MIR122

Locus Summary

Gene:MIR122; microRNA 122
Aliases: MIR122A, MIRN122, mir-122, MIRN122A, miRNA122, miRNA122A, hsa-mir-122
Location:18q21.31
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.

  • Down-Regulation
  • Tumor Burden
  • Gene Expression Profiling
  • Hepacivirus
  • Wnt Signaling Pathway
  • Colorectal Cancer
  • Single Nucleotide Polymorphism
  • Hepatocellular Carcinoma
  • Neoadjuvant Therapy
  • Cell Proliferation
  • Biomarkers, Tumor
  • TRPV Cation Channels
  • Virus Replication
  • Apoptosis
  • Chromosome 18
  • 3' Untranslated Regions
  • Hep G2 Cells
  • Messenger RNA
  • Neoplasm Invasiveness
  • Liver
  • Base Sequence
  • Case-Control Studies
  • Virus Activation
  • Mice, Inbred BALB C
  • Polymerase Chain Reaction
  • Liver Cancer
  • ROC Curve
  • Reproducibility of Results
  • RT-PCR
  • Osteosarcoma
  • Risk Factors
  • MicroRNAs
  • beta Catenin
  • Risk Assessment
  • RNA Interference
  • Prostate Cancer
  • Silicon Dioxide
  • MicroRNA miR-122
  • Oleanolic Acid
  • Regression Analysis
  • Hepatitis C
  • Oncogenes
  • Cancer Gene Expression Regulation
  • Hepatitis B virus
Tag cloud generated 11 March, 2017 using data from PubMed, MeSH and CancerIndex

Specific Cancers (4)

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)MIR122 Function in CancerEffect
liver (14)
-hepatocellular carcinoma (12)
-HBV+ hepatocellular carcinoma (1)
-hepatocelluar carcinoma (1)
IGF1R (2)
PTTG1IP (1)
NDRG3 (1)
ADAM10 (1)
ADAM17 (1)
CDK4 (1)
CCNG1 (1)
WNT1 (1)
CUX1 (1)
SRF (1)
BCL2L2 (1)
HBV (1)
HNF3B (1)
HNF3A (1)
HNF1A (1)
GSK3B (1)
CEBPA (1)
inhibit cell growth (4)
inhibit cell migration (3)
inhibit cell invasion (3)
induce apoptosis (2)
induce doxorubicin-induced apoptosis (1)
inhibit in vivo tumorigenesis (1)
inhibit angiogenesis (1)
inhibit intrahepatic metastasis (1)
decrease clonogenic survival (1)
reduce cell invasion (1)
increase cell viability (1)
regulate mitochondrial metabolism (1)
promote cell apoptosis (1)
induce cell cycle G2/M arrest (1)
repress unfolded protein response (UPR) pathway (1)
promote drug-induced apoptosis (1)
inhibit cell proliferation (1)
inhibit HBV replication (1)
inhibit tumor agressiveness characteristics (1)
suppress cell proliferation (1)
reduce cell viability (1)
tumor-suppressive (12)
oncogenic (1)
breast (1)
-breast cancer (1)
IGF1R (1)
inhibit cell proliferation (1)
inhibit colony formation (1)
induce cell cycle G1 arrest (1)
reduce tumorigenicity (1)
tumor-suppressive (1)
blood (1)
-cutaneous T-cell lymphoma (1)
decrease chemotherapy-induced apoptosis (1)
activate Akt signaling (1)

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

Latest Publications: MIR122 (cancer-related)

Zhang S, Tang D, Zang W, et al.
Synergistic Inhibitory Effect of Traditional Chinese Medicine Astragaloside IV and Curcumin on Tumor Growth and Angiogenesis in an Orthotopic Nude-Mouse Model of Human Hepatocellular Carcinoma.
Anticancer Res. 2017; 37(2):465-473 [PubMed] Related Publications
AIM: The aim of the present study was to investigate the efficacy of the traditional Chinese medicine (TCM), astragaloside IV (AS-IV) and curcumin on tumor growth and angiogenesis in an orthotopic nude-mouse model of human hepatocellular carcinoma (HCC). We have previously shown the usefulness of orthotopic models of human cancer for evaluation of the efficacy of TCM.
MATERIALS AND METHODS: Nude mice with orthotopic HepG2 HCC were treated with vehicle control (0.01 ml/g normal saline), cisplatinum (2 mg/kg), AS-IV (20 mg/kg), curcumin (100 mg/kg) or AS-IV plus curcumin (20 mg/kg + 100 mg/kg). Tumor inhibition in each group was evaluated by tumor weight at autopsy. The effect of AS-IV and curcumin on tumor angiogenesis was assessed by CD34 staining and expression of fibroblast growth factor-2 (FGF2), matrix metalloproteinase 2 (MMP2), vascular endothelial growth factor (VEGF), hepatocyte growth factor (HGF), thrombosis-related factor tissue factor (TF) and coagulation factor VII (FVII), as well as microRNAs miR-122 and miR-221.
RESULTS: AS-IV and curcumin alone and in combination significantly reduced mean tumor weight compared to vehicle control (p<0.05). Tumor microvessel count was reduced by AS-IV and curcumin alone. Expression of FGF2, MMP2, VEGF, HGF, TF and FVII was reduced by AS-IV and curcumin alone. AS-IV and curcumin alone up-regulated expression of miR-122 and down-regulated that of miR-221. The combination of AS-IV and curcumin demonstrated significant synergistic effects on microvessel count as well as on expression of angiogenic and thrombosis-related factors and microRNAs.
CONCLUSION: The present study indicates future clinical potential of combination therapy with AS-IV and curcumin for HCC.

