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: 11 March, 2017

Cancer Overview

Research Indicators

Publications Per Year (1992-2017)
Graph generated 11 March 2017 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 11 March, 2017 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)

Sarlinova M, Halasa M, Mistuna D, et al.
miR-21, miR-221 and miR-150 Are Deregulated in Peripheral Blood of Patients with Colorectal Cancer.
Anticancer Res. 2016; 36(10):5449-5454 [PubMed] Related Publications
The Aim of this study was to evaluate the expression levels of miR-21, miR-221, miR-150, let-7a and miR-126a in peripheral blood of 71 patients with colorectal cancer and 80 matched healthy control individuals. We determined expression levels of these microRNAs in peripheral blood samples and used small nucleolar RNA (RNU48) as an internal control. Expression levels of miR-21 (p<0.0001) and miR-221 (p<0.0001) were significantly higher, whereas expression levels of miR-150 (p=0.0054) were significantly lower in the blood samples of patients with colorectal cancer in comparison to the control group. The combination of these three microRNAs enabled us to distinguish patients with colorectal cancer from healthy donors with a sensitivity of 80% and specificity of 74% (p<0.0001). We did not observe any correlation of the studied microRNAs with clinicopathological features of colorectal cancer, indicating that expression of these microRNAs is more likely related to the host response to the tumour than the tumour itself.

Iseki Y, Shibutani M, Maeda K, et al.
Prognostic Significance of MicroRNA-21 Expression in Patients with Unresectable Metastatic Colon Cancer.
Anticancer Res. 2016; 36(10):5145-5151 [PubMed] Related Publications
BACKGROUND/AIM: MicroRNA (miR)-21 is overexpressed in most solid tumors and a high expression of miR-21 in tumor tissue is associated with a poor clinical outcome. The aim of this study was to clarify the association between the miR-21 expression in the tumor and the chemotherapeutic outcomes and survival for unresectable metastatic colon cancer (CC).
MATERIALS AND METHODS: Formalin-fixed, paraffin-embedded (FFPE) samples of primary tumor were obtained from 32 patients who underwent primary tumor resection and received palliative chemotherapy for unresectable metastatic CC. MiR-21 was extracted from the FFPE and the expression of miR-21 was evaluated using quantitative real time-polymerase chain reaction (RT-PCR). The expression of miR-21 was calculated with 2-ΔΔCT.
RESULTS: A high miR-21 expression was associated with reduced progression-free survival (PFS) (p=0.0109) and tended to reduce overall survival (OS) (p=0.0675).
CONCLUSION: miR-21 expression might be a useful prognostic marker for chemotherapeutic outcome and survival in patients with unresectable metastatic CC.

Zhou B, Wang J, Zheng G, Qiu Z
Methylated urolithin A, the modified ellagitannin-derived metabolite, suppresses cell viability of DU145 human prostate cancer cells via targeting miR-21.
Food Chem Toxicol. 2016; 97:375-384 [PubMed] Related Publications
Urolithins are bioactive ellagic acid-derived metabolites produced by human colonic microflora. Although previous studies have demonstrated the cytotoxicity of urolithins, the effect of urolithins on miRNAs is still unclear. In this study, the suppressing effects of methylated urolithin A (mUA) on cell viability in human prostate cancer DU145 cells was investigated. mUA induced caspase-dependent cell apoptosis, mitochondrial depolarization and down-regulation of Bcl-2/Bax ratio. The results showed that upon exposure to mUA, miR-21 expression was decreased and the expression of PTEN and Pdcd4 protein was elevated. mUA could further suppress Akt phosphorylation and increase protein expression of FOXO3a, and the effects of mUA on Akt phosphorylation and protein expression of FOXO3a were blocked by PTEN silence. Moreover, mUA suppressed the Wnt/β-catenin-mediated transcriptional activation of MMP-7 and c-Myc, and this function of mUA on MMP-7 and c-Myc was attenuated by over-expression of miR-21. In conclusion, our data suggest that mUA can suppress cell viability in DU145 cells through modulating miR-21 and its downstream series-wound targets, including PTEN, Akt and Wnt/β-catenin signaling.

Song L, Liu S, Zhang L, et al.
MiR-21 modulates radiosensitivity of cervical cancer through inhibiting autophagy via the PTEN/Akt/HIF-1α feedback loop and the Akt-mTOR signaling pathway.
Tumour Biol. 2016; 37(9):12161-12168 [PubMed] Related Publications
MiR-21 is an important microRNA (miRNA) modulating radiosensitivity of cervical cancer cells. However, the underlying mechanism of miR-21 upregulation in radioresistant cervical cancer has not been fully understood. In addition, autophagy may either promote or alleviate radioresistance, depending on the types of cancer and tumor microenvironment. How autophagy affects radiosensitivity in cervical cancer and how miR-21 is involved in this process has not been reported. This study showed that miR-21 upregulation in radioresistant cervical cancer is related to HIF-1α overexpression. MiR-21 overexpression decreases PTEN, increases p-Akt, and subsequently increases HIF-1α expression, while miR-21 inhibition results in increased PTEN, decreased p-Akt, and then decreased HIF-1α. Therefore, we inferred that there is a HIF-1α-miR-21 positive feedback loop through the PTEN/Akt/HIF-1α pathway in cervical cancer cells. In addition, we also demonstrated that miR-21 confers decreased autophagy in cervical cancer cells after IR via the Akt-mTOR signaling pathway. Decreased autophagy is one of the potential mechanisms of increased radioresistance in cervical cancer cells. These findings expand our understanding of radioresistance development in cervical cancer.

