MIRLET7G

Locus Summary

Gene:MIRLET7G; microRNA let-7g
Aliases: LET7G, let-7g, MIRNLET7G, hsa-let-7g
Location:3p21.2
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: 02 September, 2019

Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 02 September 2019 using data from PubMed using criteria.

Literature Analysis

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

Tag cloud generated 02 September, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (7)

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

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

MicroRNA Function

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

TissueTarget Gene(s)Regulator(s)MIRLET7G Function in CancerEffect
lung (2)
-non-small cell lung cancer (2)
HMGA2 (1)
inhibit cell migration (1)
induce cell cycle arrest (1)
induce cell death (1)
inhibit cell proliferation (1)
tumor-suppressive (2)
liver (2)
-hepatocellular carcinoma (2)
BCL2L1 (1)
COL1A2 (1)
promote sorafenib-induced apoptosis (1)
inhibit cell migration (1)
inhibit cell growth (1)
tumor-suppressive (2)
breast (1)
-breast cancer (1)
GAB2 (1)
FN1 (1)
EGF (1)
estrogen (1)
inhibit metastasis (1)
inhibit cell invasion (1)
tumor-suppressive (1)

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

Latest Publications: MIRLET7G (cancer-related)

Chen L, Liu S, Li K, et al.
Evaluation of microRNA expression profiling in highly metastatic laryngocarcinoma cells.
Acta Otolaryngol. 2018; 138(12):1105-1111 [PubMed] Related Publications
BACKGROUND: Until now, little is known about the role of miRNAs in the invasion and metastasis of Laryngeal squamous cell carcinoma (LSCC).
OBJECTIVES: This study aimed to explore the relationship between microRNA and the invasion and metastasis of LSCC.
MATERIAL AND METHODS: The highly metastatic laryngocarcinoma cells were obtained from the established animal model with spontaneous lymph node metastasis of LSCC in our previous study. MicroRNA expression profiling and bioinformatic analysis were performed to analyze the microRNA expression changes in the highly metastatic laryngocarcinoma cells and the parental tumor cells (HEP-2). RT-PCR was performed for further validation of the result of microarray.
RESULTS: A total of 40 microRNAs were found to be significantly altered in the highly metastatic laryngocarcinoma cells compared to controls. Bioinformatic analysis identified that 19 key microRNAs might involve in LSCC development. Moreover, RT-PCR confirmed that miR-25, miR-100, miR-125b-5p and let-7g were differentially expressed in different laryngocarcinoma cells and human tumor specimens.
CONCLUSIONS AND SIGNIFICANCE: Our findings suggest that microRNA play an important role in the invasion and metastasis of LSCC, and provide the clues for studying the function of microRNA as well as opportunities to analyze the complex molecular abnormalities driving LSCC progression.

Zhou JL, Deng S, Fang HS, et al.
Hsa-let-7g promotes osteosarcoma by reducing HOXB1 to activate NF-kB pathway.
Biomed Pharmacother. 2019; 109:2335-2341 [PubMed] Related Publications
MicroRNA (miRNA) is known to be involved in regulating the proliferation, migration and apoptosis of cancer cells in osteosarcoma. In this study, We aim to explore the expression of hsa-let-7 g and its role in pathogenesis of osteosarcoma. By analyzing clinical data. We found high expression of hsa-let-7 g in patients with osteosarcoma. The patients with higher expression of hsa-let-7 g showed poorer prognosis and lower survival rate. After downregulation of hsa-let-7 g in cell model and animal model, we found that with downregulation of hsa-let-7 g, the proliferation of osteosarcoma cells was significantly reduced, the level of migration and invasion was down-regulated, the cell cycle was inhibited, and cell apoptosis was increased. Through Dual Luciferase Reporter, immunohistochemistry, western blot and other experiments, it was found that hsa-let-7 g down-regulated HOXB1 gene and activated NF-kB pathway to promote the development of osteosarcoma. In conclusion, hsa-let-7 g is highly expressed in osteosarcoma tissues, and high expression of hsa-let-7 g can promote the occurrence of osteosarcoma by down-regulating HOXB1 and activating NF-kB pathway.

Svedman FC, Lohcharoenkal W, Bottai M, et al.
Extracellular microvesicle microRNAs as predictive biomarkers for targeted therapy in metastastic cutaneous malignant melanoma.
PLoS One. 2018; 13(11):e0206942 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Mitogen activated-protein kinase pathway inhibitors (MAPKis) improve treatment outcome in patients with disseminated BRAFV600 mutant cutaneous malignant melanoma (CMM) but responses are of limited duration due to emerging resistance. Although extensive research in mechanisms of resistance is being performed, predictive biomarkers for durable responses are still lacking. We used miRNA qPCR to investigate if different levels of extracellular microvesicle microRNA (EV miRNA) in matched plasma samples collected from patients with metastatic IV BRAFV600 mutated CMM before, during and after therapy with MAPKis could serve as predictive biomarkers.
MATERIALS AND METHODS: EV miRNAs were extracted from plasma samples from 28 patients collected before and during therapy, measured by quantitative PCR-array and correlated to therapy outcome.
RESULTS: Increased levels of EV let-7g-5p during treatment compared to before treatment (EV let-7g-5p_delta) were associated with better disease control with MAPKis (odds ratio 8568.4, 95% CI = 4.8-1.5e+07, P = 0.000036). Elevated levels of EV miR-497-5p during therapy were associated with prolonged progression free survival (PFS) (hazard ratio = 0.27, 95% CI = 0.13-0.52, P <0.000061).
CONCLUSIONS: EV miRNAs let-7g-5p and miR-497-5p were identified as putative novel predictive biomarkers of MAPKi treatment benefit in metastatic CMM patients highlighting the potential relevance of assessing EV miRNA during and after treatment to unravel novel mechanisms of resistance.

