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. This miRNA is a member of the highly conserved miR-34 family. This miRNA functions as a tumor suppressor and dysregulation or loss of the host gene from which this miRNA is processed is associated with cancer progression in numerous cell types. [provided by RefSeq, Sep 2015]
Databases:miRBase, OMIM, HGNC, Ensembl, GeneCard, Gene
Source:NCBIAccessed: 01 September, 2019

Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 01 September 2019 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 01 September, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (7)

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)

Sun SQ, Ren LJ, Liu J, et al.
Sevoflurane inhibits migration and invasion of colorectal cancer cells by regulating microRNA-34a/ADAM10 axis.
Neoplasma. 2019; 2019 [PubMed] Related Publications
Sevoflurane is frequently used volatile anesthetic in cancer surgery. It has been suggested that treatment with sevoflurane could suppress migration and invasion of several human cancer cells in vitro. However, the effects of sevoflurane on colorectal cancer (CRC) remains largely unclear. In this study, CRC HCT116 and SW480 cells were treated by various concentrations of sevoflurane. MTT assay and Transwell assay were applied to evaluate the cell viability, migration and invasion abilities of CRC cell lines, respectively. Real-time quantitative PCR (RT-qPCR) was used to examine the expression level of miR-34a, and western blot assay was employed to detect the protein level of ADAM10. The target interaction between miR-34a and ADAM10 was verified through bioinformatics analysis, luciferase reporter gene assay system. We found Aberrant inhibitory effects induced by sevoflurane on the cell viability, migration and invasion abilities of HCT116 and SW480 cells in a dose-dependent manner were observed. Up-regulation of miR-34a strikingly suppressed the cell proliferation, migration and invasion abilities of the two cell lines. Sevoflurane could facilitate the miR-34a expression and its suppressor effects on CRC cells was reversed by pre-treatment with miR-34a inhibitors. ADAM10 was identified as a downstream gene of miR-34a, and down-regulated by miR-34a. Overexpression of ADAM10 reverted both miR-34a and sevoflurane-induced repression in the cell proliferation, migration and invasion abilities of CRC cells. Our data showed Sevoflurane inhibits the migration and invasion of colorectal cancer cells by regulating microRNA-34a/ADAM10 axis.

Ahmed MY, Salah MM, Kassim SK, et al.
Evaluation of the diagnostic and therapeutic roles of non-coding RNA and cell proliferation related gene association in hepatocellular carcinoma.
Gene. 2019; 706:97-105 [PubMed] Related Publications
Micro RNA-34a-5p (miR-34a-5p) is an important molecule that can act as a modulator of tumor growth. It controls expression of a plenty of proteins controlling cell cycle, differentiation and apoptosis and opposing processes that favor viability of cancer cells, their metastasis and resistance to chemotherapy. Bioinformatics analysis indicated that minichromosome maintenance protein 2 (MCM2) is a target gene of miR-34a-p. In this study, RT-qPCR was employed to detect the expression of miR-34a-5p and MCM2 in 10 hepatocellular carcinoma (HCC) tissues. The functional role of miR-34a-5p in HCC was investigated and the interaction between miR-34a-5p and MCM2 was explored. Results showed miR-34a-5p expression in HCC tissues was significantly lower than in non HCC liver tissues (P < 0.05), but MCM2 expression in HCC tissues was markedly higher than in non HCC liver tissues (P < 0.05). In addition, miR-34a-5p expression was negatively related to MCM2 expression. To confirm effect of miR-34a-5p on tumor growth and its possible effect on MCM2, miR-34a-5p mimic and inhibitor was transfected into HCC cell lines (HepG2). MTS assay, showed miR-34a-5p over-expression could inhibit the proliferation of HCC cells. RT-qPCR was done to detect the expression of miR-34a-5p and MCM2 in HepG2 cells before and after transfection. Results showed that MCM2 expression in HCC tissues was markedly lower in mimic transfected group than in inhibitor transfected group and control group (P < 0.05) while miR-34a-5p expression in HepG2 cells was significantly higher in mimic transfected group than in inhibitor transfected group and control group (P < 0.05). Thus, miR-34a-5p may inhibit the proliferation of HCC cells via regulating MCM2 expression. These findings provide an evidence for the emerging role of microRNAs as diagnostic markers and therapeutic targets in HCC.

Li M, Wang Y, Liu Y, et al.
Low Expression of hsa_circ_0018069 in Human Bladder Cancer and Its Clinical Significance.
Biomed Res Int. 2019; 2019:9681863 [PubMed] Free Access to Full Article Related Publications
Abnormal expression of noncoding RNA molecules such as circRNA plays an important role in the development of malignant tumors. circRNAs are stable in structure and can be useful as ideal tumor markers. Advanced bladder cancer has poor treatment options and prognosis. Thus, we examined circRNAs to further understand the pathogenesis and development of bladder cancer and to identify molecular markers for the early diagnosis of bladder carcinoma. We found that hsa_circ_0018069 was differentially expressed in our RNA sequencing data. We used qRT-PCR to detect its expression in T24 and Biu-87 cell lines and in 41 paired samples of bladder cancer and adjacent normal tissue and analyzed the correlation between expression of hsa_circ_0018069 and the clinical characteristics of patients with bladder cancer. We then performed a bioinformatics analysis to reveal the mechanism of hsa_circ_0018069 in tumorigenesis of bladder cancer. The expression of hsa_circ_0018069 was significantly reduced in T24 and Biu-87 cells and was also significantly downregulated in bladder cancer tissues. Decreased expression of hsa_circ_0018069 was related to the grade stage (P=0.024), T stage (P=0.027), and muscular invasion depth (P=0.022) of bladder cancer. Bioinformatics analysis showed that hsa_circ_0018069 was coexpressed with protein-coding mRNAs that participate in cytoskeletal protein binding and cell-substrate junction assembly and play an anticancer role through focal adhesion and calcium signaling pathways. ceRNA analysis showed that hsa_circ_0018069 functions in ErbB, Ras, FoxO, and the focal adhesion signaling pathway by harboring miR-23c, miR-34a-5p, miR-181b-5p, miR-454-3p, and miR-3666. hsa_circ_0018069 may thus play an important role in the occurrence and progression of bladder cancer and serve as a valuable biomarker for the early diagnosis of this disease.

