Locus Summary

Gene:MIR21; microRNA 21
Aliases: MIRN21, miR-21, miRNA21, hsa-mir-21
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: 30 August, 2019

Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 30 August 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 30 August, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (8)

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)MIR21 Function in CancerEffect
brain (18)
-glioblastoma (9)
-glioma (6)
-malignant glioma (1)
-medulloblastoma (1)
-glioblastoma multiforme (1)
TP63 (2)
CASP3 (1)
SOX5 (1)
TIMP3 (1)
SPRY2 (1)
MTAP (1)
RECK (1)
PDCD4 (1)
inhibit apoptosis (8)
reduce apoptosis (3)
promote cell invasion (3)
promote cell proliferation (2)
promote cell migration (2)
promote cell growth (2)
reduce taxol sensitivity (1)
promote cell cycle progression (1)
reduce tumor growth (1)
induce VM-26 resistance (1)
increase cell invasion (1)
increase cell growth (1)
increase radio-resistance (1)
reduce IR-induced cell growth arrest (1)
increase colony formation (1)
increase cell proliferation (1)
promote cell migration across basement membranes (1)
promote cell motility (1)
increase temozolomide resistance (1)
increase TRAIL resistance (1)
inhibit autophagy (1)
promote cell cycle (1)
oncogenic (14)
tumor-suppressive (1)
breast (16)
-breast cancer (14)
-third-sphere forming breast cancer stem cell-like cells (1)
-ER+ breast cancer (1)
PTEN (4)
PDCD4 (4)
BCL2 (2)
PLAT (1)
TIMP3 (1)
TPM1 (1)
ANKRD46 (1)
ICAM1 (1)
JAG1 (1)
IL1B (1)
NF-kB (1)
PLAT (1)
ZEB1 (1)
BMP6 (1)
RARA (1)
IL6 (1)
STAT3 (1)
promote cell invasion (3)
increase cell growth (3)
promote cell growth (2)
promote cell migration (2)
promote epithelial-mesenchymal transition (2)
inhibit ATRA-dependent cell motility (1)
promote metastasis (1)
increase cell proliferation (1)
inhibit senescence (1)
promote tumor growth (1)
inhibit apoptosis (1)
induce trastuzumab resistance (1)
promote cell proliferation (1)
reduce doxorubicin sensitivity (1)
reduce apoptosis (1)
promote cancer stem-like cell phenotype (1)
increase metastasis (1)
promote DNA damage-induced apoptosis (1)
increase the metastatic potential (1)
increase cell migration (1)
increase cell invasion (1)
increase self-renewal (1)
increase clonogenicity (1)
increase tumor growth (1)
oncogenic (14)
colorectum (12)
-colorectal cancer (7)
-colon cancer (4)
-colon carcinoma (1)
PTEN (2)
RHOB (1)
TIAM1 (1)
TGFBR2 (1)
MSH6 (1)
PDCD4 (1)
CCL20 (1)
MSH2 (1)
CDC25A (1)
PTP4A3 (1)
TNFA (1)
TGFB1 (1)
NF- (1)
NTS (1)
NTSR1 (1)
ETV4 (1)
ETS transcription fa (1)
RAS (1)
EGF (1)
increase cell invasion (3)
increase cell proliferation (2)
promote cell invasion (2)
induce apoptosis (1)
inhibit cell cycle G1/S transtion (1)
promote cell motility (1)
enhance cell morphological changes (1)
reduce 5-FU sensitivity (1)
reduce apoptosis (1)
reduce 5-FU-induced cell cycle G2/M damage arrest (1)
promote tumor growth (1)
promote colony formation (1)
inhibit apoptosis (1)
incrase cell migration (1)
promote cell proliferation (1)
increase tumor formation (1)
increase sphere forming ability (1)
increase cell viability (1)
promote cell migration (1)
inhibit cell cycle progression (1)
participate DNA damage-induced cell cycle G2/M checkpoint (1)
oncogenic (10)
liver (8)
-hepatocellular carcinoma (4)
-cholangiocarcinoma (3)
-liver cancer (1)
PTEN (4)
PDCD4 (3)
TIMP3 (1)
RECK (1)
ZBTB7A (1)
promote cell proliferation (3)
inhibit apoptosis (2)
promote cell growth (1)
increase IFN- (1)
promote cell invasion (1)
increase cell proliferation (1)
increase cell migration (1)
increase cell invasion (1)
decrease apoptosis (1)
oncogenic (7)
head and neck (8)
-oral squamous cell carcinoma (3)
-head and neck squamous cell carcinoma (2)
-laryngeal squamous cell carcinoma (1)
-laryngeal carcinoma (1)
-tongue squamous cell carcinoma (1)
RECK (1)
BTG2 (1)
PDCD4 (1)
CDK2AP1 (1)
CD44 (1)
STAT3 (1)
promote cell proliferation (3)
inhibit apoptosis (2)
promote cell invasion (2)
promote cell growth (1)
increase cell survival (1)
promote cell cycle G1/S transition (1)
promote tumor growth (1)
reduce apoptosis (1)
reduce cell cycle G1 arrest (1)
induce HA chemoresistance (1)
reduce cisplatin sensitivity (1)
increase cell growth (1)
oncogenic (6)
prostate (7)
-prostate cancer (7)
BTG2 (1)
BMPR2 (1)
PDCD4 (1)
IFNA (1)
AR (1)
NF- (1)
STAT3 (1)
IFNB (1)
promote epithelial-mesenchymal transition (1)
promote cell motility (1)
inhibit apoptosis (1)
overcome castration-induced growth arrest (1)
promote tumor growth (1)
promote cell proliferation (1)
increase docetaxel resistance (1)
suppress IFN-induced apoptosis (1)
activate AKT/ERK signaling (1)
induce tumor angiogeneis (1)
promote cell invasion (1)
oncogenic (5)
blood (6)
-multiple myeloma (3)
-leukemia (2)
-acute promyelocytic leukemia (1)
PDCD4 (3)
PIAS3 (1)
STAT3 (1)
IL6 (1)
reduce apoptosis (3)
reduce cell cycle G1 arrest (2)
promote cell growth (2)
inhibit apoptosis (2)
increase cell proliferation (1)
increase cell viability (1)
reduce arabinosylcytosine sensitivity (1)
increase cell cycle progression (1)
increase cell growth (1)
increase STAT3 signaling (1)
induce ATO resistance (1)
oncogenic (5)
lung (5)
-non-small cell lung cancer (4)
-lung cancer (1)
PTEN (2)
PDCD4 (1)
MSH2 (1)
promote cell growth (1)
increase cell growth (1)
activate Ras/MEK/ERK signaling (1)
inhibit apoptosis (1)
enhance tumorigenesis (1)
reduce apoptosis (1)
increase cell proliferation (1)
increase cells in S phase (1)
promote cell proliferation (1)
enhance chemo- or radioresistance (1)
promote cell invasion (1)
increase cell invasion (1)
oncogenic (5)
stomach (4)
-gastric cancer (4)
PTEN (1)
RECK (1)
NF- (1)
increase cell proliferation (1)
decrease apoptosis (1)
promote nicotine-induced cell proliferation (1)
promote cell proliferation (1)
promote cell invasion (1)
inhibit apoptosis (1)
promote cell migration (1)
oncogenic (3)
kidney (4)
-renal cell carcinoma (3)
-renal cancer (1)
TCF21 (1)
TIMP3 (1)
PDCD4 (1)
increase cell migration (2)
increase cell invasion (2)
inhibit apoptosis (2)
increase cell proliferation (1)
promote cell cycle (1)
promote cell proliferation (1)
promote cell survival (1)
oncogenic (3)
esophagus (3)
-esophageal squamous cell carcinoma (3)
PDCD4 (1)
promote cell proliferation (2)
increase cell proliferation (1)
increase cell invasion (1)
oncogenic (3)
pancreas (3)
-pancreatic ductal adenocarcinoma (1)
-pancreatic adenocarcinoma (1)
-pancreatic cancer (1)
promote cell proliferation (2)
inhibit cell death (1)
inhibit apoptosis (1)
reduce cell cycle G1 arrest (1)
reduce gemcitabine sensitivity (1)
increase cell proliferation (1)
increase cell invasion (1)
increase gemcitabine chemoresistance (1)
oncogenic (3)
cervix (2)
-cervical squamous carcinoma (1)
-cervical carcinoma (1)
CCL20 (1)
PDCD4 (1)
increase cell proliferation (1)
inhibit apoptosis (1)
increase cell migration (1)
promote cell proliferation (1)
oncogenic (2)
thyroid (1)
-papillary thyroid carcinoma (1)
THRB (1)
skin (1)
-melanoma (1)
PTEN (1)
BTG2 (1)
PDCD4 (1)
promote cell proliferation (1)
promote cell migration (1)
oncogenic (1)
uterus (1)
-endometrioid endometrial cancer (1)
PTEN (1)
promote cell proliferation (1)
oncogenic (1)
nerve (1)
-vestibular schwannoma (1)
increase cell proliferation (1)
inhibit apoptosis (1)
oncogenic (1)
bladder (1)
-bladder cancer (1)
promote cell proliferation (1)
promote doxorubicin chemoreistance (1)
inhibit apoptosis (1)
oncogenic (1)
bone and muscle (1)
-osteosarcoma (1)
RECK (1)
promote cell invasion (1)
promote cell migration (1)
oncogenic (1)

