blot analysis were used to detect the site variation effect on the expression of c‑Met, a target gene of miR‑34a. The G>A variation downregulated the suppression of c‑Met in two OS cell lines. Furthermore, it was found that reduced miR‑34a expression decreased the suppression of OS cell proliferation in vitro. In conclusion, the present study established the association between miR‑34a and the risk of suffering OS in a Chinese Han population by identifying one functional single nucleotide polymorphism site in pre‑miR‑34a. These findings may give insight into the mechanism of OS development and create an opportunity to approach the diagnosis and treatment of OS.

Long Z, Wang B, Tao D, et al.
Hypofractionated radiotherapy induces miR-34a expression and enhances apoptosis in human nasopharyngeal carcinoma cells.
Int J Mol Med. 2014; 34(5):1388-94 [PubMed] Related Publications
Nasopharyngeal carcinoma (NPC) is a relatively radiosensitive disease. However, the therapeutic effects of radiotherapy are not always satisfactory due to radioresistance. The hypofractionated schema is currently widely used in clinical practice. In the present study, we investigated the effects of hypofractionated radiotherapy on NPC cells and explored the mechanisms involved. In addition, we aimed to determine the role of miR-34a in the effects of hypofractionated radiotherapy and whether these effects occur in a p53-dependent manner. For this purpose, we used CNE1 and CNE2 NPC cells which were subjected to hyperfractionated and hypofractionated radiotherapy. The viability of the cells was measured by MTT assay and acridine orange (AO) and ethidium bromide (EB) staining was used to observe morphological changes. In addition, Annexin V-propidium iodide (PI) staining and flow cytometry were used to determine the number of apoptotic cells and mRNA and protein expression was measured by qPCR and western blot analysis, respectively. The results revealed that hypofractionated radiotherapy enhanced apoptosis and increased the expression of miR-34a and p53 in the NPC cells. In addition, it stimulated p53 promoter activity and downregulated the protein expression of c-Myc in the human NPC cells. Furthermore, the knockdown of miR-34a suppressed the growth inhibitory effects induced by hypofractionated radiotherapy. Thus, our results suggest that the enhanced apoptosis of NPC cells may be associated with the miR-34a-mediated suppression of c-Myc in a p53-dependent manner.

Xiao Z, Li CH, Chan SL, et al.
A small-molecule modulator of the tumor-suppressor miR34a inhibits the growth of hepatocellular carcinoma.
Cancer Res. 2014; 74(21):6236-47 [PubMed] Related Publications
Small molecules that restore the expression of growth-inhibitory microRNAs (miRNA) downregulated in tumors may have potential as anticancer agents. miR34a functions as a tumor suppressor and is downregulated or silenced commonly in a variety of human cancers, including hepatocellular carcinoma (HCC). In this study, we used an HCC cell-based miR34a luciferase reporter system to screen for miR34a modulators that could exert anticancer activity. One compound identified as a lead candidate, termed Rubone, was identified through its ability to specifically upregulate miR34a in HCC cells. Rubone activated miR34a expression in HCC cells with wild-type or mutated p53 but not in cells with p53 deletions. Notably, Rubone lacked growth-inhibitory effects on nontumorigenic human hepatocytes. In a mouse xenograft model of HCC, Rubone dramatically inhibited tumor growth, exhibiting stronger anti-HCC activity than sorafenib both in vitro and in vivo. Mechanistic investigations showed that Rubone decreased expression of cyclin D1, Bcl-2, and other miR34a target genes and that it enhanced the occupancy of p53 on the miR34a promoter. Taken together, our results offer a preclinical proof of concept for Rubone as a lead candidate for further investigation as a new class of HCC therapeutic based on restoration of miR34a tumor-suppressor function.