Zekri AN, Youssef AS, El-Desouky ED, et al.
Serum microRNA panels as potential biomarkers for early detection of hepatocellular carcinoma on top of HCV infection.
Tumour Biol. 2016; 37(9):12273-12286 [PubMed] Related Publications
The identification of new high-sensitivity and high-specificity markers for hepatocellular carcinoma (HCC) is essential. We aimed at identifying serum microRNAs (miRNAs) as potential biomarkers for early detection of HCC on top hepatitis C virus (HCV) infection. We investigated serum expression of 13 miRNAs in 384 patients with HCV-related chronic liver disease (192 with HCC, 96 with liver cirrhosis (LC), and 96 with chronic hepatitis C (CHC)) in addition to 96 healthy participants enrolled as a control group. The miRNA expression was performed using real-time quantitative PCR-based SYBR Green custom miRNA arrays. The area under the receiver operating characteristic curve (AUC) was used to evaluate the diagnostic performance of miRNA panels for early detection of HCC. Using miRNA panel of miR-122, miR-885-5p, and miR-29b with alpha fetoprotein (AFP) provided high diagnostic accuracy (AUC = 1) for early detection of HCC in normal population while using miRNA panel of miR-122, miR-885-5p, miR-221, and miR-22 with AFP provided high diagnostic accuracy (AUC = 0.982) for early detection of HCC in LC patients. However, using miRNA panel of miR-22 and miR-199a-3p with AFP provided high diagnostic accuracy (AUC = 0.988) for early detection of HCC in CHC patients. We identified serum miRNA panels that could have a considerable clinical use in early detection of HCC in both normal population and high-risk patients.

Ahsani Z, Mohammadi-Yeganeh S, Kia V, et al.
WNT1 Gene from WNT Signaling Pathway Is a Direct Target of miR-122 in Hepatocellular Carcinoma.
Appl Biochem Biotechnol. 2017; 181(3):884-897 [PubMed] Related Publications
Hepatocellular carcinoma (HCC) is an invasive form of hepatic cancer arising from the accumulation of multiple genetic alterations. In this study, the causal role of disturbed canonical Wnt/β-catenin pathway was approved, and some of HCC-driven important gene candidates were determined. MicroRNAs (miRNAs), small non-coding RNAs, are the key regulators of important cancer genes, and their participation in tumorigenesis has been shown. By reviewing literature, WNT1 gene with functional significance was selected to approve miRNAs as new subjects for targeted therapy.For proper and fast miRNA detection and also confirmation of the role of bioinformatics in obtaining practical data, we benefited from different bioinformatics tools such as TargetScan, miRanda, and DIANA. In order to use an HCC model, we used HepG2 cell line. Luciferase assay was applied to assess the ability of the selected miRNAs in targeting WNT1 3'-UTR. To overexpress the selected miRNA in HepG2 cell line, viral construct was prepared. Quantitative real-time PCR was performed to evaluate selected miRNA and target gene expression levels. miR-122 was selected according to data concerning various bioinformatics tools.miR-122 was downregulated and WNT1 gene expression was upregulated in HepG2 cell line. After viral construct transduction, miR-122 expression was elevated and WNT1 expression was notably declined. Finally, we introduced WNT1 gene as one of the important genes in HCC, and also, we showed that miR-122 can regulate WNT1 gene expression.Moreover, our study determines the potential of bioinformatics analyses in providing accurate and reliable data for miRNA: messenger RNA (mRNA) prediction.

Vychytilova-Faltejskova P, Pesta M, Radova L, et al.
Genome-wide microRNA Expression Profiling in Primary Tumors and Matched Liver Metastasis of Patients with Colorectal Cancer.
Cancer Genomics Proteomics. 2016 Jul-Aug; 13(4):311-6 [PubMed] Related Publications
BACKGROUND: Primary tumor spread to the liver is the major cause of disease progression and death in patients with colorectal cancer (CRC). MicroRNAs (miRNAs) are small non-coding RNAs that are involved in cancer development and progression, but their role in metastasis has not been extensively investigated.
MATERIALS AND METHODS: Firstly, expression profiling of 752 miRNAs in 20 primary tumors and their corresponding liver metastases was performed. Secondly, validation of the results was carried out on an independent cohort of 66 patients with metastatic CRC using reverse transcription-quantitative polymerase chain (RT-qPCR) reaction.
RESULTS: In total, 33 miRNAs were found to be significantly deregulated in liver metastases compared to their primary tumors. Fifteen miRNAs were chosen for subsequent validation, which confirmed significantly reduced expression of miR-143, miR 10b, and miR-28-5p, and increased expression of miR 122, miR-122*, and miR 885-5p in the tissue of liver metastases.
CONCLUSION: These results indicate that miRNAs could serve as new therapeutic targets in patients with metastatic CRC.

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.

Yin S, Fan Y, Zhang H, et al.
Differential TGFβ pathway targeting by miR-122 in humans and mice affects liver cancer metastasis.
Nat Commun. 2016; 7:11012 [PubMed] Free Access to Full Article Related Publications
Downregulation of a predominantly hepatocyte-specific miR-122 is associated with human liver cancer metastasis, whereas miR-122-deficient mice display normal liver function. Here we show a functional conservation of miR-122 in the TGFβ pathway: miR-122 target site is present in the mouse but not human TGFβR1, whereas a noncanonical target site is present in the TGFβ1 5'UTR in humans and other primates. Experimental switch of the miR-122 target between the receptor TGFβR1 and the ligand TGFβ1 changes the metastatic properties of mouse and human liver cancer cells. High expression of TGFβ1 in human primary liver tumours is associated with poor survival. We identify over 50 other miRNAs orthogonally targeting ligand/receptor pairs in humans and mice, suggesting that these are evolutionarily common events. These results reveal an evolutionary mechanism for miRNA-mediated gene regulation underlying species-specific physiological or pathological phenotype and provide a potentially valuable strategy for treating liver-associated diseases.