Kubatka P, Uramova S, Kello M, et al.
Anticancer Activities of
Int J Mol Sci. 2019; 20(7) [PubMed] Free Access to Full Article Related Publications
Naturally-occurring mixtures of phytochemicals present in plant foods are proposed to possess tumor-suppressive activities. In this work, we aimed to evaluate the antitumor effects of

Bao Y, Lu Y, Feng W, et al.
COUP‑TFII promotes epithelial‑mesenchymal transition by inhibiting miR‑34a expression in colorectal cancer.
Int J Oncol. 2019; 54(4):1337-1344 [PubMed] Related Publications
Chicken ovalbumin upstream promoter‑transcription factor II (COUP‑TFII) expression is upregulated in colorectal cancer and is associated with its progression and a poor prognosis. The aim of the present study was to determine whether COUP‑TFII regulates colorectal cancer cell (CRC) invasion and migration by inhibiting microRNA (miR)‑34a. Transwell system and wound healing assays were performed to examine cell invasiveness and migration, respectively. Reverse transcription polymerase chain reaction and western blotting were used to detect the RNA and protein levels of target molecules, respectively. The results revealed that COUP‑TFII knockdown significantly inhibited CRC invasion and migration. In addition, the expression of miR‑34a, a well‑known tumor suppressor was revealed to be inversely correlated with COUP‑TFII expression. The miR‑34a mimic significantly reduced CRC invasion and migration abilities, while the miR‑34a inhibitor enhanced CRC invasion and migration activity. There was no significant difference between the negative small interfering RNA and miR‑34a inhibitor groups following knockdown of COUP‑TFII. Furthermore, western blotting demonstrated that miR‑34a mimics inhibited the epithelial‑mesenchymal transition (EMT) process of CRCs, while the miR‑34a inhibitor had the opposite effect. Taken together, the results demonstrate that miR‑34a regulates CRC invasion and migration by examining the mechanism by which COUP‑TFII regulates EMT.

Márton É, Lukács J, Penyige A, et al.
Circulating epithelial-mesenchymal transition-associated miRNAs are promising biomarkers in ovarian cancer.
J Biotechnol. 2019; 297:58-65 [PubMed] Related Publications
Ovarian cancer is the fifth most common cause of cancer death among women that is mostly due to the difficulty of early diagnosis. Circulating miRNAs proved to be reliable biomarkers in various cancers. We screened 9 miRNAs, which are involved in epithelial-mesenchymal transition, in the plasma samples of patients with malignant (n = 28) or non-malignant (n = 12) ovarian tumors and disease-free healthy volunteers (n = 60) by qRT-PCR. The expression levels of miR200a, miR200b, miR200c, miR141, miR429, miR203a, miR34b (p < 0.001) and miR34a (p < 0.01) were significantly higher in the malignant samples than in healthy controls. MiR203a, miR141 (p < 0.01), miR200a and miR429 (p < 0.05) levels were also higher in malignant compared to non-malignant samples. ROC-AUC was the highest in the case of miR200c: 0.861 (95%CI = 0.776-0.947). Spearman's rank correlation analysis revealed positive correlation between the plasma levels of the studied miRNAs that was the highest between miR200b and miR200c (r

Jia Y, Lin R, Jin H, et al.
MicroRNA-34 suppresses proliferation of human ovarian cancer cells by triggering autophagy and apoptosis and inhibits cell invasion by targeting Notch 1.
Biochimie. 2019; 160:193-199 [PubMed] Related Publications
Ovarian cancer is one the prevalent cancers in women and is responsible for 5% of all the cancer related mortalities in women. Owing to late diagnosis, frequent relapses, side effects of chemotherapy, development of drug resistance, there is pressing need to screen out novel and effective treatment options. Accumulating evidences suggest that miRNAs may prove essential therapeutic targets for the treatment of cancer. This study was designed to investigate the role and therapeutic potential of miR-34 in ovarian cancer. It was found that miR-34 is significantly downregulated in ovarian cancer cell lines. Overexpression of miR-34 causes significant decrease in the proliferation of OVACAR-3 ovarian cancer cells via activation of apoptosis and autophagy. The miR-34 overexpression was concomitant with upsurge of apoptosis related proteins (Bax) and the autophagy associated protein (LC3 II and p62). TargetScan analysis showed Notch 1 to be the main target of miR-34 in OVACAR-3 cells which was further validated by luciferase reporter assay. The qRT-PCR results showed Notch 1 to be 3.2-4.1 fold higher in the ovarian cancer cell lines relative to the non-cancerous cells. Nonetheless, miR-34 overexpression in OVACAR-3 cells resulted in the post-transcriptional suppression of Notch 1 expression. Silencing of Notch 1 also caused inhibition of OVACAR-3 cell proliferation via induction of apoptosis and autophagy. Overexpression of Notch 1 could partially rescue the effects of miR-34 overexpression on the proliferation of OVACAR-3 cells. Moreover, overexpression of miR-34 causes significant inhibition of the invasion of the OVACAR-3 cells. The findings of the present study indicate the tumor suppressive role of miR-34 in ovarian cancer and may therefore prove to be a potential therapeutic target.

Ji Y, Wang M, Li X, Cui F
The Long Noncoding RNA NEAT1 Targets miR-34a-5p and Drives Nasopharyngeal Carcinoma Progression via Wnt/β-Catenin Signaling.
Yonsei Med J. 2019; 60(4):336-345 [PubMed] Free Access to Full Article Related Publications
PURPOSE: Long noncoding RNA nuclear paraspeckle assembly transcript 1 (NEAT1) has been deemed an oncogene in many human cancers. However, the underlying mechanism of NEAT1 in nasopharyngeal carcinoma (NPC) progression remains largely unclear.
MATERIALS AND METHODS: Quantitative real-time PCR assay was performed to assess the expression of NEAT1 and miR-34a-5p in NPC tissues and cells. Western blot analysis was used to observe cell epithelial to mesenchymal transition (EMT) and the activation of Wnt/β-catenin signaling in 5-8F cells. MiRNA directly interacting with NEAT1 were verified by dual-luciferase reporter assay and RNA immunoprecipitation. Cell proliferation ability was determined by CCK-8 assay, and cell migration and invasion capacities were assessed by transwell assays. An animal model was used to investigate the regulatory effect of NEAT1 on tumor growth
RESULTS: Our data revealed that NEAT1 is upregulated, while miR-34a-5p is downregulated in NPC tissues and cell lines. NEAT1 knockdown repressed tumor growth
CONCLUSION: Our study demonstrated that NEAT1 targets miR-34a-5p at least partly to drive NPC progression by regulating Wnt/β-catenin signaling, suggesting a potential therapeutic target for NPC.