Wu YR, Qi HJ, Deng DF, et al.
MicroRNA-21 promotes cell proliferation, migration, and resistance to apoptosis through PTEN/PI3K/AKT signaling pathway in esophageal cancer.
Tumour Biol. 2016; 37(9):12061-12070 [PubMed] Related Publications
Our study aimed to explore associations between microRNA-21 (miR-21) and PTEN/PI3K/AKT signaling pathway and, further, to elucidate the regulation of miR-21 on biological behaviors in human esophageal cancer cells. The expressions of miR-21, PTEN, PI3K, and AKT were detected in 89 esophageal cancer samples and 58 adjacent normal tissues respectively. The human esophageal cancer cells (TE11) were grouped as following: blank (TE11 cells without transfection), negative (TE11 cells with miR-21 negative inhibitor), and Inhibition-miR21 (TE11 cells with miR-21 inhibitor). Western blot was used for detection of PTEN, P13K, and AKT protein expressions, MTT method for cell proliferation, Transwell assay for cell migration and invasion, and flow cytometry for cell cycle and apoptosis. MiR-21, PI3K, and AKT have higher expressions, but PTEN has lower expression in esophageal cancer tissues compared with adjacent normal tissues. The esophageal cancer tissues with lymph node metastasis and poor differentiation showed significantly low positive rate of PTEN protein, but high positive rates of PI3K and AKT proteins. Compared with blank and negative groups, PTEN expression of TE11 cells in Inhibition-miR21 group was significantly up-regulated, but PI3K and AKT were down-regulated. Further, PTEN was a target gene of miR-21. Besides, compared with blank and negative groups, the proliferation, migration, and invasion of TE11 cells were less active in Inhibition-miR21 group. TE11 cells were significantly increased in the G0/G1 phase of cell cycles, but decreased in the S and G2/M phase in Inhibition-miR21 group. The TE11 cells exhibited significantly increased apoptosis rates. MiR-21 targets key proteins in PTEN/PI3K/AKT signal pathway, promoting proliferation, migration, invasion, and cell cycle, and inhibiting apoptosis of human esophageal cancer cells. It may serve as a novel therapeutic target in esophageal cancer.

Samsonov R, Burdakov V, Shtam T, et al.
Plasma exosomal miR-21 and miR-181a differentiates follicular from papillary thyroid cancer.
Tumour Biol. 2016; 37(9):12011-12021 [PubMed] Related Publications
Thyroid cancer (TC) is the most common endocrine malignancy and its incidence has increased over the last few decades. As has been revealed by a number of studies, TC tissue's micro-RNA (miRNA) profile may reflect histological features and the clinical behavior of tumor. However, alteration of the miRNA profile of plasma exosomes associated with TC development has to date not been explored. We isolated exosomes from plasma and assayed their characteristics using laser diffraction particle size analysis, atomic force microscopy, and western blotting. Next, we profiled cancer-associated miRNAs in plasma exosomes obtained from papillary TC patients, before and after surgical removal of the tumor. The diagnostic value of selected miRNAs was evaluated in a large cohort of patients displaying different statuses of thyroid nodule disease. MiRNA assessment was performed by RT-qPCR. In total, 60 patients with different types of thyroid nodal pathology were included in the study. Our results revealed that the development of papillary TC is associated with specific changes in exosomal miRNA profiles; this phenomenon can be used for differential diagnostics. MiRNA-31 was found to be over-represented in the plasma exosomes of patients with papillary TC vs. benign tumors, while miRNA-21 helped to distinguish between benign tumors and follicular TC. MiRNA-21 and MiRNA-181a-5p were found to be expressed reciprocally in the exosomes of patients with papillary and follicular TC, and their comparative assessment may help to distinguish between these types of TC with 100 % sensitivity and 77 % specificity.

Zheng Z, Li X, Zhu Y, et al.
Prognostic Significance of MiRNA in Patients with Diffuse Large B-Cell Lymphoma: a Meta-Analysis.
Cell Physiol Biochem. 2016; 39(5):1891-1904 [PubMed] Related Publications
INTRODUCTION: This pooled analysis study aimed to reveal the prognostic relevance of microRNAs (miRNAs) in patients with diffuse large B-cell lymphoma (DLBCL).
MATERIALS AND METHODS: We examined the impact of miRNAs on clinical outcome. Eligible studies were identified and quality assessed using multiple search strategies. Data were extracted from included studies which correlated survival with expression of miRNAs (serum or tissue).
RESULTS: We pooled proper studies, and combined the hazard ratios with 95% confidence intervals to estimate strength of the correlations. There were 18 studies including 1950 patients with DLBCL eligible for pooled analysis. We found significant combined HRs for poor overall survival for high expression of miR-21 and low expression of miR-224 in tumor tissue, but for favorable relapse free survival for high expression of miR-21 in serum. Progression free survival was shortened in patients with low expression of miR-199a/b, miR-146b-5p, miR-224 and high expression of miR-222.
CONCLUSION: MiRNAs may act as independent prognostic factors in patients with DLBCL, and useful in risk stratification.

Tang XJ, Huang KM, Gui H, et al.
Pluronic-based micelle encapsulation potentiates myricetin-induced cytotoxicity in human glioblastoma cells.
Int J Nanomedicine. 2016; 11:4991-5002 [PubMed] Free Access to Full Article Related Publications
As one of the natural herbal flavonoids, myricetin has attracted much research interest, mainly owing to its remarkable anticancer properties and negligible side effects. It holds great potential to be developed as an ideal anticancer drug through improving its bioavailability. This study was performed to investigate the effects of Pluronic-based micelle encapsulation on myricetin-induced cytotoxicity and the mechanisms underlying its anticancer properties in human glioblastoma cells. Cell viability was assessed using a methylthiazol tetrazolium assay and a real-time cell analyzer. Immunoblotting and quantitative reverse transcriptase polymerase chain reaction techniques were used for determining the expression levels of related molecules in protein and mRNA. The results indicated that myricetin-induced cytotoxicity was highly potentiated by the encapsulation of myricetin. Mitochondrial apoptotic pathway was demonstrated to be involved in myricetin-induced glioblastoma cell death. The epidermal growth factor receptor (EGFR)/PI3K/Akt pathway located in the plasma membrane and cytosol and the RAS-ERK pathway located in mitochondria served as upstream and downstream targets, respectively, in myricetin-induced apoptosis. MiR-21 inhibitors interrupted the expression of EGFR, p-Akt, and K-Ras in the same fashion as myricetin-loaded mixed micelles (MYR-MCs) and miR-21 expression were dose-dependently inhibited by MYR-MCs, indicating the interaction of miR-21 with MYR-MCs. This study provided evidence supportive of further development of MYR-MC formulation for preferentially targeting mitochondria of glioblastoma cells.