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

Latest Publications: MIR21 (cancer-related)

Chen S, Yang C, Sun C, et al.
miR-21-5p Suppressed the Sensitivity of Hepatocellular Carcinoma Cells to Cisplatin by Targeting FASLG.
DNA Cell Biol. 2019; 38(8):865-873 [PubMed] Related Publications
Accumulating evidence has suggested that microRNAs play important roles in the development of hepatocellular carcinoma (HCC) and are involved in drug resistance. miR-21-5p was overexpressed in a variety of cancers and promoted the tumorigenesis; however, the function of miR-21-5p in HCC still remains unknown. In this study, our results showed that miR-21-5p was highly expressed in HCC tissues and cell lines. Notably, the level of miR-21-5p was relatively higher in cisplatin (DDP)-resistant HCC patients. Overexpression of miR-21-5p attenuated the inhibitory effect of DDP on the proliferation and apoptosis of HCC cells. Mechanistically, the luciferase report assay-identified FAS ligand (FASLG) was a direct target of miR-21-5p. Overexpression of miR-21-5p decreased both the mRNA and protein levels of FASLG in HCC cells. FASLG was downregulated in HCC tissues and was significantly negatively correlated with the expression of miR-21-5p. Restoring the expression of FASLG upregulated the chemosensitivity of HCC cells expressing miR-21-5p. In conclusion, our results demonstrated that miR-21-5p targeted FASLG and suppressed the sensitivity of HCC cells to DDP treatment.

Jerez S, Araya H, Hevia D, et al.
Extracellular vesicles from osteosarcoma cell lines contain miRNAs associated with cell adhesion and apoptosis.
Gene. 2019; 710:246-257 [PubMed] Article available free on PMC after 20/08/2020 Related Publications
Osteosarcoma is the most common primary bone tumor during childhood and adolescence. Several reports have presented data on serum biomarkers for osteosarcoma, but few reports have analyzed circulating microRNAs (miRNAs). In this study, we used next generation miRNA sequencing to examine miRNAs isolated from microvesicle-depleted extracellular vesicles (EVs) derived from six different human osteosarcoma or osteoblastic cell lines with different degrees of metastatic potential (i.e., SAOS2, MG63, HOS, 143B, U2OS and hFOB1.19). EVs from each cell line contain on average ~300 miRNAs, and ~70 of these miRNAs are present at very high levels (i.e., >1000 reads per million). The most prominent miRNAs are miR-21-5p, miR-143-3p, miR-148a-3p and 181a-5p, which are enriched between 3 and 100 fold and relatively abundant in EVs derived from metastatic SAOS2 cells compared to non-metastatic MG63 cells. Gene ontology analysis of predicted targets reveals that miRNAs present in EVs may regulate the metastatic potential of osteosarcoma cell lines by potentially inhibiting a network of genes (e.g., MAPK1, NRAS, FRS2, PRCKE, BCL2 and QKI) involved in apoptosis and/or cell adhesion. Our data indicate that osteosarcoma cell lines may selectively package miRNAs as molecular cargo of EVs that could function as paracrine agents to modulate the tumor micro-environment.

Tao L, Wu YQ, Zhang SP
MiR-21-5p enhances the progression and paclitaxel resistance in drug-resistant breast cancer cell lines by targeting PDCD4.
Neoplasma. 2019; 2019 [PubMed] Related Publications
MiR-21-5p has been identified as an oncogene to enhance human tumor progression. Here, we explored the mechanism by which miR-21-5p regulated the progression and paclitaxel (PTX) resistance in drug-resistant breast cancer (BC) cell lines. qRT-PCR assays were used to assess the expression levels of miR-21-5p and PDCD4 mRNA, and western blotting was used to detect PDCD4 protein level in PTX-resistant BC cell lines. Dual-luciferase reporter assay was used to observe the interaction between miR-21-5p and PDCD4 in PTX-resistant BC cell lines. Cell proliferation ability and IC50 values of PTX were measured by CCK-8 assay, cell cycle progression and apoptosis were determined with flow cytometry analysis, and cell migration and invasion capacities were analyzed using Transwell assay. Xenograft mice assay was used to validate the important role of miR-21-5p as a regulator on PTX-resistance BC cells growth in vivo. Then, we found that miR-21-5p was upregulated and PDCD4 was downregulated in BC tissues and PTX-resistant BC cell lines. MiR-21-5p silencing or PDCD4 overexpression ameliorated PTX resistance and inhibited the progression in PTX-resistant BC cell lines. Moreover, PDCD4 was demonstrated to be a direct target of miR-21-5p. MiR-21-5p exerted its regulatory effect by PDCD4 in PTX-resistant BC cell lines. Additionally, miR-21-5p silencing inhibited tumor growth in vivo. Therefore, our study demonstrated that miR-21-5p silencing ameliorated PTX resistance and inhibited the progression in PTX-resistant BC cell lines at least partly by targeting PDCD4, providing miR-21-5p as an effective therapeutic target for PTX-resistant BC treatment.