Weng YS, Tseng HY, Chen YA, et al.
MCT-1/miR-34a/IL-6/IL-6R signaling axis promotes EMT progression, cancer stemness and M2 macrophage polarization in triple-negative breast cancer.
Mol Cancer. 2019; 18(1):42 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Triple-negative breast cancer (TNBC) is a poor prognostic breast cancer with the highest mutations and limited therapeutic choices. Cytokine networking between cancer cells and the tumor microenvironment (TME) maintains the self-renewing subpopulation of breast cancer stem cells (BCSCs) that mediate tumor heterogeneity, resistance and recurrence. Immunotherapy of those factors combined with targeted therapy or chemoagents may advantage TNBC treatment.
RESULTS: We found that the oncogene Multiple Copies in T-cell Malignancy 1 (MCT-1/MCTS1) expression is a new poor-prognosis marker in patients with aggressive breast cancers. Overexpressing MCT-1 perturbed the oncogenic breast epithelial acini morphogenesis and stimulated epithelial-mesenchymal transition and matrix metalloproteinase activation in invasive TNBC cells, which were repressed after MCT-1 gene silencing. As mammary tumor progression was promoted by oncogenic MCT-1 activation, tumor-promoting M2 macrophages were enriched in TME, whereas M2 macrophages were decreased and tumor-suppressive M1 macrophages were increased as the tumor was repressed via MCT-1 knockdown. MCT-1 stimulated interleukin-6 (IL-6) secretion that promoted monocytic THP-1 polarization into M2-like macrophages to increase TNBC cell invasiveness. In addition, MCT-1 elevated the soluble IL-6 receptor levels, and thus, IL-6R antibodies antagonized the effect of MCT-1 on promoting M2-like polarization and cancer cell invasion. Notably, MCT-1 increased the features of BCSCs, which were further advanced by IL-6 but prevented by tocilizumab, a humanized IL-6R antibody, thus MCT-1 knockdown and tocilizumab synergistically inhibited TNBC stemness. Tumor suppressor miR-34a was induced upon MCT-1 knockdown that inhibited IL-6R expression and activated M1 polarization.
CONCLUSIONS: The MCT-1 pathway is a novel and promising therapeutic target for TNBC.

Soltani-Sedeh H, Irani S, Mirfakhraie R, Soleimani M
Potential using of microRNA-34A in combination with paclitaxel in colorectal cancer cells.
J Cancer Res Ther. 2019 Jan-Mar; 15(1):32-37 [PubMed] Related Publications
Background: MicroRNAs are small noncoding RNAs which modulate gene expression at different levels. It has been shown that downregulation of miR-34a occurs in varieties of cancers including colorectal cancer (CRC). In this study, we investigated the potential tumor inhibitory effects of miR-34a alone or in combination with paclitaxel in CRC cells.
Materials and Methods: SW480 cells were transduced with lentiviral overexpressed miR-34a. First, using 3-(4,5-Dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide assay, the effect of miR-34a induction alone or in combination with paclitaxel on the cell viability and cell proliferation were estimated. Then, the expression level of target genes was measured using quantitative reverse transcription-polymerase chain reaction analysis. Eventually, the role of miR-34a and paclitaxel on cell cycle were determined with flow cytometry.
Results: Gene expression analysis showed that miR-34a downregulates the expression of BCL2 and SIRT1 genes at mRNA level. Furthermore, miR-34a has a potential to reduce cell viability and cell cycle arrest at G1 phase. Combination of paclitaxel with overexpression of miR-34a significantly decreased cell viability compared to cell treated with miR-34a or paclitaxel alone. Interestingly, a combination of miR-34a and paclitaxel arrested cell cycle at two phases.
Conclusion: Our results suggested that combination therapy of miR-34a and paclitaxel could be considered as the potential treatment of CRC.

Steele TM, Talbott GC, Sam A, et al.
Obatoclax, a BH3 Mimetic, Enhances Cisplatin-Induced Apoptosis and Decreases the Clonogenicity of Muscle Invasive Bladder Cancer Cells via Mechanisms That Involve the Inhibition of Pro-Survival Molecules as Well as Cell Cycle Regulators.
Int J Mol Sci. 2019; 20(6) [PubMed] Free Access to Full Article Related Publications
Several studies by our group and others have determined that expression levels of Bcl-2 and/or Bcl-xL, pro-survival molecules which are associated with chemoresistance, are elevated in patients with muscle invasive bladder cancer (MI-BC). The goal of this study was to determine whether combining Obatoclax, a BH3 mimetic which inhibits pro-survival Bcl-2 family members, can improve responses to cisplatin chemotherapy, the standard of care treatment for MI-BC. Three MI-BC cell lines (T24, TCCSuP, 5637) were treated with Obatoclax alone or in combination with cisplatin and/or pre-miR-34a, a molecule which we have previously shown to inhibit MI-BC cell proliferation via decreasing Cdk6 expression. Proliferation, clonogenic, and apoptosis assays confirmed that Obatoclax can decrease cell proliferation and promote apoptosis in a dose-dependent manner. Combination treatment experiments identified Obatoclax + cisplatin as the most effective treatment. Immunoprecipitation and Western analyses indicate that, in addition to being able to inhibit Bcl-2 and Bcl-xL, Obatoclax can also decrease cyclin D1 and Cdk4/6 expression levels. This has not previously been reported. The combined data demonstrate that Obatoclax can inhibit cell proliferation, promote apoptosis, and significantly enhance the effectiveness of cisplatin in MI-BC cells via mechanisms that likely involve the inhibition of both pro-survival molecules and cell cycle regulators.