Yadav P, Mirza M, Nandi K, et al.
Serum microRNA-21 expression as a prognostic and therapeutic biomarker for breast cancer patients.
Tumour Biol. 2016; 37(11):15275-15282 [PubMed] Related Publications
MiRNA-21 is recognized as the main active candidate and high expression in many solid tumors consequential cell proliferation, differentiation, apoptosis, and closely related to metastasis of disease. The study aimed to evaluate the serum miRNA-21 expression and therapy outcome in breast cancer patients and cell lines. Seventy-five histopathologically confirmed newly diagnosed breast cancer patients were included in the study; before and after therapy, patient's blood sample were collected and analyzed for serum microRNA-21 expression by quantitative real-time PCR. In patients, 8.9 mean fold increased microRNA-21 expression was observed compared to controls. Increased expression was found to be associated with advanced stage (11.72-fold), lymph node involvement (11.12-fold), and distant metastases (20.17-fold). After treatment significant decrease in miRNA-21 expression was observed and found to be significant (p < 0.0001). Patients treated with neoadjuvant therapy had significant impact on miRNA-21 suppression and found to be significantly associated with different clinicopathological features of patients. Increased miRNA-21 expression was also found to be significantly associated with poor survival of breast cancer patients (p = 0.002). MicroRNA-21 expression could be used as promising predictive indicators for breast cancer prognosis. MicroRNA-21 over-expression was associated with response to neoadjuvant therapy and may perhaps be considered as primary treatment choice.

Patel S, Rawal R
Role of miRNA dynamics and cytokine profile in governing CD44v6/Nanog/PTEN axis in oral cancer: modulating the master regulators.
Tumour Biol. 2016; 37(11):14565-14575 [PubMed] Related Publications
Late diagnosis, low therapeutic response, and metastasis are accountable for poor 5-year survival rate of OSCC. These failures are attributed to the existence of "cancer stem cell (CSC)" subpopulation. Hence, it is necessary to identify and understand the mechanism of CSCs in tumor development, metastasis, and chemotherapeutic response. Propelling evidences suggest that microRNA (miRNA)-mediated regulation and cytokines of tumor microenvironment have the ability to modulate CSC signalling pathway; however, their exact mechanism needs to be elucidated. Thus, in this study, we characterized CSC markers and highlighted the miRNA dynamics and cytokine profile regulating these CSCs in a pathway-dependent manner. Our results demonstrated CD44+ subpopulation as tumor-initiating cells with self-renewal capability, tumorigenic growth potential and intrinsic chemoresistance. These tumors exhibited increased expression of CSC markers (CD44v3, CD44v6, Nanog, and Bmi1) and significantly reduced expression of PTEN and ATM in OSCC patients. Pathway analysis of these CSC markers demonstrated a prospective pathway regulated by miRNA and cytokine network. On analyzing these modulators, we observed decreased expression of miRNA542-3p, miRNA34a and miRNA9, and significant upregulation of miRNA21, thus forming an unexplored axis. Cytokine profiling revealed significantly increased levels of IL-6 and IL-8 compared to normals and demonstrated their strong association with CD44v6. Collectively, this study indicates that miR5423p and miR34a targets the CD44v6-Nanog-PTEN axis, thus playing a vital role in regulating the CSC properties. Furthermore, we speculate an impinging role of cytokines IL-6 and IL-8 in regulating this CSC-mediated pathway which can have prognostic and therapeutic implications.

Gui F, Hong Z, You Z, et al.
MiR-21 inhibitor suppressed the progression of retinoblastoma via the modulation of PTEN/PI3K/AKT pathway.
Cell Biol Int. 2016; 40(12):1294-1302 [PubMed] Related Publications
MicroRNA-21 (miR-21) was reported to act as an oncogene during the development of many human tumors. However, little was revealed about the function of miR-21 in retinoblastoma (RB). In this study, we examined the expression of miR-21 in RB tissues and explored the relationship between miR-21 and phosphatase and tensin homolog (PTEN)/phosphatidylinositol-3-OH kinase (PI3K)/AKT signal. Quantitative real-time PCR (qRT-PCR) results showed that the level of miR-21 in RB tissues was higher than that in retinal normal tissues. In Weri-Rb-1 cells, miR-21 inhibitor suppressed the expression of miR-21 and cell viability, but improved cell apoptotic rates by modulating the levels of PDCD4, Bax, and Bcl-2. Meanwhile, miR-21 inhibitor suppressed cell migration and invasion via inhibiting the protein levels of MMP2 and MMP9 and significantly affected the expression of PTEN, PI3K, and p-AKT. Taken together, miR-21 inhibitor suppressed cell proliferation, migration, and invasion via the PTEN/PI3K/AKT signal. These findings revealed the molecular basis of miR-21 functioning in the progression of RB and provided a new means for cell therapy in RB.