Latchana N, DiVincenzo MJ, Regan K, et al.
Alterations in patient plasma microRNA expression profiles following resection of metastatic melanoma.
J Surg Oncol. 2018; 118(3):501-509 [PubMed] Free Access to Full Article Related Publications
BACKGROUND AND OBJECTIVES: MicroRNAs (miRs) are noncoding RNAs that regulate protein translation and melanoma progression. Changes in plasma miR expression following surgical resection of metastatic melanoma are under-investigated. We hypothesize differences in miR expression exist following complete surgical resection of metastatic melanoma.
METHODS: Blood collection pre- and post-surgical resection was performed in six individuals with solitary melanoma metastases. miR expression in extracted RNA was quantified using the NanoString nCounter Digital Analyzer.
RESULTS: Pre- and post-surgical plasma samples contained 216 miRs with expression above baseline. Comparison of postsurgical to preresection samples revealed differential expression of 25 miRs: miR-let-7a, miR-let7g, miR-15a, miR-16, miR-22, miR-30b, miR-126, miR-140, miR-145, miR-148a, miR-150-5p, miR-191, miR-378i, miR-449c, miR-494, miR-513b, miR-548aa, miR-571, miR-587, miR-891b, miR-1260a, miR 1268a, miR-1976, miR-4268, miR-4454 (P < 0.05). Utilizing P < 0.0046 as a cutoff to control for one false positive among the 216 miRs revealed that postsurgical melanoma plasma samples had upregulation of miR-1260a (P = 0.0007) and downregulation of miR-150-5p (P = 0.0026) relative to pre-surgical samples.
CONCLUSIONS: Differential expression of miR-150-5p and miR-1260a is present in plasma following surgical resection of metastatic melanoma in this small sample (n = 6) of melanoma patients. Therefore, further investigation of these plasma miRs as noninvasive biomarkers for melanoma is warranted.

Sim J, Kim Y, Kim H, et al.
Identification of recurrence-associated microRNAs in stage I lung adenocarcinoma.
Medicine (Baltimore). 2018; 97(25):e10996 [PubMed] Free Access to Full Article Related Publications
Lung cancer is the most common cause of cancer-associated death worldwide. Postoperative relapse and subsequent metastasis result in a high mortality rate, even in early stage lung cancer. MicroRNAs (miRNAs) are small non-coding RNAs that regulate gene expression at the post-transcriptional level and are frequently dysregulated in various cancers. The aim of this study was to identify recurrence-associated miRNAs in early stage lung cancer. To screen for differentially expressed miRNAs related to postoperative recurrence, miRNA microarray data derived from stage I lung adenocarcinoma formalin-fixed paraffin-embedded (FFPE) tissue samples (n = 6) and publically available the Cancer Genome Atlas (TCGA) data were analyzed. An independent sample (n = 29) was used to validate candidate miRNAs by quantitative real-time polymerase chain reaction (qRT-PCR). In miRNA expression profiling, we identified 60 significantly dysregulated miRNAs in the relapsed group. Additionally, 20 dysregulated miRNAs were found using TCGA data set. Three miRNAs (let-7g-5p, miR-143-3p, and miR-374a-5p) were associated with postoperative recurrence in both microarray and TCGA data sets. All 3 candidate miRNAs were validated in the independent cohort of stage I adenocarcinoma by qRT-PCR. We discovered 3 recurrence-associated miRNAs of stage I lung adenocarcinoma samples using FFPE tissue, which showed possible clinical utility as biomarkers predicting recurrence after curative surgery. Further investigation of the functional properties of these miRNAs is needed.

Pero-Gascon R, Sanz-Nebot V, Berezovski MV, Benavente F
Analysis of Circulating microRNAs and Their Post-Transcriptional Modifications in Cancer Serum by On-Line Solid-Phase Extraction-Capillary Electrophoresis-Mass Spectrometry.
Anal Chem. 2018; 90(11):6618-6625 [PubMed] Related Publications
In this paper, an on-line solid-phase extraction capillary electrophoresis-mass spectrometry (SPE-CE-MS) method is described for the purification, preconcentration, separation, and characterization of endogenous microRNA (miRNA) and their post-transcriptional modifications in serum. First, analysis by CE-MS was optimized using a standard mixture of hsa-miR-21-5p (miR-21-5p) and hsa-let-7g-5p (let-7g-5p). For SPE-CE-MS, a commercial silicon carbide (SiC) resin was used to prepare the microcartridges. Under the optimized conditions with standards, the microcartridge lifetime (>25 analyses) and repeatability (2.8% RSD for the migration times; 4.4 and 6.4% RSD for the miR-21-5p and let-7g-5p peak areas, respectively) were good, the method was linear between 25 and 100 nmol·L