Jiang ZC, Tang XM, Zhao YR, Zheng L
A functional variant at miR-34a binding site in toll-like receptor 4 gene alters susceptibility to hepatocellular carcinoma in a Chinese Han population.
Tumour Biol. 2014; 35(12):12345-52 [PubMed] Related Publications
Toll-like receptor 4 (TLR4) plays a key role in prompting the innate or immediate response. A growing body of evidence suggests that genetic variants of TLR4 gene were associated with the development of cancers. This study aimed to investigate the relationship of a functional variant (rs1057317) at microRNA-34a (miR-34a) binding site in toll-like receptor 4 gene and the risk of hepatocellular carcinoma. A single center-based case-control study was conducted. In this study, the polymerase chain reaction (PCR) and direct sequencing were used to genotype sequence variants of TLR4 in 426 hepatocellular carcinoma cases and 438 controls. The modification of rs1057317 on the binding of hsa-miR-34a to TLR4 messenger RNA (mRNA) was measured by luciferase activity assay. Individuals carrying the AA genotypes for the rs1057317 were associated significantly with increased risk of hepatocellular carcinoma comparing with those carrying wild-type homozygous CC genotypes (adjusted odds ratio [OR] by sex and age, from 1.116 to 2.452, P = 0.013). The activity of the reporter vector was lower in the reporter vector carrying C allele than the reporter vector carrying A allele. Furthermore, the expression of TLR4 was detected in the peripheral blood mononucleated cell of hepatocellular carcinoma (HCC) patients, suggesting that mRNA and protein levels of TLR4 might be associated with SNP rs1057317. Collectively, these results suggested that the risk of hepatocellular carcinoma was associated with a functional variant at miR-34a binding site in toll-like receptor 4 gene. miR-34a/TLR4 axis may play an important role in the development of hepatocellular carcinoma.

Sandhu R, Rein J, D'Arcy M, et al.
Overexpression of miR-146a in basal-like breast cancer cells confers enhanced tumorigenic potential in association with altered p53 status.
Carcinogenesis. 2014; 35(11):2567-75 [PubMed] Article available free on PMC after 01/11/2015 Related Publications
The tumor suppressor p53 is the most frequently mutated gene in human cancers, mutated in 25-30% of breast cancers. However, mutation rates differ according to breast cancer subtype, being more prevalent in aggressive estrogen receptor-negative tumors and basal-like and HER2-amplified subtypes. This heterogeneity suggests that p53 may function differently across breast cancer subtypes. We used RNAi-mediated p53 knockdown (KD) and antagomir-mediated KD of microRNAs to study how gene expression and cellular response to p53 loss differ in luminal versus basal-like breast cancer. As expected, p53 loss caused downregulation of established p53 targets (e.g. p21 and miR-34 family) and increased proliferation in both luminal and basal-like cell lines. However, some p53-dependent changes were subtype specific, including expression of miR-134, miR-146a and miR-181b. To study the cellular response to miR-146a upregulation in p53-impaired basal-like lines, antagomir KD of miR-146a was performed. KD of miR-146a caused decreased proliferation and increased apoptosis, effectively ablating the effects of p53 loss. Furthermore, we found that miR-146a upregulation decreased NF-κB expression and downregulated the NF-κB-dependent extrinsic apoptotic pathway (including tumor necrosis factor, FADD and TRADD) and antagomir-mediated miR-146a KD restored expression of these components, suggesting a plausible mechanism for miR-146a-dependent cellular responses. These findings are relevant to human basal-like tumor progression in vivo, since miR-146a is highly expressed in p53 mutant basal-like breast cancers. These findings suggest that targeting miR-146a expression may have value for altering the aggressiveness of p53 mutant basal-like tumors.

Xue W, Dahlman JE, Tammela T, et al.
Small RNA combination therapy for lung cancer.
Proc Natl Acad Sci U S A. 2014; 111(34):E3553-61 [PubMed] Article available free on PMC after 01/11/2015 Related Publications
MicroRNAs (miRNAs) and siRNAs have enormous potential as cancer therapeutics, but their effective delivery to most solid tumors has been difficult. Here, we show that a new lung-targeting nanoparticle is capable of delivering miRNA mimics and siRNAs to lung adenocarcinoma cells in vitro and to tumors in a genetically engineered mouse model of lung cancer based on activation of oncogenic Kirsten rat sarcoma viral oncogene homolog (Kras) and loss of p53 function. Therapeutic delivery of miR-34a, a p53-regulated tumor suppressor miRNA, restored miR-34a levels in lung tumors, specifically down-regulated miR-34a target genes, and slowed tumor growth. The delivery of siRNAs targeting Kras reduced Kras gene expression and MAPK signaling, increased apoptosis, and inhibited tumor growth. The combination of miR-34a and siRNA targeting Kras improved therapeutic responses over those observed with either small RNA alone, leading to tumor regression. Furthermore, nanoparticle-mediated small RNA delivery plus conventional, cisplatin-based chemotherapy prolonged survival in this model compared with chemotherapy alone. These findings demonstrate that RNA combination therapy is possible in an autochthonous model of lung cancer and provide preclinical support for the use of small RNA therapies in patients who have cancer.