Wang H, Wang F, Wang X, et al.
Friend or Foe: A Cancer Suppressor MicroRNA-34 Potentially Plays an Adverse Role in Vascular Diseases by Regulating Cell Apoptosis and Extracellular Matrix Degradation.
Med Sci Monit. 2019; 25:1952-1959 [PubMed] Free Access to Full Article Related Publications
BACKGROUND MicroRNAs (miRNAs) have emerged as central regulators of many processes. MiRNA-34 (miR-34) functions as a well-known tumor suppressor. The aim of this study was to investigate the mechanisms underlying how miR-34 participates in vascular disorders. MATERIAL AND METHODS Three miR-34 family members (miR-34a, miR-34b, and miR-34c) were overexpressed or silenced in human vascular smooth muscle cells (VSMCs) and umbilical vein endothelial cells (UVECs), respectively, before the proliferation and apoptosis of cells were detected by using Cell Counting Kit-8 assay and Annexin V- fluorescein isothiocyanate/propidium iodide flow cytometry. The protein expression of apoptosis biomarkers was detected by western blot. Dual-luciferase reporter assay was performed to determine the candidate target of miR-34, and enzyme-linked immune sorbent assay was used to evaluate the effect of miR-34 on the expression of the target gene. RESULTS Overexpression of miR-34 family members repressed proliferation and promoted apoptosis of VSMCs and UVECs, whereas miR-34 knockdown led to the opposite results. In addition, miR-34a inhibited the expression of alpha-1 antitrypsin (AAT), a serine protease inhibitor that suppresses the degradation of extracellular matrix, through a miR-34-binding site within the 3'-UTR of AAT. CONCLUSIONS MiR-34 promoted apoptosis of VSMC and UVEC cells by inhibiting AAT expression. This finding provides an update on the understanding of the clinical value of miR-34, which might assist to uncover novel and effective therapeutic strategies for the treatment of vascular diseases.

Sun Z, Zhang T, Chen B
Long Non-Coding RNA Metastasis-Associated Lung Adenocarcinoma Transcript 1 (MALAT1) Promotes Proliferation and Metastasis of Osteosarcoma Cells by Targeting c-Met and SOX4 via miR-34a/c-5p and miR-449a/b.
Med Sci Monit. 2019; 25:1410-1422 [PubMed] Free Access to Full Article Related Publications
BACKGROUND Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) is a functional long non-coding RNA involved in many biologic processes. The study was aimed to explore the functional roles of MALAT1 in osteosarcoma progression. MATERIAL AND METHODS A total of 76 osteosarcoma tissues and paired adjacent non-tumor tissues were collected from surgical resection. MALAT1, miRNAs, and genes mRNA expression levels were detected using quantitative real-time PCR (qRT-PCR). Protein expression level, cell proliferation, migration, and invasion were assessed using western blot, Cell Counting Kit-8 (CCK-8), wound-healing assay, and Matrigel invasion assay respectively. The target relationships among miRNAs, MALAT1, and mRNA were detected via dual-luciferase reporter assay. RESULTS We found that MALAT1 was frequently upregulated in osteosarcoma samples and cell lines and a high level of MALAT1 predicted poor overall survival in osteosarcoma patients. Knockdown of MALAT1 inhibited proliferation, migration, and invasion of osteosarcoma cells. Further study showed a positive correlation between MALAT1 and c-Met or SOX4 expression. Mechanistic investigations demonstrated that MALAT1, as a competing endogenous RNA (ceRNA), regulated osteosarcoma proliferation and metastasis through competitively binding to miR-34a/c-5p and miR-449a/b. CONCLUSIONS Taken together, our study illustrates a new regulatory mechanism for MALAT1 and may provide a novel therapeutic strategy for the treatment of osteosarcoma.

Nie D, Fu J, Chen H, et al.
Roles of MicroRNA-34a in Epithelial to Mesenchymal Transition, Competing Endogenous RNA Sponging and Its Therapeutic Potential.
Int J Mol Sci. 2019; 20(4) [PubMed] Free Access to Full Article Related Publications
MicroRNA-34a (miR-34a), a tumor suppressor, has been reported to be dysregulated in various human cancers. MiR-34a is involves in certain epithelial-mesenchymal transition (EMT)-associated signal pathways to repress tumorigenesis, cancer progression, and metastasis. Due to the particularity of miR-34 family in tumor-associated EMT, the significance of miR-34a is being increasingly recognized. Competing endogenous RNA (ceRNA) is a novel concept involving mRNA, circular RNA, pseudogene transcript, and long noncoding RNA regulating each other's expressions using microRNA response elements to compete for the binding of microRNAs. Studies showed that miR-34a is efficient for cancer therapy. Here, we provide an overview of the function of miR-34a in tumor-associated EMT. ceRNA hypothesis plays an important role in miR-34a regulation in EMT, cancer progression, and metastasis. Its potential roles and challenges as a microRNA therapeutic candidate are discussed. As the negative effect on cancer progression, miR-34a should play crucial roles in clinical diagnosis and cancer therapy.

Song Z, Liang X, Wang Y, et al.
Phenylboronic acid-functionalized polyamidoamine-mediated miR-34a delivery for the treatment of gastric cancer.
Biomater Sci. 2019; 7(4):1632-1642 [PubMed] Related Publications
In the present research, a tumor-targeted gene carrier, PPP, was constructed through the modification of phenylboronic acid onto the surface of a polyamidoamine dendrimer, and then miR-34a delivery was employed as a model to evaluate its anti-tumor efficacy. The carrier PPP was identified to possess favorable miR-34a binding and condensation ability and meanwhile protect miR-34a against nuclease degradation. Through confocal laser scanning microscopy and flow cytometry analysis, PPP-mediated cellular uptake of miR-34a was found to proceed through a sialic acid-dependent endocytosis pathway and the nanoparticles could achieve endosome/lysosome escape within 6 h. Further, an anti-proliferative effect could be obtained after PPP/miR-34a transfection through the induction of cell apoptosis. Meanwhile, the inhibition of migration and invasion could be realized through blocking the Notch-1 signaling pathway after PPP/miR-34a treatment. Finally, PPP possessed acceptable safety and inhibited in vivo tumor growth through the in situ apoptosis of tumor sites, which relied on the specific tumor-targeting ability and long circulation time in the blood. In summary, the derivative PPP could be potentially utilized as an efficient carrier for miR-34a delivery to achieve an anti-tumor response in clinical use.