Liu R, Wang Q, Li Q, et al.
Surface plasmon resonance biosensor for sensitive detection of microRNA and cancer cell using multiple signal amplification strategy.
Biosens Bioelectron. 2017; 87:433-438 [PubMed] Related Publications
A sensitive and versatile surface plasmon resonance (SPR) biosensor was proposed for the detection of microRNA (miRNA) and cancer cell based on multiple signal amplification strategy. Thiol-modified hairpin probe, including a sequence complementary to the target miRNA, was first immobilized on the Au film. In the presence of target miRNA, the stem-loop structure of hairpin probe was unfolded, and then DNA-linked Au nanoparticles (AuNPs) were hybridized with the terminus of the unfolded hairpin probe. Subsequently, DNA-linked AuNPs initiated the formation of DNA supersandwich structure through the addition of two report DNA sequences. Owing to the electronic coupling between localized plasmon of the AuNPs and the surface plasmon wave, as well as the enhancement of the refractive index of the medium over the Au film induced by DNA supersandwich structure, the SPR response was significantly enhanced. Next, numerous positively charged silver nanoparticles (AgNPs) were absorbed onto the long-range DNA surpersandwich equably, resulting in a further increase of SPR response. Due to the enzyme-free multiple signal amplification strategy, as low as ca. 0.6 fM miRNA-21 could be detected. In addition, this biosensor showed high selectivity toward single-base mismatch. More importantly, this SPR biosensor was also used for cancer cell detection coupled with the cell-specific aptamer modified magnetic nanoparticles. Given that the biosensor avoided enzyme introduction, the limitation of the enzyme was overcome. The versatile biosensor has great potential for the broad applications in the field of clinical analysis.

Yin D, Wang Y, Sai W, et al.
HBx-induced miR-21 suppresses cell apoptosis in hepatocellular carcinoma by targeting interleukin-12.
Oncol Rep. 2016; 36(4):2305-12 [PubMed] Related Publications
Hepatitis B virus (HBV) X protein (HBx) plays a key role in the initiation and progression of HBV infection‑induced hepatocellular carcinoma (HCC). Oncogenic microRNA-21 (miR-21) can be modulated by HBx protein in HCC. However, critical regulator genes in the pathway of HBx-induced miR-21 in HCC remain unclear. This study aimed to investigate the role of HBx-induced miR-21 in the apoptosis of HCC cells. In the study, interleukin-12 (IL-12) was demonstrated as a direct target of miR-21 by dual‑luciferase report assay, and miR-21 was highly expressed in HCC cells (HepG2 and HepG2 2.2.15) compared to L02 cells, but IL-12 was weakly expressed as detected by real-time quantitative PCR (RT-qPCR). Furthermore, miR-21 mimics, inhibitor, HBx-targeted siRNA, and the HBx overexpression vector (pHBx) were used to observe the regulatory effects of HBx-induced miR-21 via IL-12, and cell apoptosis was assessed. The results showed that overexpression of HBx resulted in the inhibition of IL-12. A high level of miR-21 resulted in a significant increase in proliferation and a decrease in IL-12 expression. Inhibition of miR-21 resulted in a significant increase in apoptosis and increased IL-12 expression. The results suggest that HCC cell apoptosis was suppressed at least partially through HBx-induced miR-21 by targeting IL-12.

Gong C, Tan W, Chen K, et al.
Prognostic Value of a BCSC-associated MicroRNA Signature in Hormone Receptor-Positive HER2-Negative Breast Cancer.
EBioMedicine. 2016; 11:199-209 [PubMed] Free Access to Full Article Related Publications
PURPOSE: Breast cancer patients with high proportion of cancer stem cells (BCSCs) have unfavorable clinical outcomes. MicroRNAs (miRNAs) regulate key features of BCSCs. We hypothesized that a biology-driven model based on BCSC-associated miRNAs could predict prognosis for the most common subtype, hormone receptor (HR)-positive, HER2-negative breast cancer patients.
PATIENTS AND METHODS: After screening candidate miRNAs based on literature review and a pilot study, we built a miRNA-based classifier using LASSO Cox regression method in the training group (n=202) and validated its prognostic accuracy in an internal (n=101) and two external validation groups (n=308).
RESULTS: In this multicenter study, a 10-miRNA classifier incorporating miR-21, miR-30c, miR-181a, miR-181c, miR-125b, miR-7, miR-200a, miR-135b, miR-22 and miR-200c was developed to predict distant relapse free survival (DRFS). With this classifier, HR+HER2- patients were scored and classified into high-risk and low-risk disease recurrence, which was significantly associated with 5-year DRFS of the patients. Moreover, this classifier outperformed traditional clinicopathological risk factors, IHC4 scoring and 21-gene Recurrence Score (RS). The patients with high-risk recurrence determined by this classifier benefit more from chemotherapy.
CONCLUSIONS: Our 10-miRNA-based classifier provides a reliable prognostic model for disease recurrence in HR+HER2- breast cancer patients. This model may facilitate personalized therapy-decision making for HR+HER2- individuals.

Mirzaei H, Khataminfar S, Mohammadparast S, et al.
Circulating microRNAs as Potential Diagnostic Biomarkers and Therapeutic Targets in Gastric Cancer: Current Status and Future Perspectives.
Curr Med Chem. 2016; 23(36):4135-4150 [PubMed] Related Publications
Gastric cancer is among the leading causes of cancer related death worldwide. Patients with gastric cancer are typically asymptomatic, and diagnosed at late stages, supporting the need for the identification of novel prognostic and diagnostic biomarkers. Recently, microRNAs have emerged as molecular regulators that can play key roles in pathogenesis and progression of different malignancies, including gastric cancer. There is a growing body of evidence showing the aberrant activation of some known circulating miRNAs, e.g. let-7a, miR-21, miR-16, miR-93, miR- 103, miR-192a s well as tissue specific-miRNAs, e.g. miR-18a, miR-10b, miR-544, miR-195, miR-378, miR-34a, miR-145 in patients affected by gastric cancer, which involved with modulation of gastric-cancer-associated genes. In addition, there are mounting evidences on the value of miRNAs which are detected to be associated with drug-resistance mechanisms; suggesting their modulation as a potential approach to overcome chemo-resistance. Attuned with these facts, in this review we highlight several recent preclinical and clinical studies performed on circulating and tissue-specific miRNAs as promising biomarkers for detection of patients at early stages, prediction of prognosis, and monitoring of the patients in response to therapy.