Hayes CN, Chayama K
MicroRNAs as Biomarkers for Liver Disease and Hepatocellular Carcinoma.
Int J Mol Sci. 2016; 17(3):280 [PubMed] Free Access to Full Article Related Publications
Serum levels of liver enzymes, such as alanine transaminase, aspartate transaminase, and α-fetoprotein, provide insight into liver function and are used during treatment of liver disease, but such information is limited. In the case of hepatocellular carcinoma (HCC), which is often not detected until an advanced stage, more sensitive biomarkers may help to achieve earlier detection. Serum also contains microRNAs, a class of small non-coding RNAs that play an important role in regulating gene expression. miR-122 is specific to the liver and correlates strongly with liver enzyme levels and necroinflammatory activity, and other microRNAs are correlated with the degree of fibrosis. miR-122 has also been found to be required for hepatitis C virus (HCV) infection, whereas other microRNAs have been shown to play antiviral roles. miR-125a-5p and miR-1231 have been shown to directly target hepatitis B virus (HBV) transcripts, and others are up- or down-regulated in infected individuals. MicroRNA profiles also differ in the case of HBV and HCV infection as well as between HBeAg-positive and negative patients, and in patients with occult versus active HBV infection. In such patients, monitoring of changes in microRNA profiles might provide earlier warning of neoplastic changes preceding HCC.

Venkatadri R, Muni T, Iyer AK, et al.
Role of apoptosis-related miRNAs in resveratrol-induced breast cancer cell death.
Cell Death Dis. 2016; 7:e2104 [PubMed] Related Publications
Breast cancer is the most frequently diagnosed cancer in women, and one of the leading causes of cancer-related deaths worldwide. Recent evidences indicate that dietary agents such as resveratrol may inhibit cancer progression through modulation of microRNAs (miRNAs). We demonstrate that resveratrol regulates apoptotic and cell cycle machinery in breast cancer cells by modulating key tumor-suppressive miRNAs including miR-125b-5p, miR-200c-3p, miR-409-3p, miR-122-5p and miR-542-3p. Resveratrol-mediated miRNA modulation regulates key anti-apoptotic and cell cycle proteins including Bcl-2, X-linked inhibitor of apoptosis protein and CDKs, which are critical for its activity. Modulating miRNAs with mimics or inhibitors further validated a key role for miR-542-3p in MCF-7 and miR-122-5p in MDA-MB-231 breast cancer cell death in response to resveratrol. In conclusion, this study reveals novel miRNAs modulated by resveratrol that have a key role in breast cancer cell death.

Zhang J, Shi H, Xue M, et al.
An insertion/deletion polymorphism in the interleukin-1A 3'untranslated region confers risk for gastric cancer.
Cancer Biomark. 2016; 16(3):359-65 [PubMed] Related Publications
OBJECTIVE: The aim of the study was to evaluate whether the insertion/deletion polymorphism (rs3783553) locating in the 3' untranslated region (3'UTRs) of IL-1A was related to the risk of gastric cancer (GC) in a Chinese population and explore the possible molecular mechanism.
METHODS: Genomic DNA was extracted from peripheral venous blood of 519 GC patients and 536 healthy control individuals. The IL-1A rs3783553 polymorphism was genotyped by using a polymerase chain reaction assay. The vectors containing the insertion or deletion allele were constructed, and luciferase assay was used to detect the effect of the polymorphism on the transcriptional activity of IL-1A.
RESULTS: Strong evidence of association was observed between the IL-1A rs3783553 polymorphism and susceptibility to GC in the study. In addition, the `TTCA' insertion allele of rs3783553 disrupts the binding site for miR-122 and miR-378, thereby increasing transcription of IL-1α in vitro.
CONCLUSION: These findings suggest that functional polymorphism rs3783553 in IL-1A could contribute to GC susceptibility, possibly or at least partially through affecting the transcriptional activity of IL-1A.

Chakraborty C, Das S
Profiling cell-free and circulating miRNA: a clinical diagnostic tool for different cancers.
Tumour Biol. 2016; 37(5):5705-14 [PubMed] Related Publications
Effective cancer management depends on early diagnosis and treatment. There are several microRNAs (miRNAs) which are used for detection of various cancers. Cell-free and circulating miRNAs originate from plasma, either from blood cells or endothelial cells. Cell-free and circulating miRNAs are very much important in the diagnosis and prognosis of cancer therapy. Admittedly, biological knowledge of extracellular miRNAs is still at its preliminary level. Recent discoveries of novel cell-free and circulating miRNAs from the body fluids are now being considered as important biomarkers that may help us in the early diagnosis of any cancer. In the present review, we highlight the biogenesis of miRNAs and their current extracellular pattern, the discovery of circulating miRNA, significant advantages, and different profiling techniques. Finally, we discuss the different circulating miRNAs such as miR-21, miR-20a, miR-155, miR‑221, miR-210, miR-218, miR-200-family, miR-141, miR-122, miR-486-5p, miR‑423-5p, miR-29a, and miR-500 for clinical diagnosis of various cancers. The present review may be beneficial for future researches concerned with miRNAs which are used for detection of various cancers.