Maroof H, Salajegheh A, Smith RA, Lam AK
Role of microRNA-34 family in cancer with particular reference to cancer angiogenesis.
Exp Mol Pathol. 2014; 97(2):298-304 [PubMed] Related Publications
MicroRNA-34 is involved in pathogenesis in cancer by targeting different tumor-related genes. It could be a biomarker for predicting the prognosis of patients with cancer. In addition, miR-34 is involved in the tumor angiogenesis. Understanding the mechanism of the miR-34 in cancer and tumor angiogenesis will open horizons for development of anti-cancer and anti-angiogenesis drugs.

Li Y, Li D, Yan Z, et al.
Potential relationship and clinical significance of miRNAs and Th17 cytokines in patients with multiple myeloma.
Leuk Res. 2014; 38(9):1130-5 [PubMed] Related Publications
We evaluated the potential relationship between miRNAs and Th17 cytokines in multiple myeloma (MM) patients. Twenty-seven newly diagnosed myeloma patients and eight normal donors were studied. We determined that the relative expression levels of miR-15a/16, miR-34a, miR-194 in MM patients were significantly lower than those in the healthy controls with exception for miR-181a/b, which showed significantly higher in MM patients (P<0.05). In contrast, the levels of IL-17, IL-21 and IL-27 were up-regulated in MM patients compared to healthy controls while IL-22 was down-regulated (P<0.05). The expression patterns of them were differentially present in various groups according to the International Staging System (ISS) criteria. Up-regulated IL-17, IL-21 and IL-27 may potentially down-regulate the expression of several miRNAs in MM patients. Establishment of the relationship may be useful for understanding the pathogenesis of MM and for clinical diagnosis of the disease.

Achari C, Winslow S, Ceder Y, Larsson C
Expression of miR-34c induces G2/M cell cycle arrest in breast cancer cells.
BMC Cancer. 2014; 14:538 [PubMed] Article available free on PMC after 01/11/2015 Related Publications
BACKGROUND: MicroRNA-34 is a family of three miRNAs that have been reported to function as tumor suppressor miRNAs and show decreased expression in various cancers. Here, we examine functions of miR-34c in basal-like breast cancer cells.
METHODS: Data from The Cancer Genome Atlas (TCGA) were used for evaluation of expression in primary breast cancers. Cellular processes affected by miR-34c were investigated by thymidine incorporation, Annexin V-assays and cell cycle analysis using breast cancer cell lines. Effects on potential targets were analyzed with qPCR and Western blot.
RESULTS: TCGA data revealed that miR-34c was expressed at lower levels in basal-like breast cancer tumors and low expression was associated with poor prognosis. Ectopic expression of miR-34c in basal-like breast cancer cell lines resulted in suppressed proliferation and increased cell death. Additionally, miR-34c influenced the cell cycle mainly by inducing an arrest in the G2/M phase. We found that expression levels of the known cell cycle-regulating miR-34 targets CCND1, CDK4 and CDK6, were downregulated upon miR-34c expression in breast cancer cell lines. In addition, the levels of CDC23, an important mediator in mitotic progression, were suppressed following miR-34c expression, and siRNAs targeting CDC23 mimicked the effect of miR-34c on G2/M arrest. However, protein levels of PRKCA, a predicted miR-34c target and a known regulator of breast cancer cell proliferation were not influenced by miR-34c.
CONCLUSIONS: Together, our results support the role of miR-34c as a tumor suppressor miRNA also in breast cancer.