Zhu D, Zhou J, Liu Y, et al.
LncRNA TP73-AS1 is upregulated in non-small cell lung cancer and predicts poor survival.
Gene. 2019; 710:98-102 [PubMed] Related Publications
The present study was carried out to investigate the role of lncRNA TP73-AS1 in non-small cell lung cancer (NSCLC). We found that TP73-AS1 was upregulated in tumor tissues than in non-tumor tissues of NSCLC patients, and high expression levels of TP73-AS1 predicted poor survival. MiR-21 was also upregulated in tumor tissues and positively correlated with TP73-AS1. TP73-AS1 overexpression led to miR-21 upregulation, while miR-21 overexpression failed to affect TP73-AS1. TP73-AS1 and miR-21 overexpression caused the accelerated invasion and migration of NSCLC cells. However, TP73-AS1 overexpression failed to affect cell proliferation. Therefore, TP73-AS1 may upregulate miR-21 to promote NSCLC cell migration and invasion.

Dundar HZ, Aksoy F, Aksoy SA, et al.
Overexpression of miR-21 Is Associated With Recurrence in Patients With Hepatitis B Virus-Mediated Hepatocellular Carcinoma Undergoing Liver Transplantation.
Transplant Proc. 2019; 51(4):1157-1161 [PubMed] Related Publications
Liver transplantation (LT) is the best treatment option for hepatitis B virus (HBV)-mediated hepatocellular carcinoma (HCC). Nevertheless, recurrence is the most important issue after LT. The aims of the present study were to evaluate the relation of dysregulated expression of microRNAs (miRNAs) in recurrence formation in HBV-mediated HCC cases. A total of 42 HBV-mediated HCC patients were evaluated in this study. Among 21 miRNAs, the expression level of miR-106a and miR-21 were higher and miR-143 and miR145 were lower in patients with HCC compared with noncancerous liver tissues (P = .0388, P = .0214, P = .0321, and P = .002, respectively). Compared with nonrecurrent patients, the expression level of miR-21 was 3.54-fold higher and miR-145 was 2.42-fold lower in patients with recurrence during the 5-year follow-up (P = .004 and P = .032; respectively). In addition, according to multivariate Cox regression analysis, the overexpression of miR-21 was found to be a prognostic indicator in HBV-mediated HCC patients (P = .002). In conclusion, we show a significant association between high expression of miR-21 and recurrence in HBV-mediated HCC. Therefore, up-regulation of miR-21 could serve as a promising prognostic marker for HCC.

Liu L, Kuang Y, Yang H, Chen Y
An amplification strategy using DNA-Peptide dendrimer probe and mass spectrometry for sensitive MicroRNA detection in breast cancer.
Anal Chim Acta. 2019; 1069:73-81 [PubMed] Related Publications
MicroRNAs (miRNAs) are emerging as novel biomarkers for diagnosis and treatment of various cancers, including breast cancer. Because the value of biomarkers primarily depends on whether they are quantifiable, great effort has been taken to develop assays for sensitive and accurate quantification of miRNAs. However, most of current assays have high nonspecific amplification effect, which limits quantification accuracy. In this study, we circumvented copying of nucleic acid sequence and developed a signal amplification strategy based on a novel DNA-peptide dendrimer (DPD) probe coupled with mass spectrometry. The DPD probe RP8-MAP4-DNA contained three functional domains, including substrate peptides containing eight reporter peptides and tryptic cleavage sites, peptide dendrimer scaffold and DNA complementary to target miRNA. The probe was first hybridized with the target miRNA (i.e., miR-21) that was biotinylated and attached to streptavidin agarose in advance. After trypsin digestion, the reporter peptide was liberated and quantified using LC-MS/MS. The signal intensity was approximately 8 fold greater than that without signal amplification. Finally, the developed assay was applied for the quantitative analysis of miR-21 in 3 human breast cell lines and 102 matched pairs of breast tissue samples. The miR-21 expression in tissue was also evaluated depend on histopathological features, molecular subtypes and prognosis of breast cancer. The result demonstrated that combination of DPD probe and mass spectrometry is a promising strategy for quantification of miRNAs and illustration of their biomarker potential, especially those at low abundance.

Zhou J, Guo H, Yang Y, et al.
A meta-analysis on the prognosis of exosomal miRNAs in all solid tumor patients.
Medicine (Baltimore). 2019; 98(16):e15335 [PubMed] Article available free on PMC after 20/08/2020 Related Publications
BACKGROUND: It has been reported that the encapsulated miRNAs from exosomes are potential biomarkers of tumors prognosis. Yet, the results are controversial, so it is obliged to do a meta-analysis to reach a definite conclusion.
MATERIALS AND METHODS: Studies were searched for published in PubMed, Embase, and Web of Science databases until April 20, 2018. A meta-analysis was conducted to appraise the role of exosomal miRNAs in prognosis of cancer patients.
RESULTS: The different exosomal miRNAs expression was remarkably related to overall survival (OS) (hazard ratio [HR] = 2.02, 95% confidence interval [CI]: 1.84-2.21) and disease-free survival (DFS) (HR = 2.43, 95% CI: 1.86-3.17) of cancer patients. High exosomal miR-21 expression was associated with poor OS (HR = 2.59; 95% CI: 1.71-3.90) and DFS (HR = 1.84; 95% CI: 1.37-2.47). High exosomal miR-451a expression was associated with poor OS (HR = 4.81; 95% CI: 2.33-9.93) and DFS (HR = 2.64; 95% CI: 1.62-4.31). High exosomal miR-1290 expression was associated with poor OS (HR = 1.73; 95% CI: 1.29-2.33). Low exosomal miR-638 expression was associated with poor OS (HR = 2.25; 95% CI: 1.46-3.46).
CONCLUSION: The expression levels of exosomal miRNAs, particularly miR-21, miR-451a, miR-1290, and miR-638 could strongly predict prognosis of solid tumor patients and might be a potential target for tumor treatment.