Zhu H, Mi Y, Jiang X, et al.
Hepatocyte nuclear factor 6 inhibits the growth and metastasis of cholangiocarcinoma cells by regulating miR-122.
J Cancer Res Clin Oncol. 2016; 142(5):969-80 [PubMed] Related Publications
PURPOSE: Hepatocyte nuclear factor 6 (HNF6) is a liver-enriched transcription factor and highly expressed in mature bile duct epithelial cells. This study sought to investigate the role of HNF6, particularly the molecular mechanisms for how HNF6 is involved in the growth and metastasis of cholangiocarcinoma (CCA) cells.
METHODS: The expression of HNF6, miR-122 and key molecules was examined by Western blot analysis and real-time RT-PCR. Stable transfectants, HCCC-HNF(low) and RBE-HNF(high), were generated from human CCA HCCC-9810 and RBE cells, respectively. The regulatory effect of HNF6 on miR-122 was evaluated by luciferase reporter assay. Cell proliferation, cycle distribution, migration and invasion were analyzed. The xenograft model was used to assess the effects of HNF6 overexpression on tumorigenesis, growth, metastasis and therapeutic potentials.
RESULTS: Human CCA tissues and cells expressed lower levels of HNF6, which positively correlated with miR-122. HNF6 regulated the expression of miR-122 by stimulating its promoter. HNF6 overexpression inhibited cell proliferation by inducing cell cycle arrest at G1 phase through regulating miR-122, cyclin G1 and insulin-like growth factor-1 receptor. HNF6 inhibited the migration and invasion of CCA cells by regulating matrix metalloproteinase-2 and metalloproteinase-9, reversion-inducing-cysteine-rich protein with kazal motifs, E-cadherin and N-cadherin. Co-transfection of anti-miR-122 abrogated the effects of HNF6. HNF6 overexpression inhibited the ability of cells to form tumors and to metastasize to the lungs of mice, and the growth of established tumors.
CONCLUSIONS: The results indicate that HNF6 may serve as a tumor suppressor by regulating miR-122, and its overexpression may represent a mechanism-based therapy for CCA.

Thurnherr T, Mah WC, Lei Z, et al.
Differentially Expressed miRNAs in Hepatocellular Carcinoma Target Genes in the Genetic Information Processing and Metabolism Pathways.
Sci Rep. 2016; 6:20065 [PubMed] Free Access to Full Article Related Publications
To date, studies of the roles of microRNAs (miRNAs) in hepatocellular carcinoma (HCC) have either focused on specific individual miRNAs and a small number of suspected targets or simply reported a list of differentially expressed miRNAs based on expression profiling. Here, we seek a more in-depth understanding of the roles of miRNAs and their targets in HCC by integrating the miRNA and messenger RNA (mRNA) expression profiles of tumorous and adjacent non-tumorous liver tissues of 100 HCC patients. We assessed the levels of 829 mature miRNAs, of which 32 were significantly differentially expressed. Statistical analysis indicates that six of these miRNAs regulate a significant proportion of their in silico predicted target mRNAs. Three of these miRNAs (miR-26a, miR-122, and miR-130a) were down-regulated in HCC, and their up-regulated gene targets are primarily associated with aberrant cell proliferation that involves DNA replication, transcription and nucleotide metabolism. The other three miRNAs (miR-21, miR-93, and miR-221) were up-regulated in HCC, and their down-regulated gene targets are primarily involved in metabolism and immune system processes. We further found evidence for a coordinated miRNA-induced regulation of important cellular processes, a finding to be considered when designing therapeutic applications based on miRNAs.

Motawi TM, Sadik NA, Shaker OG, Ghaleb MH
Elevated serum microRNA-122/222 levels are potential diagnostic biomarkers in Egyptian patients with chronic hepatitis C but not hepatic cancer.
Tumour Biol. 2016; 37(7):9865-74 [PubMed] Related Publications
MicroRNAs (miRNAs) are a class of endogenous small non-coding RNAs that regulate gene expression at the post-transcriptional level. Because of their size, specificity, and relative stability in plasma, miRNAs can be used as diagnostic and prognostic biomarkers to monitor liver injury, such as that caused by hepatitis C virus (HCV) and liver cancer. In this study, we investigated miRNA expression patterns from the serum of Egyptian patients with HCV and liver cancer compared with matched healthy controls. Using microarray-based expression profiling followed by real-time quantitative polymerase chain reaction validation, we compared the levels of circulating miRNA-122 and miRNA-222 in serum from patients with hepatitis C virus (n = 40) and liver cancer (n = 60) to matched healthy controls (n = 30). MiRNA SNORD68 was the housekeeping endogenous control. We found that the serum levels of miR-122 and miR-222 were significantly elevated in HCV patients, but not in liver cancer patients, compared with controls. Receiver operating characteristic analysis revealed that miR-122 and miR-222 have a high diagnostic potential in discriminating patients with HCV from controls. Serum miR-222 was significantly higher in HCV patients compared to liver cancer patients. Our results indicate that serum miR-122 and miR-222 are elevated in Egyptian patients with chronic HCV, and these miRNAs have a strong potential to serve as novel biomarkers for liver injury but not specifically for liver cancer.

Harouaka D, Engle RE, Wollenberg K, et al.
Diminished viral replication and compartmentalization of hepatitis C virus in hepatocellular carcinoma tissue.
Proc Natl Acad Sci U S A. 2016; 113(5):1375-80 [PubMed] Free Access to Full Article Related Publications
Analysis of hepatitis C virus (HCV) replication and quasispecies distribution within the tumor of patients with HCV-associated hepatocellular carcinoma (HCC) can provide insight into the role of HCV in hepatocarcinogenesis and, conversely, the effect of HCC on the HCV lifecycle. In a comprehensive study of serum and multiple liver specimens from patients with HCC who underwent liver transplantation, we found a sharp and significant decrease in HCV RNA in the tumor compared with surrounding nontumorous tissues, but found no differences in multiple areas of control non-HCC cirrhotic livers. Diminished HCV replication was not associated with changes in miR-122 expression. HCV genetic diversity was significantly higher in livers containing HCC compared with control non-HCC cirrhotic livers. Tracking of individual variants demonstrated changes in the viral population between tumorous and nontumorous areas, the extent of which correlated with the decline in HCV RNA, suggesting HCV compartmentalization within the tumor. In contrast, compartmentalization was not observed between nontumorous areas and serum, or in controls between different areas of the cirrhotic liver or between liver and serum. Our findings indicate that HCV replication within the tumor is restricted and compartmentalized, suggesting segregation of specific viral variants in malignant hepatocytes.