Zamora-Contreras AM, Alvarez-Salas LM
Let-7 miRNA Precursors Co-express with LIN28B in Cervical Cells.
Microrna. 2018; 7(1):62-71 [PubMed] Related Publications
BACKGROUND: The let-7 microRNAs (miRNAs) are frequently dysregulated in carcinogenic processes, including cervical cancer. LIN28 proteins regulate let-7 biogenesis by binding to conserved sequences within the pre-miRNA structure. Nevertheless, recent research has shown that some let-7 miRNAs may escape LIN28 regulation.
OBJECTIVE: Correlate pre-let-7 miRNAs and LIN28B levels in cervical cell lines with different malignancy and HPV content.
METHODS: Pre-let-7 levels were determined by RTqPCR. LIN28B and other let-7 targets were analyzed by immunoblot. In silico tools were used to correlate let-7 and LIN28B expression and to analyze prelet- 7 sequences and structures.
RESULTS: Lin28B protein was detected in all tested cell lines although it was more expressed in tumor cell lines. High levels of pre-let-7c/f-1 and pre-miR-98 were present in almost all cell lines regardless malignancy and LIN28B expression. Pre-let-7g/i were mainly expressed in tumor cell lines, pre-let-7e and pre-let-7-a3 were absent in all cell lines and pre-let-7a-2 showed indistinct expression. LIN28B showed positive correlation with pre-let-7i/g/f-1 and pre-miR-98 in tumor cell lines, suggesting escape from regulation. Sequence alignment and analysis of pre-let-7 miRNAs showed distinctive structural features within the preE region that may influence the ideal pre-let-7 structuring for LIN28B interaction. Short preE-stems were present in pre-let-7 that may escape LIN28B regulation, but long preEstems were mostly associated with high-level pre-let-7 miRNAs.
CONCLUSION: The observed differences of pre-let-7 levels in cervical cell lines may be the result of alternative preE structuring affecting interaction with LIN28B thus resulting in differential let-7 regulation.

Qu TT, Chen F, Wang J, et al.
PCAF-mediated acetylation of Lin28B increases let-7 biogenesis in lung adenocarcinoma H1299 cells.
BMC Cancer. 2018; 18(1):27 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Lin28B and its paralog Lin28A are small RNA binding proteins that have similar inhibitory effects, although they target separate steps in the maturation of let-7 miRNAs in mammalian cells. Because Lin28B participates in the promotion and development of tumors mostly by blocking the let-7 tumor suppressor family members, we sought to explore the associated mechanisms to gain insights into how Lin28B might be decreased in human cancer cells to increase let-7 levels and reverse malignancy.
RESULTS: We demonstrated that the histone acetyltransferase PCAF, via its cold shock domain, directly interacts with and subsequently acetylates Lin28B in lung adenocarcinoma-derived H1299 cells. RT-qPCR assays showed that both let-7a-1 and let-7g were increased in PCAF-transfected H1299 cells. Lin28B is acetylated by ectopic PCAF and translocates from the nucleus to the cytoplasm in H1299 cells.
CONCLUSIONS: The effects of acetylated Lin28B on let-7a-1 and let-7g are similar to that of stable knockdown of Lin28B in H1299 cells. The new role of PCAF in mediating Lin28B acetylation and the specific release of its target microRNAs in H1299 cells may shed light on the potential application of let-7 in the clinical treatment of lung cancer patients.

Cai X, Wang X, Cao C, et al.
HBXIP-elevated methyltransferase METTL3 promotes the progression of breast cancer via inhibiting tumor suppressor let-7g.
Cancer Lett. 2018; 415:11-19 [PubMed] Related Publications
Methyltransferase-like 3 (METTL3) is involved in RNA metabolism through N6-methyladenosine (m

López-Aguilar JE, Velázquez-Flores MA, Simón-Martínez LA, et al.
Circulating microRNAs as Biomarkers for Pediatric Astrocytomas.
Arch Med Res. 2017; 48(4):323-332 [PubMed] Related Publications
BACKGROUND AND AIMS: Since MicroRNAs (miRNAs) are potent regulators of gene expression, their expression and function alterations are associated with different types of cancer, including pediatric astrocytoma. Since the secretion of miRNAs by tumors into corporal fluids has made it possible to identify biomarkers in cancer, their deter mination in pediatric astrocytoma is vital. In order to gain insight into the mechanisms controlled by miRNAs in these neoplasms, we tested the expression of miRNAs 130a, 145, 335, 1303, and let-7g-3p by qPCR in tumors and blood serum from pediatric patients with astrocytoma. The data was analyzed with the DIANA-miRPath v3.0 platform.
RESULTS: The data represented expression changes of all mirRNAs tested in both tumors and blood serum, which strongly suggest their use as circulating biomarkers for astrocytic tumors. The bioinformatic analysis -with DIANA-miRPath v3.0- showed the involvement of these miRNAs in extracellular matrix (ECM)-receptor interaction and proteoglycans in cancer, which control many hallmarks of cancer. In fact, the expression of the proteoglycan syndecan 4 (SDC4) and that of its biosynthetic enzymes, Exostosin Glycosyltransferase 1 (EXT1) and Xylosyltransferase 1 (XYLT1), were altered in pediatric astrocytoma.
CONCLUSIONS: Our results highlight the role of microRNAs in the biology of pediatric astrocytoma and demonstrated for the first time the potential use of some circulating microRNAs as non-invasive biomarkers for this type of tumors, particularly miRs 130a, 145, and 335.