Møller T, James JP, Holmstrøm K, et al.
Co-Detection of miR-21 and TNF-α mRNA in Budding Cancer Cells in Colorectal Cancer.
Int J Mol Sci. 2019; 20(8) [PubMed] Article available free on PMC after 20/08/2020 Related Publications
MicroRNA-21 (miR-21) is upregulated in many cancers including colon cancers and is a prognostic indicator of recurrence and poor prognosis. In colon cancers, miR-21 is highly expressed in stromal fibroblastic cells and more weakly in a subset of cancer cells, particularly budding cancer cells. Exploration of the expression of inflammatory markers in colon cancers revealed tumor necrosis factor alpha (TNF-α) mRNA expression at the invasive front of colon cancers. Surprisingly, a majority of the TNF-α mRNA expressing cells were found to be cancer cells and not inflammatory cells. Because miR-21 is positively involved in cell survival and TNF-α promotes necrosis, we found it interesting to analyze the presence of miR-21 in areas of TNF-α mRNA expression at the invasive front of colon cancers. For this purpose, we developed an automated procedure for the co-staining of miR-21, TNF-α mRNA and the cancer cell marker cytokeratin based on analysis of frozen colon cancer tissue samples (

Kuo HY, Chang WL, Yeh YC, et al.
Spasmolytic polypeptide-expressing metaplasia associated with higher expressions of miR-21, 155, and 223 can be regressed by Helicobacter pylori eradication in the gastric cancer familial relatives.
Helicobacter. 2019; 24(3):e12578 [PubMed] Related Publications
BACKGROUND AND AIMS: Spasmolytic polypeptide-expressing metaplasia (SPEM) is a preneoplastic gastric cancer lesion related to epigenetic microRNA (miRNA) expression. This study elucidated whether Helicobacter pylori-infected first-degree relatives of patients with gastric cancer (GCF) are susceptible to have SPEM and correlated with miR-21, 155, and 223 expressions. We also validated whether SPEM and these miRNAs can be regressed after H pylori eradication.
METHODS: We prospectively enrolled 148 GCF and 148 nonulcer dyspepsia (NUD) subjects without gastric cancer familial history as controls. Each case had received a panendoscopy to determine H pylori status and gastric histology, including SPEM. The cases with SPEM were followed after H pylori eradication to determine SPEM regression. The total RNA was extracted to analyze tissues miR-21, 155, and 223 before and after eradication.
RESULTS: GCF subjects had a higher prevalence of H pylori infection (73% vs 32%) and SPEM (42% vs 14%, P < 0.01) than controls. The tissue miR-21, 155, and 223 in antrum were higher in cases with SPEM than in those without SPEM (P <= 0.05). There was similar SPEM reversibility after H pylori eradication between GCF subjects and controls (72% vs 69%, P = 0.852). In the SPEM regressed cases, tissue miR-21, 155, and 223 decreased after H pylori eradication (P < 0.05).
CONCLUSION: The H pylori-infected GCF subjects were prone to have SPEM with higher tissues miR-21, 155, and 223 expressions. H pylori eradication can result in a 70% SPEM regression, accompanied by a decline in miR-21, 155, and 233 expression levels.

Yao SS, Han L, Tian ZB, et al.
Celastrol inhibits growth and metastasis of human gastric cancer cell MKN45 by down-regulating microRNA-21.
Phytother Res. 2019; 33(6):1706-1716 [PubMed] Related Publications
Celastrol could inhibit cancer cell growth in vitro. However, effect(s) of celastrol on gastric cancer is not well studied. Therefore, we investigated the effects of celastrol on human gastric cancer cell line MKN45 and the underlying mechanisms. We found that celastrol inhibited cell proliferation, migration, and invasion and induced cell apoptosis and G2/M cell cycle arrest (p < .05, p < .01, or p < .001). Under celastrol treatment, overexpression of microRNA-21 (miR-21) increased cell viability, migration, and invasion and inhibited cell apoptosis compared with negative control (p < .05, p < .01, or p < .001). In addition, the phosphorylation of PTEN was significantly up-regulated, whereas PI3K, AKT, p65, and IκBα phosphorylation was statistically decreased by celastrol (p < .05 or p < .01) and then further reversed by miR-21 overexpression (p < .05 or p < .01). On the other side, miR-21 silence showed contrary results (p < .05) as relative to miR-21 overexpression. In conclusion, celastrol inhibits proliferation, migration, and invasion and inactivates PTEN/PI3K/AKT and nuclear factor κB signaling pathways in MKN45 cells by down-regulating miR-21.

Liu Y, Xue M, Du S, et al.
Competitive endogenous RNA is an intrinsic component of EMT regulatory circuits and modulates EMT.
Nat Commun. 2019; 10(1):1637 [PubMed] Article available free on PMC after 20/08/2020 Related Publications
The competitive endogenous RNA (ceRNA) hypothesis suggests an intrinsic mechanism to regulate biological processes. However, whether the dynamic changes of ceRNAs can modulate miRNA activities remains controversial. Here, we examine the dynamics of ceRNAs during TGF-β-induced epithelial-to-mesenchymal transition (EMT). We observe that TGFBI, a transcript highly induced during EMT in A549 cells, acts as the ceRNA for miR-21 to modulate EMT. We further identify FN1 as the ceRNA for miR-200c in the canonical SNAIL-ZEB-miR200 circuit in MCF10A cells. Experimental assays and computational simulations demonstrate that the dynamically induced ceRNAs are directly coupled with the canonical double negative feedback loops and are critical to the induction of EMT. These results help to establish the relevance of ceRNA in cancer EMT and suggest that ceRNA is an intrinsic component of the EMT regulatory circuit and may represent a potential target to disrupt EMT during tumorigenesis.

Szpechcinski A, Florczuk M, Duk K, et al.
The expression of circulating miR-504 in plasma is associated with EGFR mutation status in non-small-cell lung carcinoma patients.
Cell Mol Life Sci. 2019; 76(18):3641-3656 [PubMed] Related Publications
MicroRNAs (miRNAs), key regulators of gene expression at the post-transcriptional level, are grossly misregulated in some human cancers, including non-small-cell lung carcinoma (NSCLC). The aberrant expression of specific miRNAs results in the abnormal regulation of key components of signalling pathways in tumour cells. MiRNA levels and the activity of the gene targets, including oncogenes and tumour suppressors, produce feedback that changes miRNA expression levels and indicates the cell's genetic activity. In this study, we measured the expression of five circulating miRNAs (miR-195, miR-504, miR-122, miR-10b and miR-21) and evaluated their association with EPIDERMAL GROWTH FACTOR RECEPTOR (EGFR) mutation status in 66 NSCLC patients. Moreover, we examined the discriminative power of circulating miRNAs for EGFR mutant-positive and -negative NSCLC patients using two different data normalisation approaches. We extracted total RNA from the plasma of 66 non-squamous NSCLC patients (31 of whom had tumours with EGFR mutations) and measured circulating miRNA levels using quantitative reverse transcription polymerase chain reaction (RT-qPCR). The miRNA expression levels were normalised using two endogenous controls: miR-191 and miR-16. We found significant associations between the expression of circulating miR-504 and EGFR-activating mutations in NSCLC patients regardless of the normalisation approach used (p = 0.0072 and 0.0236 for miR-16 and miR-191 normalisation, respectively). The greatest discriminative power of circulating miR-504 was observed in patients with EGFR exon 19 deletions versus wild-type EGFR normalised to miR-191 (area under the curve (AUC) = 0.81, p < 0.0001). Interestingly, circulating miR-504 levels were significantly reduced in the v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS)-mutated subgroup compared to EGFR-mutated patients (p < 0.0030) and those with EGFR/KRAS wild-type tumours (p < 0.0359). Our study demonstrated the feasibility and potential diagnostic value of plasma miR-504 expression analysis to distinguish between EGFR-mutated and wild-type NSCLC patients. However, quality control and normalisation strategies are very important and have a major impact on the outcomes of circulating miRNA analyses.