Elhanati S, Ben-Hamo R, Kanfi Y, et al.
Reciprocal Regulation between SIRT6 and miR-122 Controls Liver Metabolism and Predicts Hepatocarcinoma Prognosis.
Cell Rep. 2016; 14(2):234-42 [PubMed] Related Publications
Mice overexpressing the longevity protein SIRT6 or deficient for the liver's most prevalent microRNA miR-122 display a similar set of phenotypes, including improved lipid profile and protection against damage linked to obesity. Here, we show that miR-122 and SIRT6 negatively regulate each other's expression. SIRT6 downregulates miR-122 by deacetylating H3K56 in the promoter region. MiR-122 binds to three sites on the SIRT6 3' UTR and reduces its levels. The interplay between SIRT6 and miR-122 is manifested in two physiologically relevant ways in the liver. First, they oppositely regulate a similar set of metabolic genes and fatty acid β-oxidation. Second, in hepatocellular carcinoma patients, loss of a negative correlation between SIRT6 and miR-122 expression is significantly associated with better prognosis. These findings show that SIRT6 and miR-122 negatively regulate each other to control various aspects of liver physiology and SIRT6-miR-122 correlation may serve as a biomarker for hepatocarcinoma prognosis.

Li Y, Zhao L, Shi B, et al.
Functions of miR-146a and miR-222 in Tumor-associated Macrophages in Breast Cancer.
Sci Rep. 2015; 5:18648 [PubMed] Free Access to Full Article Related Publications
Tumor-associated macrophages (TAMs) play critical roles in promoting tumor progression and invasion. However, the molecular mechanisms underlying TAM regulation remain to be further investigated and may make significant contributions to cancer treatment. Mammalian microRNAs (miRNAs) have recently been identified as important regulators of gene expression that function by repressing specific target genes mainly at the post-transcriptional level. However, systematic studies of the functions and mechanisms of miRNAs in TAMs in tumor tissues are rare. In this study, miR-146a and miR-222 were shown to be significantly decreased in TAMs associated with the up-regulated NF-κB p50 subunit. miR-146a promoted the expression of some M2 macrophage phenotype molecules, and miR-146a antagomir transfected RAW264.7 monocyte-macrophage cells inhibited 4T1 tumor growth in vivo. Meanwhile, overexpression of miR-222 inhibited TAM chemotaxis, and miR-222 in TAMs inhibited 4T1 tumor growth by targeting CXCL12 and inhibiting CXCR4. These data revealed that miRNAs influence breast tumor growth by promoting the M2 type polarization or regulating the recruitment of TAMs. These observations suggest that endogenous miRNAs may exert an important role in controlling the polarization and function of TAMs in breast cancer.

Liu N, Jiang F, He TL, et al.
The Roles of MicroRNA-122 Overexpression in Inhibiting Proliferation and Invasion and Stimulating Apoptosis of Human Cholangiocarcinoma Cells.
Sci Rep. 2015; 5:16566 [PubMed] Free Access to Full Article Related Publications
Our study investigated whether microRNA-122 (miR-122) played important roles in the proliferation, invasion and apoptosis of human cholangiocarcinoma (CC) cells. QBC939 and RBE cells lines were chosen and divided into five groups: miR-122 mimic group, anti-miR-122 group, negative control (NC) group, mock group and blank group. MiR-122 expression was measured by qRT-PCR. Roles of miR-122 in cell proliferation, apoptosis and invasion were investigated using MTT assay, flow cytometer and Transwell invasion assay, respectively. MiR-122 expression was lower in CC tissues and QBC939 cell than that in normal bile duct tissues, HCCC-9810 and RBE cells. In both QBC939 and RBE cells lines, miR-122 expression was higher in miR-122 mimic group than that in NC group, mock group and blank group; opposite results were found in anti-miR-122 group. Cell proliferation and invasion were remarkably inhibited in miR-122 mimic group after 48 h/72 h transfection, while apoptotic cells numbers were much greater in miR-122 mimic group; the opposite results were obtained from anti-miR-122 group (all P < 0.05). MiR-122 expression was significantly weaker in CC tissues, and miR-122 overexpression might play pivotal roles in inhibiting proliferation, stimulating apoptosis and suppressing invasion of CC cells, suggesting a new target for CC diagnosis and treatment.

Xu Y, Huang J, Ma L, et al.
MicroRNA-122 confers sorafenib resistance to hepatocellular carcinoma cells by targeting IGF-1R to regulate RAS/RAF/ERK signaling pathways.
Cancer Lett. 2016; 371(2):171-81 [PubMed] Related Publications
Sorafenib is the first-line treatment for advanced hepatocellular carcinoma (HCC), but the clinical response to sorafenib is seriously limited by drug resistance. In this study, we investigated the molecular mechanisms of sorafenib resistance in HCC cells. Our miRNA microarray data indicate that liver-specific miR-122 expression was significantly reduced in sorafenib-resistant cells. Overexpression of miR-122 made drug-tolerant cells sensitive to sorafenib and induced apoptosis. Insulin-like growth factor 1 receptor (IGF-1R) was validated as a target of miR-122 and was repressed by this miRNA. miR-122-induced apoptosis was repressed by the IGF-1R activator IGFI or IGFII. Conversely, the IGF-1R inhibitor PPP or NVP-AEW541 in combination with sorafenib significantly induced cell apoptosis and disrupted tolerance to drugs in vitro. These results indicated that activation of IGF-1R by ectopic down-regulation of miR-122 counteracted the effects of sorafenib-induced apoptosis, thus conferring sorafenib resistance. Further study revealed that activation of IGF-1R by miR-122 down-regulation contributed to activation of RAS/RAF/ERK signaling, which was associated with drug resistance. Our data imply that an intimate correlation between miR-122 and IGF-1R abnormal expression is a critical determinant of sorafenib tolerance.