Zhang L, Liao Y, Tang L
MicroRNA-34 family: a potential tumor suppressor and therapeutic candidate in cancer.
J Exp Clin Cancer Res. 2019; 38(1):53 [PubMed] Free Access to Full Article Related Publications
MicroRNA-34 (miR-34) has been reported to be dysregulated in various human cancers and regarded as a tumor suppressive microRNA because of its synergistic effect with the well-known tumor suppressor p53. Along with the application of MRX34, the first tumor-targeted microRNA drug which based on miR-34a mimics, on phase I clinical trial (NCT01829971), the significance of miR-34 is increasingly recognized. miR-34 plays a crucial role on repressing tumor progression by involving in epithelial-mesenchymal transition (EMT) via EMT- transcription factors, p53 and some important signal pathways. Not only that, numerous preclinical researches revealed the giant potential of miR-34a on cancer therapy through diversiform nano-scaled delivery systems. Here, we provide an overview about the function of miR-34 in various cancers and the mechanism of miR-34 in tumor-associated EMT. Furthermore, its potential role as a microRNA therapeutic candidate is also discussed. Notwithstanding some obstacles existed, the extensive application prospect of miR-34 on oncotherapy cannot be neglected.

Cheng X, Xu Q, Zhang Y, et al.
miR-34a inhibits progression of neuroblastoma by targeting autophagy-related gene 5.
Eur J Pharmacol. 2019; 850:53-63 [PubMed] Related Publications
Neuroblastoma (NB) is a common pediatric malignancy with high mortality in childhood. Although many attentions have been gained, novel biomarkers for NB diagnosis and prognosis are still needed. microRNAs (miRNAs) played important roles in NB progression and miR-34a is a tumor suppressor in NB. However, the mechanism that underlies miR-34a regulating proliferation, migration, invasion and autophagy in NB remains poorly understood. In this study, cell proliferation was investigated by MTT and colony assay. Cell apoptosis was measured by caspase 3 activity assay. Cell migration and invasion were detected by trans-well analysis. Autophagy was measured via GFP-LC3 puncta fluorescence assay and western blots (WB). The expression of miR-34a was examined by quantitative real-time PCR (qRT-PCR). The regulatory effect of miR-34a on autophagy-related gene 5 (ATG5) was detected by qRT-PCR and WB. The interaction between miR-34a and ATG5 was probed by luciferase activity and RNA immunoprecipitation (RIP) assay. Results showed that miR-34a expression was inhibited in NB tissues and cells with low survival rate. Addition of miR-34a suppressed cell proliferation, migration, invasion and autophagy but promoted apoptosis in NB cells, whereas miR-34a deficiency played opposite roles in NB progression. Intriguingly, ATG5 was directly targeted by miR-34a. Moreover, ATG5 restoration attenuated miR-34a-mediated inhibitory effect on proliferation, apoptosis, migration, invasion and autophagy. These results indicated miR-34a suppressed proliferation, apoptosis, migration, invasion and autophagy in NB cells by targeting ATG5, providing a novel therapeutic avenue for NB treatment.

Sakata J, Sasayama T, Tanaka K, et al.
MicroRNA regulating stanniocalcin-1 is a metastasis and dissemination promoting factor in glioblastoma.
J Neurooncol. 2019; 142(2):241-251 [PubMed] Related Publications
BACKGROUND: MicroRNAs (miRs) regulate many biological processes, such as invasion, angiogenesis, and metastasis. Glioblastoma (GBM) patients with metastasis/metastatic dissemination have a very poor prognosis; therefore, inhibiting metastasis/metastatic dissemination has become an important therapeutic strategy for GBM treatment.
METHODS: Using 76 GBM tissues, we examined the expression levels of 23 GBM-related miRs and compared the miRs' expression levels between GBMs with metastasis/metastatic dissemination and GBMs without metastasis/metastatic dissemination. Using the bioinformatics web site, we searched the target genes of miRs. To analyze the function of target gene, several biological assays and survival analysis by the Kaplan-Meier method were performed.
RESULTS: We found that eight miRs were significantly decreased in GBM with metastasis/metastatic dissemination. By the bioinformatics analysis, we identified stanniocalcin-1 (STC1) as the most probable target gene against the combination of these miRs. Four miRs (miR-29B, miR-34a, miR-101, and miR-137) have predictive binding sites in STC1 mRNA, and mRNA expression of STC1 was downregulated by mimics of these miRs. Also, mimics of these miRs and knockdown of STC1 by siRNA suppressed invasion in GBM cells. GBM with metastasis/metastatic dissemination had significantly higher levels of STC1 than GBM without metastasis/metastatic dissemination. Finally, Kaplan-Meier analysis demonstrated that GBMs with high STC1 level had significantly shorter survival than GBMs with low STC1 level.
CONCLUSIONS: STC1 may be a novel metastasis/metastatic dissemination promoting factor regulated by several miRs in GBM. Because STC1 is a secreted glycoprotein and functions via the autocrine/paracrine signals, inhibiting STC1 signal may become a novel therapeutic strategy for GBM.