Mohamad M, Wahab NA, Yunus R, et al.
Roles of MicroRNA21 and MicroRNA29a in Regulating Cell Adhesion Related Genes in Bone Metastasis Secondary to Prostate Cancer.
Asian Pac J Cancer Prev. 2016; 17(7):3437-45 [PubMed] Related Publications
BACKGROUND: There is an increasing concern in the role of microRNA (miRNA) in the pathogenesis of bone metastasis (BM) secondary to prostate cancer (CaP). In this exploratory study, we hypothesized that the expression of vinculin (VCL) and chemokine X3C ligand 1 (CX3CL1) might be downregulated in clinical samples, most likely due to the posttranscriptional modification by microRNAs. Targeted genes would be upregulated upon transfection of the bone metastatic prostate cancer cell line, PC3, with specific microRNA inhibitors.
MATERIALS AND METHODS: MicroRNA software predicted that miR21 targets VCL while miR29a targets CX3CL1. Twenty benign prostatic hyperplasia (BPH) and 16 high grade CaP formalinfixed paraffin embedded (FFPE) specimens were analysed. From the bone scan results, high grade CaP samples were further classified into CaP with no BM and CaP with BM. Transient transfection with respective microRNA inhibitors was done in both RWPE1 (normal) and PC3 cell lines. QPCR was performed in all FFPE samples and transfected cell lines to measure VCL and CX3CL1 levels.
RESULTS: QPCR confirmed that VCL messenger RNA (mRNA) was significantly down regulated while CX3CL1 was upregulated in all FFPE specimens. Transient transfection with microRNA inhibitors in PC3 cells followed by qPCR of the targeted genes showed that VCL mRNA was significantly up regulated while CX3CL1 mRNA was significantly downregulated compared to the RWPE1 case.
CONCLUSIONS: The downregulation of VCL in FFPE specimens is most likely regulated by miR21 based on the in vitro evidence but the exact mechanism of how miR21 can regulate VCL is unclear. Upregulated in CaP, CX3CL1 was found not regulated by miR29a. More microRNA screening is required to understand the regulation of this chemokine in CaP with bone metastasis. Understanding miRNAmRNA interactions may provide additional knowledge for individualized study of cancers.

Torrente-Rodríguez RM, Campuzano S, Montiel VR, et al.
Sensitive electrochemical determination of miRNAs based on a sandwich assay onto magnetic microcarriers and hybridization chain reaction amplification.
Biosens Bioelectron. 2016; 86:516-21 [PubMed] Related Publications
A novel electrochemical approach for determination of miRNAs involving a sandwich hybridization assay onto streptavidin-magnetic beads (Strep-MBs), hybridization chain reaction (HCR) amplification and amperometric detection at disposable screen-printed carbon electrodes is reported. Using miRNA-21 as the target analyte, a dynamic linear range from 0.2 to 5.0nM with a 60pM (1.5fmol in 25μL) detection limit was obtained. The achieved sensitivity is 24-fold higher than a non-HCR amplification approach involving conventional sandwich type assay onto MBs. Moreover, the whole assay time lasted 1h 45min which is remarkably shorter than other reported methodologies. The methodology exhibited full selectivity against other non-complementary miRNAs as well as an acceptable discrimination between homologous miRNA family members. The applicability of this novel approach was demonstrated by determining mature miRNA-21 in total RNA (RNAt) extracted from tumor cells and human tissues.

Yang B, Liu Z, Ning H, et al.
MicroRNA-21 in peripheral blood mononuclear cells as a novel biomarker in the diagnosis and prognosis of prostate cancer.
Cancer Biomark. 2016; 17(2):223-30 [PubMed] Related Publications
OBJECTIVE: To evaluate the effects of microRNA-21 (miR-21) in peripheral blood mononuclear cells (PBMC) in the diagnosis and prognosis of prostate cancer (PCa).
METHODS: Proved by pathologic biopsy, 92 patients diagnosed with PCa and also underwent resection operation and 85 patients with benign prostatic hyperplasia (BPH) were selected in this study, as well as 97 healthy volunteers were chosen as the control group. PBMC were extracted to examine the relative expression of miR-21 by real time reverse transcriptase-polymerase chain reaction (RT-PCR). The relative operating characteristic (ROC) curves were drew to analyze the diagnosis value of PCa. The survival function curves were made by Kaplan-Meier method to show the miR-21 expression levels of PCa patients. The Log-rank test was adopted to compare the differences among the different groups. The Cox proportional hazard risk regression analysis was used to screen the independent factors affected the PCa patients.
RESULTS: The expression levels of miR-21 in PCa group were increased compared to BPH and control group (P < 0.05). The expression of miR-21 was significantly correlated with the Gleason score, clinical stages, bone metastasis and tumor recurrence (all P < 0.05). ROC curves demonstrated that the area under the curve of PCa and BPH distinguished by the miR-21 were 0.974 and 95% confidence intervals (95% CI) were 0.956∼ 0.993. The sensitivity and specificity were 93.5% and 92.9%. ROC curves demonstrated that the area under the curve of PCa and control group distinguished by the miR-21 were 0.984 and 95% CI were 0.972∼ 0.997. The sensitivity and specificity were 94.6% and 92.8%. The results of Kaplan-Meier Method demonstrated that the miR-21 expression levels were related to the prognosis of PCa (all P < 0.05). The results of the COX analysis suggested that the miR-21 expression level, tumor recurrence and bone metastasis could be the independent factors affected the prognosis of PCa patients (all P < 0.05).
CONCLUSION: miR-21 is highly expressed in the PCa patients, which could be the molecule biomarker of diagnosis and prognosis of PCa.