Falcon-Perez JM, Royo F
Circulating RNA: looking at the liver through a frosted glass.
Biomarkers. 2015; 20(6-7):339-54 [PubMed] Related Publications
CONTEXT: The evaluation of the liver condition, based on serum enzymatic activity and biopsies, is insufficient. Therefore, it is a priority to find a correlation between circulating RNAs and liver damage.
METHODS: Publications were retrieved by the search terms "circulating RNA AND liver".
RESULTS: Although differences exist between studies, a profile of RNAs that repeatedly appeared as indicators of liver damage was identified.
DISCUSSION: We highlight those circulating RNAs useful to diagnostic, and discuss the transport mechanisms.
CONCLUSION: Several studies have proven that circulating RNAs are useful to establish a diagnostic and a prognosis of liver diseases.

Marrone AK, Tryndyak V, Beland FA, Pogribny IP
MicroRNA Responses to the Genotoxic Carcinogens Aflatoxin B1 and Benzo[a]pyrene in Human HepaRG Cells.
Toxicol Sci. 2016; 149(2):496-502 [PubMed] Related Publications
Recent advances in toxicogenomics present an opportunity to develop new in vitro testing methodologies to identify human carcinogens. We have investigated microRNA expression responses to the treatment of human liver HepaRG cells with the human genotoxic carcinogens aflatoxin B1 (AFB1) and benzo[a]pyrene (B[a]P), and the structurally similar compounds aflatoxin B2 (AFB2) and benzo[e]pyrene (B[e]P) that exhibit minimal carcinogenic potential. We demonstrate that treatment of HepaRG cells with AFB1 or B[a]P resulted in specific changes in the expression of miRNAs as compared with their non-carcinogenic analogues, particularly in a marked over-expression of miR-410. An additional novel finding is the dose- and time-dependent inhibition of miR-122 in AFB1-treated HepaRG cells. Mechanistically, the AFB1-induced down-regulation of miR-122 was attributed to inhibition of the HNF4A/miR-122 regulatory pathway. These results demonstrate that HepaRG cells can be used to investigate miRNA responses to xenobiotic exposure, and illustrate the existence of early non-genotoxic events, in addition to a well-established genotoxic mode of action changes, in the mechanism of AFB1 and B[a]P carcinogenicity.

Luna JM, Michailidis E, Rice CM
Mopping up miRNA: An integrated HBV transcript disrupts liver homeostasis by sequestering miR-122.
J Hepatol. 2016; 64(2):257-9 [PubMed] Related Publications

Zhu J, Wang S, Zhang W, et al.
Screening key microRNAs for castration-resistant prostate cancer based on miRNA/mRNA functional synergistic network.
Oncotarget. 2015; 6(41):43819-30 [PubMed] Free Access to Full Article Related Publications
High-throughput methods have been used to explore the mechanisms by which androgen-sensitive prostate cancer (ASPC) develops into castration-resistant prostate cancer (CRPC). However, it is difficult to interpret cryptic results by routine experimental methods. In this study, we performed systematic and integrative analysis to detect key miRNAs that contribute to CRPC development. From three DNA microarray datasets, we retrieved 11 outlier microRNAs (miRNAs) that had expression discrepancies between ASPC and CRPC using a specific algorithm. Two of the miRNAs (miR-125b and miR-124) have previously been shown to be related to CRPC. Seven out of the other nine miRNAs were confirmed by quantitative PCR (Q-PCR) analysis. MiR-210, miR-218, miR-346, miR-197, and miR-149 were found to be over-expressed, while miR-122, miR-145, and let-7b were under-expressed in CRPC cell lines. GO and KEGG pathway analyses revealed that miR-218, miR-197, miR-145, miR-122, and let-7b, along with their target genes, were found to be involved in the PI3K and AKT3 signaling network, which is known to contribute to CRPC development. We then chose five miRNAs to verify the accuracy of the analysis. The target genes of each miRNA were altered significantly upon transfection of specific miRNA mimics in the C4-2 CRPC cell line, which was consistent with our pathway analysis results. Finally, we hypothesized that miR-218, miR-145, miR-197, miR-149, miR-122, and let-7b may contribute to the development of CRPC through the influence of Ras, Rho proteins, and the SCF complex. Further investigation is needed to verify the functions of the identified novel pathways in CRPC development.