Ye J, Cheng XD, Cheng B, et al.
MiRNA detection in cervical exfoliated cells for missed high-grade lesions in women with LSIL/CIN1 diagnosis after colposcopy-guided biopsy.
BMC Cancer. 2019; 19(1):112 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Low-grade squamous intraepithelial lesion/cervical intraepithelial neoplasia grade 1 (LSIL/CIN1) preceded by colposcopy guided biopsy is recommended conservative follow-up, although some of these lesions are actually high-grade lesions, which are missed on an initial colposcopy. Therefore, in this work, we evaluate the potential role of miRNA detection in cervical exfoliated cells in a clinic-based population for predicting missed high-grade lesions in women diagnosed with LSIL/CIN1 after colposcopy-guided biopsy.
METHODS: A total number of 177 women with a diagnosis of LSIL/CIN1 obtained by colposcopy-guided biopsy were grouped into two categories according to the histology of the conization specimens: consistent LSIL/CIN1 group (surgical pathology consistent with colposcopic diagnosis) and missed high-grade lesion group (surgical pathology found high-grade lesion). The expression of eight miRNAs, such as miRNA195, miRNA424, miRNA375, miRNA218, miRNA34a, miRNA29a, miRNA16-2, and miRNA20a was detected by real time-quantitative polymerase chain reaction (RT-qPCR) in cervical exfoliated cells of the 177 patients. Pearson Chi-Square was used to compare the performance efficiency of patients' characteristics. Nonparametric Man-Whitney U test was used to assess differences in miRNA expression. The receiver operating characteristic (ROC) curve was used to assess the performance of miRNA evaluation in detecting missed high-grade lesions.
RESULTS: Among the 177 women with biopsy-confirmed CIN1, 15.3% (27/177) had CIN2+ in the conization specimen (missed high-grade lesion group) and 84.7% (150/177) had CIN1-(consistent LSIL/CIN1 group). The relative expression of miRNA-195 and miRNA-29a in the missed high-grade lesion group was significantly lower than that in the consistent LSIL/CIN1 group. The relative expression of miRNA16-2 and miRNA20a in the missed high-grade lesion group was significantly higher than that in the consistent LSIL/CIN1 group. No significant difference was observed between these two groups regarding the other four miRNAs. Of these significant miRNAs, miRNA29a detection achieved the highest Youden index (0.733), sensitivity (92.6%), positive predictive value (46.2%), negative predictive value (98.3%) and higher specificity (80.7%) when identifying missed high-grade lesions.
CONCLUSIONS: Detection of miRNA might provide a new triage for identifying a group at higher risk of missed high-grade lesions in women with colposcopy diagnosis of LSIL/CIN1.

Córdova-Rivas S, Fraire-Soto I, Mercado-Casas Torres A, et al.
5p and 3p Strands of miR-34 Family Members Have Differential Effects in Cell Proliferation, Migration, and Invasion in Cervical Cancer Cells.
Int J Mol Sci. 2019; 20(3) [PubMed] Free Access to Full Article Related Publications
The micro RNA (miR)-34 family is composed of 5p and 3p strands of miR-34a, miR-34b, and miR-34c. The 5p strand's expression and function is studied in cervical cancer. The 3p strand's function and regulation remain to be elucidated. To study the function of the passenger strands of miR-34 family members, we overexpressed 5p and 3p strands using a synthetic miRNA in cervical cell lines. Cell proliferation was evaluated using crystal violet. Migration and invasion were tested using transwell assays, Western blot, and zymography. Possible specific targets and cell signaling were investigated for each strand. We found that miR-34a-5p inhibited proliferation, migration, and cell invasion accompanied by matrix metalloproteinase 9 (MMP9) activity and microtubule-associated protein 2 (MAP2) protein reduction. We also found that miR-34b-5p and miR-34c-5p inhibit proliferation and migration, but not invasion. In contrast, miR-34c-5p inhibits MMP9 activity and MAP2 protein, while miR-34b-5p has no effect on these genes. Furthermore, miR-34a-3p and miR-34b-3p inhibit proliferation and migration, but not invasion, despite the later reducing MMP2 activity, while miR-34c-3p inhibit proliferation, migration, and cell invasion accompanied by MMP9 activity and MAP2 protein inhibition. The difference in cellular processes, MMP2 and MMP9 activity, and MAP2 protein inhibition by miR-34 family members suggests the participation of other regulated genes. This study provides insights into the roles of passenger strands (strand*) of the miR-34 family in cervical cancer.

Wang Z, Lv J, Zou X, et al.
A three plasma microRNA signature for papillary thyroid carcinoma diagnosis in Chinese patients.
Gene. 2019; 693:37-45 [PubMed] Related Publications
Whether plasma miRNAs could be used as novel non-invasive biomarkers in diagnosing papillary thyroid carcinoma (PTC) remains unknown. In this study, we designed a four-phase study to identify differentially expressed plasma miRNAs in Chinese PTC patients. Exiqon panel was initially utilized to conduct plasma miRNA profile (3 PTC pools VS. 1 healthy control (HC) pool; each 10 samples were pooled as 1 sample). The dysregulated miRNAs were then analyzed in the training (30 PTC VS. 30 HCs), testing (57 PTC VS. 54 HCs) and external validation phases (33 PTC VS. 30HCs). The identified miRNAs were further affirmed in benign nodules (2 nodular goiter (NG) pool VS. 1 HC pool). We also verified the expression of identified miRNAs in 17 matched malignant and normal tissue samples, NG plasma samples (29 PTC VS. 29 NG) and plasma exosomes (25 PTC VS. 25 HCs). Receiver operating characteristic (ROC) curves were constructed to evaluate the diagnostic value of the identified miRNAs. As a result, the screening phase demonstrated 30 dysregulated plasma miRNAs in PTC patients compared with HCs. After multiphase experiment processes, miR-346, miR-10a-5p and miR-34a-5p were found significantly elevated in PTC plasma samples relative to HCs. The areas under the ROC curve (AUC) of the three-miRNA panel for the training, testing and validation phases were 0.926, 0.811 and 0.816, separately. The panel could also differentiate PTC from NG with the AUC of 0.877. MiR-346 and miR-34a-5p but not miR-10a-5p were up-regulated in PTC tissues. And the three miRNAs showed consistently up-regulation in PTC plasma exosomes. In conclusion, our study established a three-miRNA panel in plasma with considerable clinical value in discriminating PTC from HC or NG.