Świtlik WZ, Karbownik MS, Suwalski M, et al.
Serum miR-210-3p as a Potential Noninvasive Biomarker of Lung Adenocarcinoma: A Preliminary Study.
Genet Test Mol Biomarkers. 2019; 23(5):353-358 [PubMed] Related Publications

Emami SS, Nekouian R, Akbari A, et al.
Evaluation of circulating miR-21 and miR-222 as diagnostic biomarkers for gastric cancer.
J Cancer Res Ther. 2019 Jan-Mar; 15(1):115-119 [PubMed] Related Publications
Introduction: Gastric cancer is responsible for a large number of death worldwide and its high death rate is associated with a lack of noninvasive tools in GC diagnosis. MicroRNAs (miRNAs), as gene regulators, were shown to dysregulate in different types of cancer. Moreover, it is proven that miRNAs are stable in serum/plasma, so they can be used as a potential noninvasive marker in GC diagnosis. The objective of this study is to investigate the plasma miRNA expression in GC samples compared to controls as a potential biomarker in cancer diagnosis.
Materials and Methods: Expression levels of miR-21 and miR-222 were assessed using quantitative real-time polymerase chain reaction in plasma of 30 GC patients and 30 healthy controls. Diagnostic value of selected miRNAs was evaluated using receiver operating characteristic curve. Target prediction was done using bioinformatics tools to investigate the signaling pathways and function of the selected miRNAs.
Results: Our results demonstrated that the expression levels of miR-21 and miR-222 were significantly higher in GC plasma than in the controls (P < 0.0001, P = 0.043). The sensitivity and specificity for miR-21 and in plasma were 86.7% and 72.2% and for miR-222 were 62.5% and 56.2%, respectively. Bioinformatics analysis revealed that most target genes of miR-21 and miR-222 are involved in cancer-related signaling pathway such as tumor initiation and progression.
Conclusion: Our results indicated that miR-21 and miR-222 in plasma samples can be served as a potential noninvasive tool in GC detection. Furthermore, the miRNA target prediction manifested that miR-21 and miR-222 involve in key processes associated with GC initiation and development.

Liu H, Wang J, Tao Y, et al.
Curcumol inhibits colorectal cancer proliferation by targeting miR-21 and modulated PTEN/PI3K/Akt pathways.
Life Sci. 2019; 221:354-361 [PubMed] Related Publications
AIMS: The purpose of this study was to demonstrate how curcumol affected the expression of miR-21 and whether its effects on miR-21 was associated with the activation of PTEN/PI3K/Akt pathways in CRC cells.
MAIN METHODS: MTT and xenograft assay were used to examine how curcumol inhibits colorectal cancer (CRC) cells' growth. Q-PCR and western blot analysis were employed to test the role of miR-21 in the inhibition of curcumol on proliferation and PTEN/PI3K/Akt pathways of CRC cells.
KEY FINDINGS: We found that curcumol effectively inhibited CRC cells from proliferating via the PTEN/PI3K/Akt pathways and reduced expression of miR-21 both in vitro and in vivo. miR-21 mimics were found to decrease the protein level of PTEN and increase the expression of PI3K, phospho-Akt (p-Akt) and NF-κB, while miR-21 sponge (miR-21-SP) enhanced the expression of PTEN and reduced the activity of PI3K, Akt and NF-κB. Furthermore, miR-21-SP strengthened the role of curcumol in up-regulating PTEN and inhibiting PI3K/Akt pathways, but miR-21 reversed the effect of curcumol on the PTEN/PI3K/Akt pathways.
SIGNIFICANCE: Our research demonstrated that curcumol reduced the proliferation of CRC cells through PTEN/PI3K/Akt by targeting miR-21 and miR-21 could be a target molecule of curcumol for CRC treatment.

Qu A, Sun M, Xu L, et al.
Quantitative zeptomolar imaging of miRNA cancer markers with nanoparticle assemblies.
Proc Natl Acad Sci U S A. 2019; 116(9):3391-3400 [PubMed] Article available free on PMC after 20/08/2020 Related Publications
Multiplexed detection of small noncoding RNAs responsible for posttranscriptional regulation of gene expression, known as miRNAs, is essential for understanding and controlling cell development. However, the lifetimes of miRNAs are short and their concentrations are low, which inhibits the development of miRNA-based methods, diagnostics, and treatment of many diseases. Here we show that DNA-bridged assemblies of gold nanorods with upconverting nanoparticles can simultaneously quantify two miRNA cancer markers, namely miR-21 and miR-200b. Energy upconversion in nanoparticles affords efficient excitation of fluorescent dyes via energy transfer in the superstructures with core-satellite geometry where gold nanorods are surrounded by upconverting nanoparticles. Spectral separation of the excitation beam and dye emission wavelengths enables drastic reduction of signal-to-noise ratio and the limit of detection to 3.2 zmol/ng

Ren W, Hou J, Yang C, et al.
Extracellular vesicles secreted by hypoxia pre-challenged mesenchymal stem cells promote non-small cell lung cancer cell growth and mobility as well as macrophage M2 polarization via miR-21-5p delivery.
J Exp Clin Cancer Res. 2019; 38(1):62 [PubMed] Article available free on PMC after 20/08/2020 Related Publications
OBJECTIVE: To investigate the lung cancer-promoting mechanism of mesenchymal stem cell-secreted extracellular vesicles (MSC-EV).
METHODS: EV were isolated from culture media of human bone marrow-derived MSCs that were pre-challenged with or without hypoxia (referred to as H-EV and N-EV, respectively). After treatment with N-EV or H-EV, A549 and H23 cell proliferation, apoptosis, trans-well invasion and epithelial-to-mesenchymal transition (EMT) were examined. Polarization of human primary monocytes-derived macrophages with or without N-EV or H-EV induction were analyzed by flow cytometry and ELISA. PTEN, PDCD4 or RECK gene was overexpressed in A549 cells, while miR-21-5p was knocked down in MSCs, A549 or H23 lung cancer cells or primary monocytes by miR-21-5p inhibitor transfection. Protein level of PTEN, PDCD4, RECK, AKT or STAT3 as well as phosphorylation level of AKT or STAT3 protein were assayed by western blot. Tumorigenicity of A549 and H23 cells with or without MSC-EV co-injection was assayed on immunocompromised mice. The xenograft tumor were examined for cell proliferation, angiogenesis, apoptosis and intra-tumoral M1/M2 macrophage polarization.
RESULTS: Comparing to N-EV, H-EV treatment significantly increased A549 and H23 cell proliferation, survival, invasiveness and EMT as well as macrophage M2 polarization. MiR-21-5p knocked down significantly abrogated the cancer-promoting and macrophage M2 polarizing effects of H-EV treatment. H-EV treatment downregulated PTEN, PDCD4 and RECK gene expression largely through miR-21-5p. Overexpressing PTEN, PDCD4 and RECK in A549 cells significantly reduced the miR-21-5p-mediated anti-apoptotic and pro-metastatic effect of H-EV, while overexpressing PTEN in monocytes significantly reduced macrophage M2 polarization after induction with the presence of H-EV. H-EV co-injection significantly increased tumor growth, cancer cell proliferation, intra-tumoral angiogenesis and M2 polarization of macrophages in vivo partially through miR-21-5p.
CONCLUSIONS: Increased miR-21-5p delivery by MSC-EV after hypoxia pre-challenge can promote lung cancer development by reducing apoptosis and promoting macrophage M2 polarization.