Lou G, Song X, Yang F, et al.
Exosomes derived from miR-122-modified adipose tissue-derived MSCs increase chemosensitivity of hepatocellular carcinoma.
J Hematol Oncol. 2015; 8:122 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Hepatocellular carcinoma (HCC) displays high resistance to conventional chemotherapy. Considering that microRNA-122 (miR-122) performs an essential function to promote chemosensitivity of HCC cells, an effective vehicle-mediated miR-122 delivery may represent a promising strategy for HCC chemotherapy. An increasing interest is focused on the use of exosomes as biological vehicles for microRNAs (miRNA) transfer. Mesenchymal stem cells (MSCs) are known for their capacity to produce large amounts of exosomes. This study aimed to determine whether adipose tissue-derived MSC (AMSC) exosomes can be used for miR-122 delivery.
METHODS: AMSCs were transfected with a miR-122 expression plasmid. At 48 h after transfection, AMSC-derived exosomes (122-Exo) were harvested and added to recipient HCC cells. Expression levels of miR-122 in AMSCs, exosomes, and HCC cells were quantified by real-time PCR. The mRNA and protein levels of miR-122-target genes in recipient HCC cells were quantified by real-time PCR and Western blot, respectively. The effects of 122-Exo on cell viability, apoptosis, and cell cycle of HCC cells were evaluated by MTT and flow cytometry analysis. Xenograft models were used to determine whether 122-Exo can sensitize HCC cells to sorafenib in vivo.
RESULTS: Data showed that miR-122-transfected AMSC can effectively package miR-122 into secreted exosomes, which can mediate miR-122 communication between AMSCs and HCC cells, thereby rendering cancer cells sensitive to chemotherapeutic agents through alteration of miR-122-target gene expression in HCC cells. Moreover, intra-tumor injection of 122-Exo significantly increased the antitumor efficacy of sorafenib on HCC in vivo.
CONCLUSIONS: The findings suggest that the export of miR-122 via AMSC exosomes represents a novel strategy to enhance HCC chemosensitivity.

Song K, Kwon H, Han C, et al.
Active glycolytic metabolism in CD133(+) hepatocellular cancer stem cells: regulation by MIR-122.
Oncotarget. 2015; 6(38):40822-35 [PubMed] Free Access to Full Article Related Publications
Although altered metabolic pathway is an important diagnostic maker and therapeutic target in cancer, it is poorly understood in cancer stem cells (CSCs). Here we show that the CD133 (+) hepatocellular CSCs have distinct metabolic properties, characterized by more active glycolysis over oxidative phosphorylation, compared to the CD133 (-) cells. Inhibition of PDK4 and LDHA markedly suppresses CD133 (+) stemness characteristics and overcome resistance to sorafenib (current chemotherapeutic agent for hepatocellular cancer). Addition of glucose or lactate to CD133 (-) cells promotes CSC phenotypes, as evidenced by increased CD133 (+) cell population, elevated stemness gene expression and enhanced spheroid formation. Furthermore, the liver-specific miRNA, miR-122, inhibits CSC phenotypes by regulating glycolysis through targeting PDK4. Our findings suggest that enhanced glycolysis is associated with CD133 (+) stem-like characteristics and that metabolic reprogramming through miR-122 or PDK4 may represent a novel therapeutic approach for the treatment of hepatocellular cancer.

Brunschweiger A, Gebert LF, Lucic M, et al.
Site-specific conjugation of drug-like fragments to an antimiR scaffold as a strategy to target miRNAs inside RISC.
Chem Commun (Camb). 2016; 52(1):156-9 [PubMed] Related Publications
We synthesized a miR-122 antimiR library in which drug-like fragments were site-specifically introduced to short 2'-O-methyl-RNAs. At some sites selected fragments elevated cellular antimiR activity to that of an unmodified 23mer antimiR, whereas at others the same fragments abolished activity. The potency of the antimiRs correlated with uptake into miRISC.

Poynter JN, Bestrashniy JR, Silverstein KA, et al.
Cross platform analysis of methylation, miRNA and stem cell gene expression data in germ cell tumors highlights characteristic differences by tumor histology.
BMC Cancer. 2015; 15:769 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Alterations in methylation patterns, miRNA expression, and stem cell protein expression occur in germ cell tumors (GCTs). Our goal is to integrate molecular data across platforms to identify molecular signatures in the three main histologic subtypes of Type I and Type II GCTs (yolk sac tumor (YST), germinoma, and teratoma).
METHODS: We included 39 GCTs and 7 paired adjacent tissue samples in the current analysis. Molecular data available for analysis include DNA methylation data (Illumina GoldenGate Cancer Methylation Panel I), miRNA expression (NanoString nCounter miRNA platform), and stem cell factor expression (SABiosciences Human Embryonic Stem Cell Array). We evaluated the cross platform correlations of the data features using the Maximum Information Coefficient (MIC).
RESULTS: In analyses of individual datasets, differences were observed by tumor histology. Germinomas had higher expression of transcription factors maintaining stemness, while YSTs had higher expression of cytokines, endoderm and endothelial markers. We also observed differences in miRNA expression, with miR-371-5p, miR-122, miR-302a, miR-302d, and miR-373 showing elevated expression in one or more histologic subtypes. Using the MIC, we identified correlations across the data features, including six major hubs with higher expression in YST (LEFTY1, LEFTY2, miR302b, miR302a, miR 126, and miR 122) compared with other GCT.
CONCLUSIONS: While prognosis for GCTs is overall favorable, many patients experience resistance to chemotherapy, relapse and/or long term adverse health effects following treatment. Targeted therapies, based on integrated analyses of molecular tumor data such as that presented here, may provide a way to secure high cure rates while reducing unintended health consequences.

Voigtländer T, Gupta SK, Thum S, et al.
MicroRNAs in Serum and Bile of Patients with Primary Sclerosing Cholangitis and/or Cholangiocarcinoma.
PLoS One. 2015; 10(10):e0139305 [PubMed] Free Access to Full Article Related Publications
BACKGROUND AND AIM: Patients with primary sclerosing cholangitis (PSC) are at high risk for the development of cholangiocarcinoma (CC). Analysis of micro ribonucleic acid (MiRNA) patterns is an evolving research field in biliary pathophysiology with potential value in diagnosis and therapy. Our aim was to evaluate miRNA patterns in serum and bile of patients with PSC and/or CC.
METHODS: Serum and bile from consecutive patients with PSC (n = 40 (serum), n = 52 (bile)), CC (n = 31 (serum), n = 19 (bile)) and patients with CC complicating PSC (PSC/CC) (n = 12 (bile)) were analyzed in a cross-sectional study between 2009 and 2012. As additional control serum samples from healthy individuals were analyzed (n = 12). The miRNA levels in serum and bile were determined with global miRNA profiling and subsequent miRNA-specific polymerase chain reaction-mediated validation.
RESULTS: Serum analysis revealed significant differences for miR-1281 (p = 0.001), miR-126 (p = 0.001), miR-26a (p = 0.001), miR-30b (p = 0.001) and miR-122 (p = 0.034) between patients with PSC and patients with CC. All validated miRNAs were significantly lower in healthy individuals. MiR-412 (p = 0.001), miR-640 (p = 0.001), miR-1537 (p = 0.003) and miR-3189 (p = 0.001) were significantly different between patients with PSC and PSC/CC in bile.
CONCLUSIONS: Patients with PSC and/or CC have distinct miRNA profiles in serum and bile. Furthermore, miRNA concentrations are different in bile of patients with CC on top of PSC indicating the potential diagnostic value of these miRNAs.