Lee HY, Chen YJ, Li CC, et al.
Deduction of Novel Genes Potentially Involved in Upper Tract Urothelial Carcinoma Using Next-Generation Sequencing and Bioinformatics Approaches.
Int J Med Sci. 2019; 16(1):93-105 [PubMed] Free Access to Full Article Related Publications
Upper tract urothelial carcinoma (UTUC) is a relatively uncommon cancer worldwide, however it accounts for approximately 30% of urothelial cancer in the Taiwanese population. The aim of the current study is to identify differential molecular signatures and novel miRNA regulations in UTUC, using next-generation sequencing and bioinformatics approaches. Two pairs of UTUC tumor and non-tumor tissues were collected during surgical resection, and RNAs extracted for deep sequencing. There were 317 differentially expressed genes identified in UTUC tissues, and the systematic bioinformatics analyses indicated dysregulated genes were enriched in biological processes related to aberration in cell cycle and matrisome-related genes. Additionally, 15 candidate genes with potential miRNA-mRNA interactions were identified. Using the clinical outcome prediction database, low expression of

Proença MA, Biselli JM, Succi M, et al.
Relationship between
World J Gastroenterol. 2018; 24(47):5351-5365 [PubMed] Free Access to Full Article Related Publications
AIM: To examine the effect of
METHODS: Levels of
RESULTS: Overabundance of
CONCLUSION: Our findings indicate that

Manzanarez-Ozuna E, Flores DL, Gutiérrez-López E, et al.
Model based on GA and DNN for prediction of mRNA-Smad7 expression regulated by miRNAs in breast cancer.
Theor Biol Med Model. 2018; 15(1):24 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: The Smad7 protein is negative regulator of the TGF-β signaling pathway, which is upregulated in patients with breast cancer. miRNAs regulate proteins expressions by arresting or degrading the mRNAs. The purpose of this work is to identify a miRNAs profile that regulates the expression of the mRNA coding for Smad7 in breast cancer using the data from patients with breast cancer obtained from the Cancer Genome Atlas Project.
METHODS: We develop an automatic search method based on genetic algorithms to find a predictive model based on deep neural networks (DNN) which fit the set of biological data and apply the Olden algorithm to identify the relative importance of each miRNAs.
RESULTS: A computational model of non-linear regression is shown, based on deep neural networks that predict the regulation given by the miRNA target transcripts mRNA coding for Smad7 protein in patients with breast cancer, with R
CONCLUSIONS: We developed a genetic algorithm to select best features as DNN inputs (miRNAs). The genetic algorithm also builds the best DNN architecture by optimizing the parameters. Although the confirmation of the results by laboratory experiments has not occurred, the results allow suggesting that miRNAs profile could be used as biomarkers or targets in targeted therapies.

Li Q, Wang C, Cai L, et al.
miR‑34a derived from mesenchymal stem cells stimulates senescence in glioma cells by inducing DNA damage.
Mol Med Rep. 2019; 19(3):1849-1857 [PubMed] Related Publications
Insights into the roles of microRNAs (miRNAs/miRs) in development and disease, particularly in cancer, have made miRNAs attractive tools and targets for novel therapeutic approaches in the treatment of glioma. miR‑34a, as a well‑known tumor suppressor miRNA, is closely related with cellular senescence. Mesenchymal stem cells (MSCs) are a major component of the tumor microenvironment and possess the ability to deliver exogenous miRs to glioma cells to exert anti‑tumor effects. The present study investigated whether modified MSCs with miR‑34a possess an anti‑tumor function in glioma cells. A Transwell system was used to co‑culture U87 glioma cells and MSCs overexpressing miR‑34a, and cell proliferation and senescence assessed. The expression of senescence‑related genes p53, Cdkn1a, and Cdkn2c were tested using reverse transcription‑quantitative polymerase chain reaction and protein expression levels of sirtuin 1 (SIRT1) and γ‑H2A histone family, member X were detected by western blotting. Telomerase activity of U87 cells was examined using the Telo TAGGG Telomerase PCR ELISA PLUS kit. The results demonstrated that the delivered exogenous miR‑34a from MSCs significantly decreased expression of the target gene SIRT1. In addition, the delivered miR‑34a decreased the proliferation of glioma cells and provoked the expression of senescence‑related genes p53, Cdkn1a, and Cdkn2c. In addition, upregulation of miR‑34a induced DNA damage, shortened telomere length and impaired telomerase activity. However, these pro‑senescent effects were reversed by forced SIRT1 upregulation. In conclusion, the results demonstrated a novel role for miR‑34a, inducing glioma cell senescence, whereas miR‑34a modulation of SIRT1, inducing DNA damage, is crucial for miRNA replacement therapy in glioma treatment.

Li Q, Song W, Wang J
TUG1 confers Adriamycin resistance in acute myeloid leukemia by epigenetically suppressing miR-34a expression via EZH2.
Biomed Pharmacother. 2019; 109:1793-1801 [PubMed] Related Publications
Increasing evidence has suggested the involvement of long non-coding RNA (lncRNA) taurine upregulated gene 1 (TUG1) in chemoresistance of cancer treatment. However, its function and molecular mechanisms in acute myeloid leukemia (AML) chemoresistance are still not well elucidated. In the present study, we investigate the functional role of TUG1 in Adriamycin (ADR) resistance of AML and discover the underlying molecular mechanism. Our study revealed that TUG1 was up-regulated in ADR-resistant AML tissues and cells. High TUG1 expression was correlated with poor prognosis of AML patients. TUG1 knockdown improved the sensitivity of HL60/ADR cells to ADR. Moreover, TUG1 could epigenetically suppress miR-34a expression via recruiting Enhancer of zeste homolog 2 (EZH2). miR-34a overexpression could mimic the functional role of down-regulated TUG1 in ADR resistance. miR-34a knockdown counteracted the inductive effect of TUG1 inhibition on ADR sensitivity of HL60/ADR cells. Furthermore, TUG1 knockdown facilitated ADR sensitivity of ADR-resistant AML cells in vivo. In summary, TUG1 knockdown overcame ADR resistance of AML by epigenetically enhancing miR-34a expression, providing a novel therapeutic target for AML.