Montagnana M, Benati M, Danese E, et al.
Plasma Expression Levels of Circulating miR-21 are not Useful for Diagnosing and Monitoring Colorectal Cancer.
Clin Lab. 2016; 62(5):967-70 [PubMed] Related Publications
BACKGROUND: Recent evidence suggests that microRNAs play an important role in cancer diagnostics. We assessed plasma microRNA-21 levels in patients with colorectal cancer (CRC) at different stages and in patients with benign polyps.
METHODS: Plasma levels of miR-21 were assessed by quantitative reverse transcription polymerase chain reaction assay in plasma samples of 76 CRC patients and in 20 patients with benign polyps. Differences between groups were evaluated with Mann-Whitney and Kruskal-Wallis tests.
RESULTS: No significant differences of miR-21 plasma levels were observed between CRC patients and subjects with benign polyps (p > 0.05). Also, no significant differences were found between CRC patients with advanced (III-IV) or early cancer stages (I-II) (p > 0.05).
CONCLUSIONS: These results do not support the hypothesis that circulating miR-21 expression is increased in adenoma-carcinoma-advanced carcinoma sequence. Accordingly, plasma miR-21 assessment does not appear to be a useful biomarker for diagnosing and staging CRC.

Cheng FF, Jiang N, Li X, et al.
Target-triggered triple isothermal cascade amplification strategy for ultrasensitive microRNA-21 detection at sub-attomole level.
Biosens Bioelectron. 2016; 85:891-6 [PubMed] Related Publications
MicroRNA-21 (miR-21) is a promising diagnostic biomarker for breast cancer screening and disease progression, thus the method for the sensitive and selective detection of miR-21 is vital to its clinical diagnosis. Herein, we develop a novel method to quantify miR-21 levels as low as attomolar sensitivity by a target-triggered triple isothermal cascade amplification (3TICA) strategy. An ingenious unimolecular DNA template with three functional parts has been designed: 5'-fragment as the miR-21 recognition unit, middle fragment as the miR-21 analogue amplification unit, and 3'-fragment as the 8-17 DNAzyme production unit. Triggered by miR-21 and accompanied by polymerase-nicking enzyme cascade, new miR-21 analogues autonomously generated for the successive re-triggering and cleavage process. Simultaneously, the 8-17 DNAzyme-contained sequence could be exponentially released and activated for the second cyclic cleavage toward a specific ribonucleotide (rA)-contained substrate, inducing a remarkably amplified generation of HRP-mimicking DNAzyme in the presence of hemin. Finally, the amperometric technique was used to record the catalytic reduction current of 3,3',5,5'-tetramethylbenzidine (TMB) in the presence of H2O2. The increase in the steady-state current was proportional with the increase of the miR-21 concentration from 1 aM to 100 pM. An ultra-low detection limit of 0.5 aM with an excellent selectivity for even discriminating differences between 1-base mismatched target and miR-21 was achieved. This simple and cost-effective 3TICA strategy is promising for the detection of any short oligonucleotides, simply by altering the target recognition unit in the template sequence.

Kushlinskii NE, Fridman MV, Braga EA
Molecular Mechanisms and microRNAs in Osteosarcoma Pathogenesis.
Biochemistry (Mosc). 2016; 81(4):315-28 [PubMed] Related Publications
This review summarizes data on microRNA (miRNA) genomic organization, biogenesis, and functions in carcinogenesis. The roles of key genes and regulatory miRNAs in molecular mechanisms and signaling pathways involved in the development of osteosarcoma, the most aggressive type of bone tumor striking mainly in adolescence and early adulthood, are discussed in detail. The most critical pathways in osteosarcoma pathogenesis are the Notch, Wnt, NF-κB, p53, PI3K/Akt, and MAPK pathways. The balance between cell survival and apoptosis is determined by the Wnt and NF-κB pathways, as well as by the ratio between the activities of the MAPK and PI3K/Akt pathways. Several miRNAs (miR-21, -34a, -143, -148a, -195a, -199a-3p, -382) regulate multiple target genes, pathways, and processes essential for osteosarcoma pathogenesis. Data on the key genes and regulatory miRNAs involved in metastasis and tumor cell response to drug treatment are presented. Possible applications of miRNA in osteosarcoma diagnostics and treatment are discussed.

Tian F, Shen Y, Chen Z, et al.
Aberrant miR-181b-5p and miR-486-5p expression in serum and tissue of non-small cell lung cancer.
Gene. 2016; 591(2):338-43 [PubMed] Related Publications
BACKGROUND: Lung cancer is the leading cause of cancer deaths in China. Non-small cell lung cancer (NSCLC) is the major type of lung cancer.
OBJECTIVES: The aim of our study was to characterize the expression profiles of miRNAs in serum and tissue of NSCLC at the same time, and to find more accurate relationship of miRNAs between serum and tissue. Furthermore, we intended to find more biomarkers of miRNAs in NSCLC samples.
METHODS: In this study, the miRNAs were sequenced in 18 paired serum and 18 paired tissue samples. The expression levels of miRNAs and targets were quantified by qRT-PCR. The function analysis was performed by using bioinformatics methods.
RESULTS: In these paired samples miR-181b-5p was up-regulated in squamous cell carcinoma (SCC), miR-486-5p was down-regulated in adenocarcinoma (AC), and miR-21-5p was up-regulated in both SCC and AC. However, miR-181b-5p and miR-486-5p were rarely reported in lung cancer related studies. The expression levels of these two miRNAs and their targets, RASSF1 and PIK3R1 were quantified in additional samples by qRT-PCR. The results showed that the targets were negatively regulated by the two miRNAs. In addition, we noted that RASSF1 and PIK3R1 were directly involved in non-small cell lung cancer pathway.
CONCLUSIONS: Our study suggested that miR-181b-5p and miR-486-5p could be new potential biomarkers for early diagnosis of NSCLC.