Yuan GQ, Wei NL, Mu LY, et al.
A 4-miRNAs signature predicts survival in glioblastoma multiforme patients.
Cancer Biomark. 2017; 20(4):443-452 [PubMed] Related Publications
BACKGROUND: Although O(6)-methylguanine DNA methyltransferase (MGMT) promoter methylation status is an important marker for glioblastoma multiforme (GBM), there is considerable variability in the clinical outcome of patients with similar methylation profles.
OBJECTIVE: We examined whether a MicroRNA (miRNA) signature can be identified for predicting clinical outcomes and helping in treatment decisions.
METHODS: The differentially expressed miRNAs were evaluated in 6 pairs of short- (⩽ 450 days) and long-term survivors (> 450 days) by using microarray. Real time quantitative PCR (qRT-PCR) was applied to further verify screened miRNAs with a greater number of samples (n= 48). Meanwhile, functional interpretation of miRNA profile was carried out based on miRNA-target databases. In addition, MGMT promoter methylation status was tested by means of pyrosequencing (PSQ) testing.
RESULTS: Six miRNAs were upregulated in the long-term survival group (fold change ⩾ 2.0, P< 0.05). The further verification by qRT-PCR indicated that the increase in let-7g-5p, miR-139-5p, miR-17-5p and miR-9-3p level in long-term survivors was statistically significant. Kaplan-Meier survival analysis showed that high expression of a prognostic 4-miRNA signature was significantly associated with good patient survival (p= 0.0012). The signature regulated signaling pathways including Calcium, MAPK, ErbB, mTOR and cell cycle involved in carcinogenesis from glial progenitor cell to primary GBM.
CONCLUSIONS: The 4-miRNA signature was identified as an independent prognostic biomarker that identified patients who have a favorable outcome.

Yerukala Sathipati S, Ho SY
Identifying the miRNA signature associated with survival time in patients with lung adenocarcinoma using miRNA expression profiles.
Sci Rep. 2017; 7(1):7507 [PubMed] Free Access to Full Article Related Publications
Lung adenocarcinoma is a multifactorial disease. MicroRNA (miRNA) expression profiles are extensively used for discovering potential theranostic biomarkers of lung cancer. This work proposes an optimized support vector regression (SVR) method called SVR-LUAD to simultaneously identify a set of miRNAs referred to the miRNA signature for estimating the survival time of lung adenocarcinoma patients using their miRNA expression profiles. SVR-LUAD uses an inheritable bi-objective combinatorial genetic algorithm to identify a small set of informative miRNAs cooperating with SVR by maximizing estimation accuracy. SVR-LUAD identified 18 out of 332 miRNAs using 10-fold cross-validation and achieved a correlation coefficient of 0.88 ± 0.01 and mean absolute error of 0.56 ± 0.03 year between real and estimated survival time. SVR-LUAD performs well compared to some well-recognized regression methods. The miRNA signature consists of the 18 miRNAs which strongly correlates with lung adenocarcinoma: hsa-let-7f-1, hsa-miR-16-1, hsa-miR-152, hsa-miR-217, hsa-miR-18a, hsa-miR-193b, hsa-miR-3136, hsa-let-7g, hsa-miR-155, hsa-miR-3199-1, hsa-miR-219-2, hsa-miR-1254, hsa-miR-1291, hsa-miR-192, hsa-miR-3653, hsa-miR-3934, hsa-miR-342, and hsa-miR-141. Gene ontology annotation and pathway analysis of the miRNA signature revealed its biological significance in cancer and cellular pathways. This miRNA signature could aid in the development of novel therapeutic approaches to the treatment of lung adenocarcinoma.

Fedorko M, Juracek J, Stanik M, et al.
Detection of let-7 miRNAs in urine supernatant as potential diagnostic approach in non-metastatic clear-cell renal cell carcinoma.
Biochem Med (Zagreb). 2017; 27(2):411-417 [PubMed] Free Access to Full Article Related Publications
INTRODUCTION: Urinary microRNAs (miRNAs) are emerging as a clinically useful tool for early and non-invasive detection of various types of cancer. The aim of this study was to evaluate whether let-7 family miRNAs differ in their urinary concentrations between renal cell carcinoma (RCC) cases and healthy controls.
MATERIALS AND METHODS: In the case-control study, 69 non-metastatic clear-cell RCC patients and 36 gender/age-matched healthy controls were prospectively enrolled. Total RNA was purified from cell-free supernatant of the 105 first morning urine specimens. Let-7 family miRNAs were determined in cell-free supernatant using quantitative miRNA real-time reverse-transcription PCR and absolute quantification approach.
RESULTS: Concentrations of all let-7 miRNAs (let-7a, let-7b, let-7c, let-7d, let-7e and let-7g) were significantly higher in urine samples obtained from RCC patients compared to healthy controls (P < 0.001; P < 0.001; P = 0.005; P = 0.006; P = 0.015 and P = 0.002, respectively). Subsequent ROC analysis has shown that let-7a concentration possesses good ability to differentiate between cases and controls with area under curve being 0.8307 (sensitivity 71%, specificity 81%).
CONCLUSIONS: We have shown that let-7 miRNAs are abundant in the urine samples of patients with clear-cell RCC, and out of six let-7 family members, let-7a outperforms the others and presents promising non-invasive biomarker for the detection of RCC.