Corcoran C, Rani S, O'Driscoll L
miR-34a is an intracellular and exosomal predictive biomarker for response to docetaxel with clinical relevance to prostate cancer progression.
Prostate. 2014; 74(13):1320-34 [PubMed] Related Publications
BACKGROUND: Docetaxel-resistance limits successful treatment of castration resistant prostate cancer. We previously demonstrated that extracellular vesicles (exosomes) may play a role in regulating docetaxel resistance. Here, we investigated intracellular and extracellular (exosomal) miRNAs related to docetaxel resistance.
METHODS: Following global miRNA profiling of cell line models of docetaxel-resistance and their corresponding exosomes, we investigated the clinical relevance of four selected miRNAs (miR-598, miR-34a, miR-146a, miR-148a) in four publically available clinical cohorts representing both primary and advanced disease in tissue and urine specimens. One of these miRNAs, miR-34a was selected for functional evaluation by miRNA inhibition and over-expression in vitro. We further assessed the panel of miRNAs for their combined clinical relevance as a biomarker signature by examining their common predicted targets.
RESULTS: A strong correlation was found between the detection of miRNAs in exosomes and their corresponding cells of origin. Of the miRNAs chosen for further validation and clinical assessment, decreased miR-34a levels showed substantial clinical relevance and so was chosen for further analysis. Manipulating miR-34a in prostate cancer cells confirms that this miRNA regulates BCL-2 and may, in part, regulate response to docetaxel. When combined, these miRNAs are predicted to regulate a range of common mRNA targets, two of which (e.g., SNCA, SCL7A5) demonstrate a strong relationship with prostate cancer progression and poor prognosis.
CONCLUSIONS: This study supports the extracellular environment as an important source of minimally invasive predictive biomarkers representing their cellular origin. Using miR-34a as example, we showed that biomarkers identified in this manner may also hold functional relevance.

Nagel S, Meyer C, Kaufmann M, et al.
Deregulated FOX genes in Hodgkin lymphoma.
Genes Chromosomes Cancer. 2014; 53(11):917-33 [PubMed] Related Publications
FOX genes encode transcription factors which regulate basic developmental processes during embryogenesis and in the adult. Several FOX genes show deregulated expression in particular malignancies, representing oncogenes or tumor suppressors. Here, we screened six Hodgkin lymphoma (HL) cell lines for FOX gene activity by comparative microarray profiling, revealing overexpression of FOXC1 and FOXD1, and reduced transcription of FOXN3, FOXO1, and FOXP1. In silico expression analyses of these FOX gene candidates in HL patient samples supported the cell line data. Chromosomal analyses demonstrated an amplification of the FOXC1 locus at 6p25 and a gain of the FOXR2 locus at Xp11, indicting genomic aberrations for their upregulation. Comparative expression profiling and ensuing stimulation experiments revealed implementation of the TGFβ- and WNT-signaling pathways in deregulation of FOXD1 and FOXN3. Functional analysis of FOXP1 implicated miR9 and miR34a as upstream regulators and PAX5, TCF3, and RAG2 as downstream targets. A similar exercise for FOXC1 revealed repression of MSX1 and activation of IPO7, both mediating inhibition of the B-cell specific homeobox gene ZHX2. Taken together, our data show that aberrantly expressed FOX genes and their downstream targets are involved in the pathogenesis of HL via deregulation of B-cell differentiation and may represent useful diagnostic markers and/or therapeutic targets.

Krzeszinski JY, Wei W, Huynh H, et al.
miR-34a blocks osteoporosis and bone metastasis by inhibiting osteoclastogenesis and Tgif2.
Nature. 2014; 512(7515):431-5 [PubMed] Article available free on PMC after 01/11/2015 Related Publications
Bone-resorbing osteoclasts significantly contribute to osteoporosis and bone metastases of cancer. MicroRNAs play important roles in physiology and disease, and present tremendous therapeutic potential. Nonetheless, how microRNAs regulate skeletal biology is underexplored. Here we identify miR-34a as a novel and critical suppressor of osteoclastogenesis, bone resorption and the bone metastatic niche. miR-34a is downregulated during osteoclast differentiation. Osteoclastic miR-34a-overexpressing transgenic mice exhibit lower bone resorption and higher bone mass. Conversely, miR-34a knockout and heterozygous mice exhibit elevated bone resorption and reduced bone mass. Consequently, ovariectomy-induced osteoporosis, as well as bone metastasis of breast and skin cancers, are diminished in osteoclastic miR-34a transgenic mice, and can be effectively attenuated by miR-34a nanoparticle treatment. Mechanistically, we identify transforming growth factor-β-induced factor 2 (Tgif2) as an essential direct miR-34a target that is pro-osteoclastogenic. Tgif2 deletion reduces bone resorption and abolishes miR-34a regulation. Together, using mouse genetic, pharmacological and disease models, we reveal miR-34a as a key osteoclast suppressor and a potential therapeutic strategy to confer skeletal protection and ameliorate bone metastasis of cancers.