Li Y, Shang YM, Wang QW
MicroRNA-21 promotes the proliferation and invasion of neuroblastoma cells through targeting CHL1.
Minerva Med. 2016; 107(5):287-93 [PubMed] Related Publications
BACKGROUND: Neuroblastoma (NB) is one of the most common solid tumors in infants and children. Numerous reports demonstrated that microRNAs (miRNAs) play important roles in the carcinogenesis of neuroblastoma. miR-21 functions as a tumor oncogene in some malignancies. However, its role in NB remains poorly understood.
METHODS: miR-21 expression was quantified in NB tissues and matched adjacent non-tumor tissues using quantitative real-time PCR (RT-PCR). Cell proliferation, migration, and invasion were measured following overexpression of miR-21 expression by miR-21 mimics. miR-21 targets were scanned using target prediction programs. Following the overexpression of miR-21, target gene expression was detected by western blotting. In addition, cell proliferation, migration, and invasion were measured following inhibition of CHL1 expression by siRNA.
RESULTS: In the present study, our results showed that miR-21 was increased in NB tissues compared with matched adjacent non-tumor tissues. Forced overexpression of miR-21 significantly increased NB cell proliferation, migration, and invasion. Close homolog of LI (CHL1) was found to be a target of miR-21. Furthermore, downregulation of CHL1 by siRNA performed similar effects with overexpression of miR-21 in NB cells.
CONCLUSIONS: We suggested that miR-21 promoted neuroblastoma cell growth and motility partially by targeting CHL1, indicating the potential utility of miR-21 inhibition as a novel therapeutic strategy against neuroblastoma.

Tian F, Li R, Chen Z, et al.
Differentially Expressed miRNAs in Tumor, Adjacent, and Normal Tissues of Lung Adenocarcinoma.
Biomed Res Int. 2016; 2016:1428271 [PubMed] Free Access to Full Article Related Publications
Lung cancer is the leading cause of cancer deaths. Non-small-cell lung cancer (NSCLC) is the major type of lung cancer. The aim of this study was to characterize the expression profiles of miRNAs in adenocarcinoma (AC), one major subtype of NSCLC. In this study, the miRNAs were detected in normal, adjacent, and tumor tissues by next-generation sequencing. Then the expression levels of differential miRNAs were quantified by quantitative reverse transcription-polymerase chain reaction (qRT-PCR). In the results, 259, 401, and 389 miRNAs were detected in tumor, adjacent, and normal tissues of pooled AC samples, respectively. In addition, for the first time we have found that miR-21-5p and miR-196a-5p were gradually upregulated from normal to adjacent to tumor tissues; miR-218-5p was gradually downregulated with 2-fold or greater change in AC tissues. These 3 miRNAs were validated by qRT-PCR. Lastly, we predicted target genes of these 3 miRNAs and enriched the potential functions and regulatory pathways. The aberrant miR-21-5p, miR-196a-5p, and miR-218-5p may become biomarkers for diagnosis and prognosis of lung adenocarcinoma. This research may be useful for lung adenocarcinoma diagnosis and the study of pathology in lung cancer.

Pant K, Gupta P, Damania P, et al.
Mineral pitch induces apoptosis and inhibits proliferation via modulating reactive oxygen species in hepatic cancer cells.
BMC Complement Altern Med. 2016; 16:148 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Mineral Pitch (MP) is a dark brown coloured humic matter originating from high altitude rocks. It is an Ayurvedic medicinal food, commonly used by the people of the Himalayan regions of Nepal and India for various body ailments.
METHODS: The Huh-7 cells were treated with different concentrations of MP for 24 h, and both apoptosis and proliferation was determined by the TUNEL and MTT assays respectively. The formation of ROS and nitric oxide was analysed by DCFH-DA and Griess reagent respectively. The expression of miRNA-21 and miRNA-22 were checked by the real time PCR. Effect of miRNA-22 on proliferation and c-myc was studied by over-expressing miRNA-22 premiRs in Huh-7 cells.
RESULTS: We found that MP enhanced anti-cancer effects by inducing apoptosis and inhibiting proliferation. MP induced both ROS and NO, upon neutralizing them, there was a partial recovery of apoptosis and proliferation. MP also induced miRNA-22 expression, while miRNA-21 expression was inhibited. Over-expression of miRNA-22 resulted in a significant inhibition of proliferation. miRNA-22 directly targeted c-myc gene, thereby inhibited proliferation. These results clearly show that MP induces its anti-cancer activity by more than one pathway.
CONCLUSION: The data clearly indicate that MP induced apoptosis via the production of ROS, and inhibited proliferation by inducing miRNA-22 and inhibiting miRNA-21 in Huh-7 cells.

Lin L, Tu HB, Wu L, et al.
MicroRNA-21 Regulates Non-Small Cell Lung Cancer Cell Invasion and Chemo-Sensitivity through SMAD7.
Cell Physiol Biochem. 2016; 38(6):2152-62 [PubMed] Related Publications
BACKGROUND/AIMS: SMAD7 is a key inhibitor of transforming growth factor β (TGFβ) receptor signaling, which regulates the alteration of cancer cell invasiveness through epithelial-mesenchymal cell conversion. Carboplatin is a commonly used drug in the chemotherapy for non-small cell lung cancer (NSCLC). Nevertheless, the molecular mechanisms underlying its suppressive effects on the NSCLC cell invasion are not completely understood. In the current study, we addressed this question by analyzing the effects of Carboplatin on microRNA-regulated SMAD7.
METHODS: We used Carboplatin to treat NSCLC cell lines. We performed bioinformatics analyses on the binding of microRNA-21 (miR-21) to the 3'-UTR of SMAD7 mRNA, and verified the biological effects of this binding using promoter luciferase reporter assay. The effects of Carboplatin or miR-21-modification on NSCLC cell invasion were evaluated in either a transwell cell invasion assay, or a scratch wound healing assay.
RESULTS: We found that Carboplatin inhibited the NSCLC cell invasion, in either a transwell cell invasion assay, or a scratch wound healing assay. Moreover, Carboplatin increased the levels of SMAD7 protein, but not mRNA, in NSCLC cells, suggesting presence of post-transcriptional control of SMAD7 by Carboplatin. Furthermore, expression of miR-21 was found to be inhibited by Carboplatin, and bioinformatics analyses showed that miR-21 targeted the 3'-UTR of SMAD7 mRNA to inhibit its translation, which was confirmed by luciferase reporter assay.
CONCLUSION: Carboplatin may upregulate SMAD7 through suppression of miR-21 to inhibit TGFβ receptor signaling mediated NSCLC cell invasion.