Zhang H, Deng T, Ge S, et al.
Exosome circRNA secreted from adipocytes promotes the growth of hepatocellular carcinoma by targeting deubiquitination-related USP7.
Oncogene. 2019; 38(15):2844-2859 [PubMed] Free Access to Full Article Related Publications
Hepatocellular carcinoma (HCC), the major form of liver cancer, has shown increasing incidence and poor prognosis. Adipose tissue is known to function in energy storage and metabolism regulation by the secretion of adipokines. Circular RNAs (circRNAs), a novel type of noncoding RNA, have recently been recognized as key factors in tumor development, but the role of exosome circRNAs derived from adipose tissues has not been defined yet. Here, adipose-secreted circRNAs were found to regulate deubiquitination in HCC, thus facilitating cell growth. It was observed that exosome circ-deubiquitination (circ-DB) is upregulated in HCC patients with higher body fat ratios. Moreover, in vitro and in vivo studies showed that exo-circ-DB promotes HCC growth and reduces DNA damage via the suppression of miR-34a and the activation of deubiquitination-related USP7. Finally, the results showed that the effects of adipose exosomes on HCC cells can be reversed by knockdown of circ-DB. These results indicate that exosome circRNAs secreted from adipocytes promote tumor growth and reduce DNA damage by suppressing miR-34a and activating the USP7/Cyclin A2 signaling pathway.

Metheetrairut C, Chotigavanich C, Amornpichetkul K, et al.
Expression levels of miR-34-family microRNAs are associated with TP53 mutation status in head and neck squamous cell carcinoma.
Eur Arch Otorhinolaryngol. 2019; 276(2):521-533 [PubMed] Related Publications
PURPOSE: The majority of head and neck squamous cell carcinoma (HNSCC) cases in developing countries are associated with cigarette smoking and TP53 mutations. p53 is a transcription factor that activates downstream genes, including the hsa-miR-34a and hsa-miR-34b/c loci, to achieve cell-cycle arrest, senescence, and/or apoptosis. This study examined the differences in expression levels of miR-34 in HNSCC with or without TP53 mutations.
METHODS: We examined surgically resected tumor samples and normal adjacent tissues from HNSCC in oral cavity, larynx, and hypopharynx for TP53 mutations (exons 5-8) and miR-34 expression levels.
RESULTS: miR-34a, miR-34b, miR-34b*, and miR-34c are significantly up-regulated in tumors with wild-type TP53 genes (n = 23); while such up-regulation is not observed in tumors with mutant TP53 (n = 19). Although expression levels of miR-34-family miRNAs do not correlate with gender, age, or tumor staging, interestingly they are correlated with smoking status and tumor sites. miR-34b/b*/c are up-regulated in tumors from those who ever smoked or recently smoked (quit smoking less than 15 years ago); but such up-regulation was not seen in those who never smoked or quit smoking for at least 15 years. HNSCC of the oral cavity also up-regulated miR-34b/b*/c while no such overexpression was observed in HNSCC of the larynx and hypopharynx.
CONCLUSIONS: Surgically resected HNSCC samples with no TP53 mutations have elevated levels of miR-34a and miR-34b/b*/c, while those with TP53 mutations show no such up-regulation. miR-34b/b*/c expression is also correlated with smoking status and tumor sites.

Orangi E, Motovali-Bashi M
Evaluation of miRNA-9 and miRNA-34a as potential biomarkers for diagnosis of breast cancer in Iranian women.
Gene. 2019; 687:272-279 [PubMed] Related Publications
PURPOSE: MicroRNAs are involved in diverse biological processes and their dysregulation is a common event in various diseases including breast cancer. Breast cancer is a major threat to women's health. This study was designed to examine the expression levels of miR-9 and miR-34a in breast tumor tissue samples and plasma of breast cancer patients, compare their expression pattern between tissue samples and plasma samples of patients and analyze their relationship with tumor clinical features. Also, the potential of these miRNAs as diagnostic biomarkers for breast cancer was investigated.
MATERIALS AND METHODS: The expression levels of miR-9, miR-34a and CDH1 were measured by real-time reverse transcription polymerase chain reaction and ΔΔct method. Data were analyzed using t-test and one-way ANOVA. The sensitivity and specificity of miRNAs were determined by receiver operating characteristic (ROC) curve.
RESULTS AND DISCUSSION: The expression levels of miR-9 and miR-34a were significantly down-regulated in tumor tissues compared to healthy tissues (fold change = 0.26, p = 0.0051 for miR-9 and fold change = 0.55, p = 0.021 for miR-34a). While no significant difference was observed in the expression levels of miR-9 (p = 0.205) and miR-34a (p = 0.132) in plasma samples of patients compared to normal plasma. CDH1 expression in tumor tissue was not significantly different from normal tissue (p = 0.33). We found that expression level of miR-9 in patients with tumor size larger than 5 cm (p = 0.026) and expression level of miR-34a in patients with higher stage (lll & lV, p = 0.03) were significantly down-regulated. Also miR-34a expression level was positively correlated with patient's age (p = 0.03).
CONCLUSION: According to the ROC curves, the area under the curve (AUC) of miR-9 in tissue was 0.71 (p = 0.009) with sensitivity 83.33% and specificity 70.37%. The AUC for miR-34a in tissue was 0.72 (p = 0.007) with sensitivity 72% and specificity 76%. Thus miR-9 and miR-34a have the capability for distinguishing tumor tissues from healthy tissues and the study of their expression levels in tissue may be used as a biomarker for the diagnosis of breast cancer patients from healthy women.

Krajewska JB, Fichna J, Mosińska P
One step ahead: miRNA-34 in colon cancer-future diagnostic and therapeutic tool?
Crit Rev Oncol Hematol. 2018; 132:1-8 [PubMed] Related Publications
The discovery that microRNAs (miRNAs) - short, non-coding RNA molecules which regulate gene expression - are implicated in many types of cancer has revolutionised cancer research, giving hope for a new perspective in diagnostics and treatment. Dysregulation of miRNAs occurs in various malignancies, including colorectal cancer (CRC). CRC is one of the leading causes of cancer-related death and in most countries its incidence is still rising. Among several miRNAs which have been linked to CRC, miR-34 has attracted particular attention. This miRNA is involved in the regulation of cell cycle and apoptosis through multiple signaling pathways such as p53, Ra and Wnt signaling. Understanding its role in CRC may facilitate its future use as a diagnostic tool and therapeutic target.

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