Qiang Z, Meng L, Yi C, et al.
Curcumin regulates the miR-21/PTEN/Akt pathway and acts in synergy with PD98059 to induce apoptosis of human gastric cancer MGC-803 cells.
J Int Med Res. 2019; 47(3):1288-1297 [PubMed] Article available free on PMC after 20/08/2020 Related Publications
OBJECTIVE: PD98059 is a potent and selective inhibitor of mitogen-activated protein kinase. Substantial preclinical evidence has shown an anti-tumor effect of curcumin on various solid tumors. This study aimed to investigate whether curcumin synergistically acts with PD98059 in exerting anti-gastric cancer effects.
METHODS: The cell counting kit-8 assay was used to detect cell proliferation of the human gastric cancer MGC-803 cell line. Flow cytometry was performed to detect apoptosis. Western blotting was used to detect phosphatase and tensin homolog (PTEN) and phosphorylated Akt (p-Akt) expression levels. Quantitative reverse transcription-polymerase chain reaction was used to determine microRNA-21 (miR-21).
RESULTS: A dose of 5 to 40 µM curcumin inhibited proliferation of MGC-803 cells in a dose- and time-dependent manner. A high dose of curcumin strongly inhibited p-Akt protein expression. With increasing curcumin levels, PTEN expression increased and miR-21 levels decreased. These results suggest that curcumin negatively modulated the miR-21/PTEN/Akt pathway. Moreover, after pretreatment with PD98059, cell apoptosis induced by curcumin was significantly increased. Additionally, the inhibitory effects of curcumin on the miR-21/PTEN/Akt pathway were significantly enhanced.
CONCLUSION: PD98059 combined with curcumin may be a potential strategy for managing gastric cancer.

Kumagai-Togashi A, Uozaki H, Kikuchi Y, et al.
Tumorous CD10 Is More Strongly Related to the Progression of Urothelial Carcinoma than Stromal CD10.
Anticancer Res. 2019; 39(2):635-640 [PubMed] Related Publications
BACKGROUND/AIM: CD10 function in urothelial carcinoma (UC) remains controversial. We previously reported that miR-21 in UC may be a prognostic marker for cancer progression. The aim of this study was to examine the clinicopathological significance of CD10 expression in UC and its relationship with miR-21 expression.
MATERIALS AND METHODS: Immunohistochemistry for CD10 was performed on 232 UCs. CD10 expression in TCs and stroma was evaluated respectively, and its association with carcinogenesis and survival was analyzed.
RESULTS: High tumorous CD10 was significantly associated with higher tumor stage, histological grade and vessel infiltration, and poorer prognosis, whereas stromal CD10 was significantly associated with younger age, higher tumor stage, and vessel infiltration. On multivariable analysis, CD10 expression in TCs, miR-21 expression in TCs and TS, and tumor stage were independent prognostic factors.
CONCLUSION: Tumorous CD10 is more strongly related to progression of UC than stromal CD10 and is an independent factor for UC prognosis.

Jiang J, Chang W, Fu Y, et al.
SAV1, regulated by microRNA-21, suppresses tumor growth in colorectal cancer.
Biochem Cell Biol. 2019; 97(2):91-99 [PubMed] Related Publications
This study investigated the role and action of the Salvador 1 protein (SAV1, also called WW45) in colorectal cancer (CRC). For this, CRC SW480 and HCT116 cells were infected with lentiviruses of SAV1 overexpression vector (lenti-SAV1) and SAV1 short hairpin RNA (sh-SAV1) to overexpress and silence SAV1 respectively, or transfected with microRNA-21 (miR-21) mimic to overexpress miR-21. Relative mRNA levels of SAV1 and relative miR-21 levels in CRC tissues or cells were detected. The effects of SAV1 and miR-21 on cell proliferation and apoptosis were evaluated using the MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] assay and annexin V - fluorescein isothiocyanate (FITC) - propidium iodide (PI) flow cytometry, respectively. Our results revealed that SAV1 was downregulated in CRC tissues compared with the adjacent noncancerous tissues. Furthermore, SAV1 overexpression inhibited proliferation and promoted apoptosis in SW480 and HCT116 cells, whereas knockdown of SAV1 exerted the opposite effect. Additionally, the tumorigenesis of SW480 cells in xenografted mice was significantly inhibited by SAV1 overexpression but promoted by SAV1 knockdown. MiR-21 levels significantly and negatively correlated with SAV1 expression in CRC tissues. More importantly, miR-21 overexpression significantly abolished the SAV1-mediated inhibition of proliferation and stimulation of apoptosis of SW480. In conclusion, SAV1 suppresses tumor growth in CRC and is regulated by miR-21.

Meerson A, Eliraz Y, Yehuda H, et al.
Obesity impacts the regulation of miR-10b and its targets in primary breast tumors.
BMC Cancer. 2019; 19(1):86 [PubMed] Article available free on PMC after 20/08/2020 Related Publications
BACKGROUND: Obesity increases breast cancer (BC) risk in post-menopausal women by mostly unknown molecular mechanisms which may partly be regulated by microRNAs (miRNAs).
METHODS: We isolated RNA from paired benign and malignant biopsies from 83 BC patients and determined miRNA profiles in samples from 12 women at the extremes of the BMI distribution by RNA-seq. Candidates were validated in all samples. Associations between miR-10b expression and validated target transcript levels, and effects of targeted manipulation of miR-10b levels in a primary BC cell line on proliferation and invasion potential, were explored.
RESULTS: Of the 148 miRNAs robustly expressed in breast tissues, the levels of miR-21, miR-10b, miR-451a, miR-30c, and miR-378d were significantly associated with presence of cancer. Of these, miR-10b showed a stronger down-regulation in the tumors of the obese subjects, as opposed to the lean. In ductal but not lobular tumors, significant inverse correlations were observed between the tumor levels of miR-10b and miR-30c and the mRNA levels of cancer-relevant target genes SRSF1, PIEZO1, MAPRE1, CDKN2A, TP-53 and TRA2B, as well as tumor grade. Suppression of miR-10b levels in BT-549 primary BC-derived cells increased cell proliferation and invasive capacity, while exogenous miR-10b mimic decreased invasion. Manipulation of miR-10b levels also inversely affected the mRNA levels of miR-10b targets BCL2L11, PIEZO1 and NCOR2.
CONCLUSIONS: Our findings suggest that miR-10b may be a mediator between obesity and cancer in post-menopausal women, regulating several known cancer-relevant genes. MiR-10b expression may have diagnostic and therapeutic implications for the incidence and prognosis of BC in obese women.