Parafioriti A, Bason C, Armiraglio E, et al.
Ewing's Sarcoma: An Analysis of miRNA Expression Profiles and Target Genes in Paraffin-Embedded Primary Tumor Tissue.
Int J Mol Sci. 2016; 17(5) [PubMed] Free Access to Full Article Related Publications
The molecular mechanism responsible for Ewing's Sarcoma (ES) remains largely unknown. MicroRNAs (miRNAs), a class of small non-coding RNAs able to regulate gene expression, are deregulated in tumors and may serve as a tool for diagnosis and prediction. However, the status of miRNAs in ES has not yet been thoroughly investigated. This study compared global miRNAs expression in paraffin-embedded tumor tissue samples from 20 ES patients, affected by primary untreated tumors, with miRNAs expressed in normal human mesenchymal stromal cells (MSCs) by microarray analysis. A miRTarBase database was used to identify the predicted target genes for differentially expressed miRNAs. The miRNAs microarray analysis revealed distinct patterns of miRNAs expression between ES samples and normal MSCs. 58 of the 954 analyzed miRNAs were significantly differentially expressed in ES samples compared to MSCs. Moreover, the qRT-PCR analysis carried out on three selected miRNAs showed that miR-181b, miR-1915 and miR-1275 were significantly aberrantly regulated, confirming the microarray results. Bio-database analysis identified BCL-2 as a bona fide target gene of the miR-21, miR-181a, miR-181b, miR-29a, miR-29b, miR-497, miR-195, miR-let-7a, miR-34a and miR-1915. Using paraffin-embedded tissues from ES patients, this study has identified several potential target miRNAs and one gene that might be considered a novel critical biomarker for ES pathogenesis.

Song N, Liang B, Wang D
The function of MiR-21 expression differences and pathogenesis on familial and triple negative breast Cancer serum.
Pak J Pharm Sci. 2016; 29(2 Suppl):679-84 [PubMed] Related Publications
This paper is to detect the expression differences of serum miR-21 in breast cancer, in order to further clarify the function of miR-21 in familial and TNBC pathogenesis of breast cancer. The serum had been collected for healthy check-up females, women with high risk of breast cancer and different types of breast cancer patients. Nematodes were taken as the external reference, real-time fluorescent quantitative PCR detection were taken for expression level of miR-21 in 77 cases of serum. The miR-21 expression level of familial breast cancer group, TNBC group and breast cancer high risk group were significantly higher than that in normal control group and other breast cancer group, P<0.01. Serum miR-21 expression level was associated with lymph node metastasis and Ki67 high expression, P<0.01. Results had proved that serum miR-21 expression quantity increased in familial breast cancer and TNBC and was correlated with lymph node metastasis and Ki67 expression. Serum miR-21 was closed related with TNBC and familial breast cancer. The relative expression quantity of miR-21 in breast cancer serum had no obvious relation with unilateral or bilateral tumor and menstrual situation. Its increased expression might be correlated to the breast cancer hereditary, malignant degree and prognosis judgement and its mechanism required further research.

Kowalczyk AE, Krazinski BE, Godlewski J, et al.
SATB1 is Down-regulated in Clear Cell Renal Cell Carcinoma and Correlates with miR-21-5p Overexpression and Poor Prognosis.
Cancer Genomics Proteomics. 2016 May-Jun; 13(3):209-17 [PubMed] Related Publications
BACKGROUND: Altered expression of special AT-rich sequence binding protein 1 (SATB1) was reported in several types of human cancers. This study aimed to determine the expression levels of SATB1, as well as miR-21-5p -the post-transcriptional repressor of SATB1 expression- in clear cell renal cell carcinoma (ccRCC) and to investigate their association with the progression of ccRCC.
MATERIALS AND METHODS: Immunohistochemistry and quantitative polymerase chain reaction were used to assess the expression of SATB1 protein and mRNA as well as miR-21-5p in tumor and matched normal kidney tissues collected from 56 ccRCC patients.
RESULTS: Nuclear SATB1 immunoreactivity was elevated in ccRCC cells while its cytoplasmic expression was decreased. SATB1 mRNA level was down-regulated in ccRCC tissue and inversely correlated with the content of miR-21-5p. Down-regulation of SATB1 mRNA and up-regulation of miR-21-5p were associated with shorter patient survival.
CONCLUSION: Decreased expression of SATB1 in ccRCC may result from over-expressed miR-21-5p. Our data suggest that SATB1 may have a potential value as a prognostic marker in ccRCC.

Fiorino S, Bacchi-Reggiani ML, Visani M, et al.
MicroRNAs as possible biomarkers for diagnosis and prognosis of hepatitis B- and C-related-hepatocellular-carcinoma.
World J Gastroenterol. 2016; 22(15):3907-36 [PubMed] Free Access to Full Article Related Publications
Aim of the present review is to summarize the current knowledge about the potential relationship between miRNAs and hepatitis B virus (HBV)-hepatitis C virus (HCV) related liver diseases. A systematic computer-based search of published articles, according to the Preferred Reporting Items for Systematic reviews and Meta-Analysis Statement, was performed to identify relevant studies on usefulness of serum/plasma/urine miRNAs, as noninvasive biomarkers for early detection of HBV and HCV-induced hepatocellular carcinoma (HCC) development, as well as for its prognostic evaluation. The used Medical Subject Headings terms and keywords were: "HBV", "HCV", "hepatocellular carcinoma", "microRNAs", "miRNAs", "diagnosis", "prognosis", "therapy", "treatment". Some serum/plasma miRNAs, including miR-21, miR-122, mi-125a/b, miR-199a/b, miR-221, miR-222, miR-223, miR-224 might serve as biomarkers for early diagnosis/prognosis of HCC, but, to date, not definitive results or well-defined panels of miRNAs have been obtained. More well-designed studies, focusing on populations of different geographical areas and involving larger series of patients, should be carried out to improve our knowledge on the potential role of miRNAs for HCC early detection and prognosis.

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