Liang HW, Wang N, Wang Y, et al.
Hepatitis B virus-human chimeric transcript HBx-LINE1 promotes hepatic injury via sequestering cellular microRNA-122.
J Hepatol. 2016; 64(2):278-91 [PubMed] Related Publications
BACKGROUND & AIMS: Chronic hepatitis B virus (HBV) carriers have a high risk to develop hepatocellular carcinoma (HCC) but the underlying mechanism remains unclear. Recent studies suggest that viral-human hybrid RNA transcripts, which play a critical role in promoting HCC progression, may be the molecules responsible for the development of HCC in HBV infected patients. Here we determine whether HBx-LINE1, a hybrid RNA transcript of the human LINE1 and the HBV-encoded X gene generated in tumor cells of HBV-positive HCC, can serve as a molecular sponge for sequestering miR-122 and promoting liver cell abnormal mitosis and mouse hepatic injury.
METHODS: Paired tumor and distal normal liver tissue specimens, as well as HBx-LINE1 overexpressing hepatic cells, were used to test the relationship between HBx-LINE1 and miR-122. Levels of HBx-LINE1 and miR-122 were assayed by qRT-PCR and Northern blot. HBx-LINE1-miR-122 binding was analyzed by luciferase reporter assay. Mouse hepatic injury was monitored by tissue staining and serum aspartate transaminase, alanine aminotransferase and total bilirubin measurement.
RESULTS: HBx-LINE1 in HBV-positive HCC tissues was inversely correlated with miR-122. Each HBx-LINE1 consists of six miR-122-binding sites, and forced expression of HBx-LINE1 effectively depleted cellular miR-122, promoting hepatic cell epithelial-mesenchymal transition (EMT)-like changes, including β-catenin signaling activation, E-cadherin reduction and cell migration enhancement. Mice administered with HBx-LINE1 display a significant mouse liver cell abnormal mitosis and hepatic injury. However, all these effects of HBx-LINE1 are completely abolished by miR-122.
CONCLUSIONS: Our finding illustrates a previously uncharacterized miR-122-sequestering mechanism by which HBx-LINE1 promotes hepatic cell EMT-like changes and mouse liver injury.

Ma D, Jia H, Qin M, et al.
MiR-122 Induces Radiosensitization in Non-Small Cell Lung Cancer Cell Line.
Int J Mol Sci. 2015; 16(9):22137-50 [PubMed] Free Access to Full Article Related Publications
MiR-122 is a novel tumor suppresser and its expression induces cell cycle arrest, or apoptosis, and inhibits cell proliferation in multiple cancer cells, including non-small cell lung cancer (NSCLC) cells. Radioresistance of cancer cell leads to the major drawback of radiotherapy for NSCLC and the induction of radiosensitization could be a useful strategy to fix this problem. The present work investigates the function of miR-122 in inducing radiosensitization in A549 cell, a type of NSCLC cells. MiR-122 induces the radiosensitization of A549 cells. MiR-122 also boosts the inhibitory activity of ionizing radiation (IR) on cancer cell anchor-independent growth and invasion. Moreover, miR-122 reduced the expression of its targeted genes related to tumor-survival or cellular stress response. These results indicate that miR-122 would be a novel strategy for NSCLC radiation-therapy.

Sohn W, Kim J, Kang SH, et al.
Serum exosomal microRNAs as novel biomarkers for hepatocellular carcinoma.
Exp Mol Med. 2015; 47:e184 [PubMed] Free Access to Full Article Related Publications
Recent studies have shown that circulating microRNAs are a potential biomarker in various types of malignancies. The aim of this study was to investigate the feasibility of using serum exosomal microRNAs as novel serological biomarkers for hepatocellular carcinoma (HCC) in patients with chronic hepatitis B (CHB). We measured the serum exosomal microRNAs and serum circulating microRNAs in patients with CHB (n=20), liver cirrhosis (LC) (n=20) and HCC (n=20). Serum exosomal microRNA was extracted from 500 μl of serum using an Exosome RNA Isolation kit. The expression levels of microRNAs were quantified by real-time PCR. The expression levels of selected microRNAs were normalized to Caenorhabditis elegans microRNA (Cel-miR-39). The serum levels of exosomal miR-18a, miR-221, miR-222 and miR-224 were significantly higher in patients with HCC than those with CHB or LC (P<0.05). Further, the serum levels of exosomal miR-101, miR-106b, miR-122 and miR-195 were lower in patients with HCC than in patients with CHB (P=0.014, P<0.001, P<0.001 and P<0.001, respectively). There was no significant difference in the levels of miR-21 and miR-93 among the three groups. Additionally, the serum levels of circulating microRNAs showed a smaller difference between HCC and either CHB or LC. This study suggests that serum exosomal microRNAs may be used as novel serological biomarkers for HCC.

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