Feng M, Zhao J, Wang L, Liu J
Upregulated Expression of Serum Exosomal microRNAs as Diagnostic Biomarkers of Lung Adenocarcinoma.
Ann Clin Lab Sci. 2018; 48(6):712-718 [PubMed] Related Publications
Lung cancer is the leading cause of cancer-related death worldwide. Lung adenocarcinoma (AC) cases account for approximately 40% of lung cancers. Early diagnosis can reduce mortality, improve prognosis, prolong survival, and improve quality of life. Specific and stable biomarkers for early diagnosis of AC are still lacking. Exosomal miRNAs are enriched in the circulatory system and are remarkably stable compared to extracellular miRNAs because exosomes protect them from RNase degradation. In our study, we isolated serum exosomal miRNAs from AC patients and from healthy controls to find highly stable and sensitive biomarkers for early detection of AC. 23 AC patients and 16 healthy controls were included in this study. After microRNA (miR) extraction from serum exosomes (ex-miR), the expression of ex-miRs in cases and controls was quantified by quantitative reverse transcriptase-polymerase chain reaction (RT-qPCR). Overexpression of serum ex-miR-21-5p, -126-3p, and -140-5p was observed in AC patients. Area under the curve values for selected candidate ex-miRs were 0.97(95% confidence interval [CI], 0.846-0.99) for ex-miR-21-5p, 0.91(95% CI, 0.77-0.98) for ex-miR-126-3p, and 0.88 (95% CI, 0.73-0.97) for ex-miR-140-5p. Conclusion: Serums ex-miR-21-5p, -126-3p, and -140-5p have great potential to serve as highly sensitive, stable, and repeatable biomarkers for early diagnosis of AC. However, larger cohort studies are necessary to validate these results.

Chen J, Xu Y, Wang X, et al.
Rapid and efficient isolation and detection of extracellular vesicles from plasma for lung cancer diagnosis.
Lab Chip. 2019; 19(3):432-443 [PubMed] Related Publications
Extracellular vesicles (EVs) are cell-derived nanoscale vesicles that provide promising biomarkers for the non-invasive diagnosis of cancer because they carry important cancer-related DNA, RNA and protein biomarkers. However, the clinical application of EVs is limited by tedious and non-standardized isolation methods that require bulky instrumentation. Here, we propose an easy-to-operate, simple dielectrophoretic (DEP) method for EV isolation with higher recovery efficiency (>83%) and higher purity than ultracentrifugation (UC). The DEP chip reduces the isolation procedure from 8 h to 30 min. To facilitate subsequent analysis, our DEP chip achieved integration of EV isolation and in situ lysis of EVs for the first time. Our chip also achieved on-chip siRNA delivery to EVs isolated by DEP. We found that EVs isolated from the plasma of lung cancer patients contained higher levels of miR-21, miR-191 and miR-192 compared to those from healthy people. With on-chip detection, EGFR in EVs could distinguish lung cancer patients from healthy people. Overall, this study provides an efficient and practical approach to the isolation and detection of EVs, which could be used for the early diagnosis of lung cancer.

Proença MA, Biselli JM, Succi M, et al.
Relationship between
World J Gastroenterol. 2018; 24(47):5351-5365 [PubMed] Article available free on PMC after 20/08/2020 Related Publications
AIM: To examine the effect of
METHODS: Levels of
RESULTS: Overabundance of
CONCLUSION: Our findings indicate that

Hwang DW, Choi Y, Kim D, et al.
Graphene oxide-quenching-based fluorescence in situ hybridization (G-FISH) to detect RNA in tissue: Simple and fast tissue RNA diagnostics.
Nanomedicine. 2019; 16:162-172 [PubMed] Related Publications
FISH-based RNA detection in paraffin-embedded tissue can be challenging, with complicated procedures producing uncertain results and poor image quality. Here, we developed a robust RNA detection method based on graphene oxide (GO) quenching and recovery of fluorescence in situ hybridization (G-FISH) in formalin-fixed paraffin-embedded (FFPE) tissues. Using a fluorophore-labeled peptide nucleic acid (PNA) attached to GO, the endogenous long noncoding RNA BC1, the constitutive protein β-actin mRNA, and miR-124a and miR-21 could be detected in the cytoplasm of a normal mouse brain, primary cultured hippocampal neurons, an Alzheimer's disease model mouse brain, and glioblastoma multiforme tumor tissues, respectively. Coding and non-coding RNAs, either long or short, could be detected in deparaffinized FFPE or frozen tissues, as well as in clear lipid-exchanged anatomically rigid imaging/immunostaining-compatible tissue hydrogel (CLARITY)-transparent brain tissues. The fluorescence recovered by G-FISH correlated highly with the amount of miR-21, as measured by quantitative real time RT-PCR. We propose G-FISH as a simple, fast, inexpensive, and sensitive method for RNA detection, with a very low background, which could be applied to a variety of research or diagnostic purposes.

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] Article available free on PMC after 20/08/2020 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.

Zhou Y, Ren H, Dai B, et al.
Hepatocellular carcinoma-derived exosomal miRNA-21 contributes to tumor progression by converting hepatocyte stellate cells to cancer-associated fibroblasts.
J Exp Clin Cancer Res. 2018; 37(1):324 [PubMed] Article available free on PMC after 20/08/2020 Related Publications
BACKGROUND: Hepatocellular carcinoma (HCC) remains a global challenge due to its high morbidity and mortality rates as well as poor response to treatment. The communication between tumor-derived elements and stroma plays a critical role in facilitating cancer progression of HCC. Exosomes are small extracellular vesicles (EVs) that are released from the cells upon fusion of multivesicular bodies with the plasma membrane. There is emerging evidence indicating that exosomes play a central role in cell-to-cell communication. Much attention has been paid to exosomes since they are found to transport bioactive proteins, messenger RNA (mRNAs) and microRNA (miRNAs) that can be transferred in active form to adjacent cells or to distant organs. However, the mechanisms underlying such cancer progression remain largely unexplored.
METHODS: Exosomes were isolated by differential ultracentrifugation from conditioned medium of HCC cells and identified by electron microscopy and Western blotting analysis. Hepatic stellate cells (HSCs) were treated with different concentrations of exosomes, and the activation of HSCs was analyzed by Western blotting analysis, wound healing, migration assay, Edu assay, CCK-8 assay and flow cytometry. Moreover, the different miRNA levels of exosomes were tested by real-time quantitative PCR (RT-PCR). The angiogenic ability of activated HSCs was analyzed by qRT-PCR, CCK-8 assay and tube formation assay. In addition, the abnormal lipid metabolism of activated HSCs was analyzed by Western blotting analysis and Oil Red staining. Finally, the relationship between serum exosomal miRNA-21 and prognosis of HCC patients was evaluated.
RESULTS: We showed that HCC cells exhibited a great capacity to convert normal HSCs to cancer-associated fibroblasts (CAFs). Moreover, our data revealed that HCC cells secreted exosomal miRNA-21 that directly targeted PTEN, leading to activation of PDK1/AKT signaling in HSCs. Activated CAFs further promoted cancer progression by secreting angiogenic cytokines, including VEGF, MMP2, MMP9, bFGF and TGF-β. Clinical data indicated that high level of serum exosomal miRNA-21 was correlated with greater activation of CAFs and higher vessel density in HCC patients.
CONCLUSIONS: Intercellular crosstalk between tumor cells and HSCs was mediated by tumor-derived exosomes that controlled progression of HCC. Our findings provided potential targets for prevention and treatment of live cancer.