Greither T, Vorwerk F, Kappler M, et al.
Salivary miR-93 and miR-200a as post-radiotherapy biomarkers in head and neck squamous cell carcinoma.
Oncol Rep. 2017; 38(2):1268-1275 [PubMed] Related Publications
Head and neck squamous cell carcinoma is the 6th most malignant tumor entity worldwide and has exhibited a 5-year mortality of approximately 50% for the last fifty years. For the therapy monitoring and successful management of this tumor entity new and easily accessible biomarkers are greatly needed. The aim of the study was to determine whether and to what extent microRNAs, a class of small regulatory RNAs, are detectable in saliva post-radiation therapy. The expression and feasibility as therapy monitoring marker of the microRNAs were analyzed by RT-qPCR in 83 saliva samples from 33 patients collected at several time points pre-, during and post-radiotherapy treatment. Ten head and neck squamous cell carcinoma- or radiation-associated microRNAs (miR-93, miR-125a, miR-142-3p, miR-200a, miR-203, miR-213, let-7a, let-7b, let-7g and let-7i) were analyzed. All were detectable to a different extent in the saliva of the patients. miR-93 and miR-200a were significantly higher expressed 12 months post-radiotherapy than at baseline (p=0.047 and p=0.036). These results point towards miR-93 and miR-200a as biomarkers for the treatment monitoring post-radiation of head and neck squamous cell carcinoma.

Monzo M, Santasusagna S, Moreno I, et al.
Exosomal microRNAs isolated from plasma of mesenteric veins linked to liver metastases in resected patients with colon cancer.
Oncotarget. 2017; 8(19):30859-30869 [PubMed] Free Access to Full Article Related Publications
Before reaching a peripheral vein (PV), miRNAs released by the tumor are diluted and dispersed throughout the body or even retained in a specific organ. We hypothesized that blood drawn from the tumor-draining vein could provide more homogeneous information than blood drawn from the PV as that blood would contain all the biomarkers released by the tumor before they reach a potential metastatic site. We have profiled 754 miRNAs in 15 colon cancer plasma samples from the tumor-draining vein, the mesenteric vein (MV), identifying 13 microRNAs associated with relapse. The prognostic impact of these miRNAs were validated in 50 MV and 50 paired PV plasma samples of stage I-III colon cancer patients. Four miRNAs, let-7g, miR-15b, miR-155 and miR-328, were found overexpressed in MV compared to PV, and patients with high levels of those miRNAs in MV plasma had shorter time to relapse. Interestingly, in patients developing liver metastases, the exosomal cargo of miR-328 was much greater in MV than in PV plasma indicating a possible role of miR-328 in the development of liver metastases. Our results indicate that in colon cancer, the primary tumor releases high concentrations of miRNAs through the MV, and some of them are contained in tumor derived exosomes.

Zheng Q, Chen C, Guan H, et al.
Prognostic role of microRNAs in human gastrointestinal cancer: A systematic review and meta-analysis.
Oncotarget. 2017; 8(28):46611-46623 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Gastrointestinal cancers (GICs) mainly including esophageal, gastric and colorectal cancer, are the most common cause of cancer-related death and lead into high mortality worldwide. We performed this systematic review and meta-analysis to elucidate relationship between multiple microRNAs (miRs) expression and survival of GIC patients.
METHODS: We searched a wide range of database. Fixed-effects and random-effects models were used to calculate the pooled hazard ratio values of overall survival and disease free survival. In addition, funnel plots were used to qualitatively analyze the publication bias and verified by Begg's test while it seems asymmetry.
RESULTS: 60 studies involving a total of 6225 patients (1271 with esophageal cancer, 3467 with gastric cancer and 1517 with colorectal cancer) were included in our meta-analysis. The pooled hazard ratio values of overall survival related to different miRs expression in esophageal, gastric, colorectal and gastrointestinal cancer were 2.10 (1.78-2.49), 2.02 (1.83-2.23), 2.54 (2.14-3.02) and 2.15 (1.99-2.31), respectively. We have identified a total of 59 miRs including 23 significantly up-regulated expression miRs (miR-214, miR-17, miR-20a, miR-200c, miR-107, miR-27a, etc.) and 36 significantly down-regulated expression miRs (miR-433, let-7g, miR-125a-5p, miR-760, miR-206, miR-26a, miR-200b, miR-185, etc.) correlated with poor prognosis in GIC patients. Moreover, 35 of them revealed mechanisms.
CONCLUSION: Overall, specific miRs are significantly associated with the prognosis of GIC patients and potentially eligible for the prediction of patients survival. It also provides a potential value for clinical decision-making development and may serve as a promising miR-based target therapy waiting for further elucidation.