Yu G, Zhong N, Chen G, et al.
Downregulation of PEBP4, a target of miR-34a, sensitizes drug-resistant lung cancer cells.
Tumour Biol. 2014; 35(10):10341-9 [PubMed] Related Publications
The aim of this study was to determine the relationship and underlying mechanisms between ectopic expression of phosphatidylethanolamine-binding protein 4 (PEBP4) and cisplatin (DDP)-induced cytotoxicity in the lung cancer cell line A549 to provide an experimental basis for future chemotherapeutic applications involving PEBP4 in human lung cancer. A recombinant plasmid, pcDNA3-PEBP4, and a PEBP4-targeting small hairpin RNA (shRNA) were transfected into the lung cancer cell line A549. The PEBP4 protein expression levels were determined for each group by Western blot, and after 48 h of cisplatin (DDP) treatment, the viability of cells in the treatment and control groups was determined by 3-[4,5-dimethylthiazol-2-yl]-3,5-diphenyltetrazolium bromide (MTT) assay. Apoptosis in each treatment group was determined using flow cytometry. Western blotting was used to examine expression of the p53 protein in A549 cells from each group. We employed a luciferase reporter-gene assay to confirm PEBP4 as a target gene of miR-34a. Western blotting was used to determine the effects of miR-34a on PEBP4 protein expression in A549 cells. Following transfection of A549 cells with either the recombinant plasmid pcDNA3-PEBP4 or a PEBP4-targeting shRNA, Western blotting analyses showed PEBP4 protein expression was significantly higher in the pcDNA3-PEBP4-transfected group compared with the control or PEBP4-shRNA-transfected groups (p < 0.01). Furthermore, PEBP4 protein expression was significantly reduced in the PEBP4-shRNA-transfected group (p < 0.01). After 48 h of DDP treatment, MTT assays indicated that A549 cell viability was significantly lower in the DDP-treated group compared with the control group (p < 0.01). The viability of A549 cells in the pcDNA3-PEBP4-transfected group was lower than that in the control group (p < 0.05) but higher than that in either the DDP-treated or PEBP4-shRNA-transfected groups (p < 0.05). Moreover, the viability of A549 cells in the PEBP4-shRNA-transfected group was significantly lower than that in either the control (p < 0.01) or DDP-treated (p < 0.05) groups. Flow cytometry and Western blotting analyses indicated that the number of apoptotic cells and p53 protein expression were significantly higher in the DDP-treated group compared with the control group (p < 0.01). In the pcDNA3-PEBP4-transfected group, the number of apoptotic cells and p53 protein expression level were higher than those in the control group (p < 0.05) but lower than those in the DDP-treated and PEBP4-shRNA-transfected groups (p < 0.05). The number of apoptotic cells and p53 protein expression level in the PEBP4-shRNA-transfected group were higher than those in the control (p < 0.01) and DDP-treated (p < 0.05) groups. The luciferase reporter-gene assay showed that the relative luciferase activity after transfection with a miR-34a mimic was significantly reduced compared with the control group (p < 0.01). Western blotting analysis demonstrated that PEBP4 protein expression was significantly decreased in A549 cells 48 h after transfection with a miR-34a mimic compared with the control group (p < 0.01). In conclusion, overexpression of PEBP4 reduced the sensitivity of A549 cells to DDP-induced cytotoxicity, mainly through the altered expression of the p53 protein or the modulation of miR-34a.

Li XJ, Ren ZJ, Tang JH
MicroRNA-34a: a potential therapeutic target in human cancer.
Cell Death Dis. 2014; 5:e1327 [PubMed] Article available free on PMC after 01/11/2015 Related Publications
MicroRNAs (miRs) are small noncoding RNAs that negatively regulate gene expression by binding to the three untranslated regions of their target mRNAs. Deregulations of miRs were shown to play pivotal roles in tumorigenesis and progression. Recent research efforts have been devoted to translating these basic discoveries into applications that could improve the therapeutic outcome of patients with cancer. MiR-34a is a highly conserved miR throughout many different species. In humans, there are three homologs (hsa-miR34a, hsa-miR-34b and hsa-miR-34c). Early studies have shown that miR-34a acts as a tumor-suppressor gene by targeting many oncogenes related to proliferation, apoptosis and invasion. In this review, we provide a complex overview of miR-34a, including regulating its expression, its known functions in cancer and future challenges as a potential therapeutic target in human cancers.

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