Chen X, Cai S, Li B, et al.
MicroRNA‑21 regulates the biological behavior of esophageal squamous cell carcinoma by targeting RASA1.
Oncol Rep. 2019; 41(3):1627-1637 [PubMed] Article available free on PMC after 20/08/2020 Related Publications
MicroRNA‑21 (miR‑21) has been revealed to play a crucial role in regulating the biological behavior, including proliferation, migration, invasion and metastasis in certain cancers. However, its role in esophageal squamous cell carcinoma (ESCC) has yet to be elucidated. Based on the data of GSE13937 downloaded from Gene Expression Omnibus (GEO) database, miR‑21 was revealed to be one of the top 20 differentially expressed (DE) miRNAs screened using the Morpheus online tool. RAS p21 protein activator 1 (RASA1) was predicted as the target gene of miR‑21 using the predicting software and was combined with miR‑21 using the luciferase reporter assay. Its relative expression was significantly decreased, however, miR‑21 was increased in the tumor tissues compared to the normal adjacent tissues in patients with ESCC as determined by quantitative polymerase chain reaction (q‑PCR). Furthermore, overexpression of miR‑21 (mimic) could significantly decrease the gene level of RASA1. Conversely, downregulation of miR‑21 (inhibitor) significantly increased the gene level of RASA1, while downregulation of RASA1 (siRASA1) markedly increased the gene expression of miR‑21. Notably, the expression of Snail and vimentin were significantly increased by upregulation of miR‑21 and downregulation of RASA1. Transwell results revealed that miR‑21 and RASA1 regulated proliferation, migration and invasion in ESCC cells. In an in vivo model, miR‑21 inhibitor (antagomir) could inhibit tumor growth. In conclusion, miR‑21 regulated cell proliferation, migration, invasion and tumor growth of ESCC by directly targeting RASA1, which may have been achieved via regulation of Snail and vimentin. Anti‑miR‑21 revealed an antitumor effect. Thus, it may be considered as a possible target for ESCC therapy.

Zheng X, Dong L, Wang K, et al.
MiR-21 Participates in the PD-1/PD-L1 Pathway-Mediated Imbalance of Th17/Treg Cells in Patients After Gastric Cancer Resection.
Ann Surg Oncol. 2019; 26(3):884-893 [PubMed] Related Publications
BACKGROUND: The programmed cell death-1/programmed cell death-ligand 1 (PD-1/PD-L1) pathway has been shown to be involved in trauma-induced immunosuppression and to influence CD4
METHODS: In the present study, we analyzed the percentages of T-helper (Th)-17/regulatory T (Treg) cells and PD-1/PD-L1 expression on peripheral blood mononuclear cells (PBMCs) during the perioperative period. We also detected the secretion of interleukin (IL)-17 and transforming growth factor (TGF)-β1 using enzyme-linked immunosorbent assays (ELISAs). Furthermore, PBMCs isolated from patients were transfected with or without adenovirus-short hairpin-PD-1 (Ad-sh-PD1), pre-miR-21 or adenovirus-green fluorescent protein (Ad-GFP), and the percentages of Th17/Treg cells and related transcription factors were measured.
RESULTS: In patients who underwent gastric cancer resection, the number of Th17 cells decreased, whereas the number of Treg cells increased, accompanied by an increased expression of PD-1/PD-L1. In addition, the expression of RORγt and IL-17 decreased, whereas the expression of Foxp3 and TGF-β1 increased. In vitro, silencing PD-1 via Ad-sh-PD1 promoted the expression of miR-21 and increased the percentage of Th17 cells, but decreased the percentage of Treg cells. The overexpression of miR-21 increased the percentage of Th17 cells but decreased the percentage of Treg cells.
CONCLUSIONS: Our study demonstrated that gastric cancer resection altered the balance of Th17/Treg cells and increased PD-1/PD-L1 expression. In the in vitro experiments, the transfection of Ad-sh-PD1 ameliorated Th17/Treg cell imbalance partially by increasing the expression of miR-21.

Kopcalic K, Petrovic N, Stanojkovic TP, et al.
Association between miR-21/146a/155 level changes and acute genitourinary radiotoxicity in prostate cancer patients: A pilot study.
Pathol Res Pract. 2019; 215(4):626-631 [PubMed] Related Publications
INTRODUCTION: Nearly sixty percent of patients with prostate cancer (PCa) undergo radiation therapy (RT). During the course of treatment patients may experience normal tissue reactions. It is a well established fact that genetic and epigenetic mechanisms, such as microRNA (miRNA) level changes might be associated with radiotoxicity, as a response to irradiation.
MATERIALS AND METHODS: This is the first study that has investigated levels of radiosensory miRNAs in association with acute genitourinary radiotoxicity extracted from peripheral blood mononuclear cells (PBCs), in three points; before RT (BRT), after RT (ART) and on the first control examination (FCONT). We measured levels of miR-21/146a/155 expression by quantitative real-time PCR (qRT-PCR), comparative ΔΔCt method, in fifteen patients with localized prostate cancer, treated with three-dimensional conformal radiotherapy (3DCRT). Nine subjects have experienced acute genitourinary (GU) radiotoxicity whereas six where without GU radiotoxicity.
RESULTS: Firstly, we detected the highest levels of miR-21 in ART group (p = 0.043) in the patients with acute GU radiotoxicity. Secondly, we found trend towards higher miR-21 levels and significantly higher levels of miR-146a/155 within the patients with acute GU toxicity than in patients without (p = 0.068, p = 0.016, and p = 0.010, respectively). Thirdly, we detected significant change in miR-146a/155 levels within the patients without acute GU radiotoxicity during RT p = 0.042, and p = 0.041, respectively).
CONCLUSION: miR-21/146a/155 might be useful potential factors of radiosensitivity and acute genitourinary radiotoxicity in prostate cancer patients. miRNA might have great potential as predictors of various pathological conditions extracted from PBMCs.

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