Moridikia A, Mirzaei H, Sahebkar A, Salimian J
MicroRNAs: Potential candidates for diagnosis and treatment of colorectal cancer.
J Cell Physiol. 2018; 233(2):901-913 [PubMed] Related Publications
Colorectal cancer (CRC) is known as the third common cancer worldwide and an important public health problem in different populations. Several genetics and environmental risk factors are involved in the development and progression of CRC including chromosomal abnormalities, epigenetic alterations, and unhealthy lifestyle. Identification of risk factors and biomarkers could lead to a better understanding of molecular pathways involved in CRC pathogenesis. MicroRNAs (miRNAs) are important regulatory molecules which could affect a variety of cellular and molecular targets in CRC. A large number of studies have indicated deregulations of some known tissue-specific miRNAs, for example, miR-21, miR-9, miR-155, miR-17, miR-19, let-7, and miR-24 as well as circulating miRNAs, for example, miR-181b, miR-21, miR-183, let-7g, miR-17, and miR-126, in patients with CRC. In the current review, we focus on the findings of preclinical and clinical studies performed on tissue-specific and circulating miRNAs as diagnostic biomarkers and therapeutic targets for the detection of patients at various stages of CRC.

Zhang XH, Qian Y, Li Z, et al.
Let-7g-5p inhibits epithelial-mesenchymal transition consistent with reduction of glioma stem cell phenotypes by targeting VSIG4 in glioblastoma.
Oncol Rep. 2016; 36(5):2967-2975 [PubMed] Related Publications
Epithelial-mesenchymal transition (EMT) and stem-like glioma cells display hallmark therapeutic resistance. Understanding of the mechanisms underlying these properties will be vital for the development of effective therapies. In this study, we found that VSIG4 protein is upregulated in glioblastoma. Overexpressing VSIG4 induced EMT and significantly promoted invasion and migration in glioblastoma U-87MG cells. Moreover, we showed that its overexpression promoted formation of glioma stem cell phenotypes in U-87MG cells. P4HB, VAMP8 and Connexin 43 (CX43) can promote temozolomide (TMZ) resistance in human glioma cells. We showed that P4HB, VAMP8 and CX43 protein were upregulated by VSIG4 in U-87MG cells, implying its upregulation might be a cause for temozolomide resistance. We found that let-7g-5p can inhibit VSIG4 protein expression, but it cannot degrade VSIG4 mRNA in U-87MG cells. Contrary to VSIG4, we demonstrated that overexpressing let-7g-5p promoted mesenchymal-epithelial transition (MET) and significantly inhibited invasion and migration consistent with the reduction of glioblastoma stem cell phenotypes in U-87MG cells. Thus, we concluded that let-7g-5p inhibits epithelial-mesenchymal transition (EMT) consistent with reduction of glioma stem cell (GSC) phenotypes by targeting VSIG4 in glioblastoma.

Kumar S, Reddy PH
Are circulating microRNAs peripheral biomarkers for Alzheimer's disease?
Biochim Biophys Acta. 2016; 1862(9):1617-27 [PubMed] Free Access to Full Article Related Publications
Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by memory loss, multiple cognitive abnormalities and intellectual impairments. Currently, there are no drugs or agents that can delay and/or prevent the progression of disease in elderly individuals, and there are no peripheral biomarkers that can detect AD early in its pathogenesis. Research has focused on identifying biomarkers for AD so that treatment can be begun as soon as possible in order to restrict or prevent intellectual impairments, memory loss, and other cognitive abnormalities that are associated with the disease. One such potential biomarker is microRNAs that are found in circulatory biofluids, such as blood and blood components, serum and plasma. Blood and blood components are primary sources where miRNAs are released in either cell-free form and then bind to protein components, or are in an encapsulated form with microvesicle particles. Exosomal miRNAs are known to be stable in biofluids and can be detected by high throughput techniques, like microarray and RNA sequencing. In AD brain, enriched miRNAs encapsulated with exosomes crosses the blood brain barrier and secreted in the CSF and blood circulations. This review summarizes recent studies that have identified miRNAs in the blood, serum, plasma, exosomes, cerebral spinal fluids, and extracellular fluids as potential biomarkers of AD. Recent research has revealed only six miRNAs - miR-9, miR-125b, miR-146a, miR-181c, let-7g-5p, and miR-191-5p - that were reported by multiple investigators. Some studies analyzed the diagnostic potential of these six miRNAs through receiver operating curve analysis which indicates the significant area-under-curve values in different biofluid samples. miR-191-5p was found to have the maximum area-under-curve value (0.95) only in plasma and serum samples while smaller area-under-curve values were found for miR-125, miR-181c, miR-191-5p, miR-146a, and miR-9. This article shortlisted the promising miRNA candidates and discussed their diagnostic properties and cellular functions in order to search for potential biomarker for AD.

Eriksen AH, Andersen RF, Pallisgaard N, et al.
MicroRNA Expression Profiling to Identify and Validate Reference Genes for the Relative Quantification of microRNA in Rectal Cancer.
PLoS One. 2016; 11(3):e0150593 [PubMed] Free Access to Full Article Related Publications
INTRODUCTION: MicroRNAs (miRNAs) play important roles in regulating biological processes at the post-transcriptional level. Deregulation of miRNAs has been observed in cancer, and miRNAs are being investigated as potential biomarkers regarding diagnosis, prognosis and prediction in cancer management. Real-time quantitative polymerase chain reaction (RT-qPCR) is commonly used, when measuring miRNA expression. Appropriate normalisation of RT-qPCR data is important to ensure reliable results. The aim of the present study was to identify stably expressed miRNAs applicable as normaliser candidates in future studies of miRNA expression in rectal cancer.
MATERIALS AND METHODS: We performed high-throughput miRNA profiling (OpenArray®) on ten pairs of laser micro-dissected rectal cancer tissue and adjacent stroma. A global mean expression normalisation strategy was applied to identify the most stably expressed miRNAs for subsequent validation. In the first validation experiment, a panel of miRNAs were analysed on 25 pairs of micro dissected rectal cancer tissue and adjacent stroma. Subsequently, the same miRNAs were analysed in 28 pairs of rectal cancer tissue and normal rectal mucosa.
RESULTS: From the miRNA profiling experiment, miR-645, miR-193a-5p, miR-27a and let-7g were identified as stably expressed, both in malignant and stromal tissue. In addition, NormFinder confirmed high expression stability for the four miRNAs. In the RT-qPCR based validation experiments, no significant difference between tumour and stroma/normal rectal mucosa was detected for the mean of the normaliser candidates miR-27a, miR-193a-5p and let-7g (first validation P = 0.801, second validation P = 0.321). MiR-645 was excluded from the data analysis, because it was undetected in 35 of 50 samples (first validation) and in 24 of 56 samples (second validation), respectively. Significant difference in expression level of RNU6B was observed between tumour and adjacent stromal (first validation), and between tumour and normal rectal mucosa (second validation).
CONCLUSION: We recommend the mean expression of miR-27a, miR-193a-5p and let-7g as normalisation factor, when performing miRNA expression analyses by RT-qPCR on rectal cancer tissue.

Luan J, Wang J, Su Q, et al.
Meta-analysis of the differentially expressed microRNA profiles in nasopharyngeal carcinoma.
Oncotarget. 2016; 7(9):10513-21 [PubMed] Free Access to Full Article Related Publications
MicroRNAs(miRNAs), as non-coding molecules, were proved to be correlated with gene expression in naspharyngeal carcinoma (NPC) development. In this research, a comprehensive meta-analysis of eight independent miRNA expression studies in NPC was preformed by using robust rank aggregation method (RRA), which contained a total of 775 tumor and 227 non-cancerous samples. There were 7 significant dysregulated miRNAs identified including three increased (miR-483-5p, miR-29c-3p and miR-205-5p) and four decreased (miR-29b-3p, let-7d-5p, miR-100- 5p and let-7g-5p) miRNAs. Subsequently, the miRNA target prediction and pathway enrichment analysis were carried out to find out the biological and functional relevant genes involved in the meta-signature miRNA regulation. Finally, several signaling and cancer pathogenesis pathways were suggested to be more frequently associated with the progression of NPC. In this research the meta-signature miRNA identified may be used to develop a series of diagnostic and prognostic biomarkers for NPC that serve specificity for use in clinics.

Petrillo M, Zannoni GF, Beltrame L, et al.
Identification of high-grade serous ovarian cancer miRNA species associated with survival and drug response in patients receiving neoadjuvant chemotherapy: a retrospective longitudinal analysis using matched tumor biopsies.
Ann Oncol. 2016; 27(4):625-34 [PubMed] Related Publications
BACKGROUND: Neoadjuvant chemotherapy (NACT) has been recognized as a reliable therapeutic strategy in patients with unresectable advanced epithelial ovarian cancer (EOC). The molecular events leading to platinum (Pt) response in NACT settings have hitherto not been explored. In the present work, longitudinal changes of miRNA expression profile were investigated to identify miRNA families with prognostic role in high-grade serous EOC patients who received the NACT regimen.
PATIENTS AND METHODS: One hundred sixty-four matched tumor biopsies taken at initial laparoscopic evaluation and at interval-debulking surgery (IDS) after four courses of Pt-based therapy were selected from 82 stage IIIC-IV high-grade serous-EOC patients that were judged unsuitable for complete primary debulking and subjected the NACT protocol. miRNA profiling by microarray, real-time PCR and immuno-histochemical staining for Smad2 phosphorylation (P-Smad2) were used for data analysis.
RESULTS: Analysis revealed that 369 miRNAs were differentially expressed in matched biopsies (referred to as DEMs). DEMs were not scattered across the genome, but clustered into families: miR-199, let-7, miR-30, miR-181 and miR-29. Multivariate analysis showed that miR-199a-3p, miR-199a-5p, miR-181a-5p and let-7g-5p associated with overall and progression-free survival (P < 0.05); miR-199a-3p, miR-199a-5p and miR-181a-5p associated with residual tumor volume and Pt-free interval (P < 0.05). Immuno-histochemical staining confirmed an enrichment of P-Smad2, a marker of transforming growth factor-β activation, in tumors from patients with shorter PFS and OS, and with high levels of expression of miR-181a-5p (P < 0.05). Kaplan-Meier curves plotting concomitant expression of P-Smad2 and miR-181a-5p show significant differences in PFS and OS compared with those depicting the expression of each biomarker alone (P < 0.001).
CONCLUSIONS: This study describes several miRNA families with a prognostic role in the NACT setting. It also confirms that concomitant analysis of P-Smad2 and miR-181a-5p in surgical samples may be capable of identifying those ovarian cancer patients with poor outcome and little chance of response to Pt-based NACT.

Wu K, Yang Y, Zhao J, Zhao S
BAG3-mediated miRNA let-7g and let-7i inhibit proliferation and enhance apoptosis of human esophageal carcinoma cells by targeting the drug transporter ABCC10.
Cancer Lett. 2016; 371(1):125-33 [PubMed] Related Publications
Cisplatin (diamminedichloroplatinum, DDP) is widely used as the first-line treatment for patients with unresectable or no metastatic cancer. However, the appearance of DDP resistance frequently occurred in the treatment of cancers, including esophageal carcinoma (EC). The purposes of this study are to determine the antitumor effects of miR-let-7g/i (let-7g/i) on EC cells and to investigate whether let-7g and let-7i have a relationship with the drug resistance gene ABCC10 on EC cells. qRT-PCR and western blot analysis demonstrated that Bcl2-associated athanogene 3 (BAG3) and miR-let-7g/i have the opposite expression levels in primary esophageal squamous cell carcinoma tissues and EC cell lines. Overexpression of miR-let-7g/i significantly inhibited the cell proliferation and promoted DDP-induced apoptosis of EC109 and TE10 cells. Finally, ABCC10, a drug resistance gene, was identified as a functional and direct target gene of miR-let-7g/i. Luciferase reporter assay confirmed that let-7g and let-7i combined directly with 3'UTR of ABCC10, in consequence, inhibiting ABCC10 expression and enhancing cellular sensitivity to drugs. This study provides the first demonstration that miR-let-7g/i target ABCC10 and modulate DDP resistance in EC cell lines.

Ozcan O, Kara M, Yumrutas O, et al.
MTUS1 and its targeting miRNAs in colorectal carcinoma: significant associations.
Tumour Biol. 2016; 37(5):6637-45 [PubMed] Related Publications
Deregulated microRNA (miRNA) expression has been shown to be involved in the pathogenesis of several types of cancers including colorectal cancer (CRC). Thus, determining miRNA targets of genes that play critical role in the malignant transformation is very important. Here, expression levels of tumor suppressor microtubule-associated tumor suppressor 1 (MTUS1) and its regulatory miRNAs were reported. Predicted and validated targets of MTUS1 gene was determined by a computational approach. Expressions of MTUS1 and miRNAs were determined by using 96.96 Dynamic Array™ integrated fluidic circuit (Fluidigm). As a result, MTUS1 levels were found to be diminished in formalin-fixed, paraffin-embedded (FFPE) tissue samples of CRC patients compared to controls. Also, several of MTUS1 targeting miRNAs were found to be upregulated in CRC samples (miR-373-3p, 183-5p, 142-5p, 200c-3p, 19a-3p, -20a-5p, -181a-5p, -184, -181d-5p, -372-3p, 27b-3p, 98-5p, -let-7i-5p, -let-7d-5p, -let-7g-5p, -let-7b-5p, and -let-7c-5p). Of these miRNAs, miR-135b-5p, -373-3p, 183-5p, 142-5p, 200c-3p, 19a-3p showed marked expression levels. In contrast, expression levels of let-7a-5p, 7e-5p, 7f-5p, hsa-miR-125a-5p, and 125b-5p were found to be downregulated in CRC tissues. Accordingly, some of the overexpressed miRNAs especially the miR-135b-5p, -373-3p, 183-5p, 142-5p, 200c-3p, and 19a-3p may play key roles in CRC pathophysiology through MTUS1. In contrast, let-7a-5p, 7e-5p, 7f-5p, miR-125a-5p, and 125b-5p may play important roles in CRC carcinogenesis independent from the MTUS1. In conclusion, MTUS1 targeting miRNAs may play key roles in the development of CRC by downregulating tumor suppressor MTUS1.

Calura E, Bisognin A, Manzoni M, et al.
Disentangling the microRNA regulatory milieu in multiple myeloma: integrative genomics analysis outlines mixed miRNA-TF circuits and pathway-derived networks modulated in t(4;14) patients.
Oncotarget. 2016; 7(3):2367-78 [PubMed] Free Access to Full Article Related Publications
The identification of overexpressed miRNAs in multiple myeloma (MM) has progressively added a further level of complexity to MM biology. miRNA and gene expression profiles of two large representative MM datasets, available from retrospective and prospective series and encompassing a total of 249 patients at diagnosis, were analyzed by means of in silico integrative genomics methods, based on MAGIA2 and Micrographite computational procedures. We first identified relevant miRNA/transcription factors/target gene regulation circuits in the disease and linked them to biological processes. Members of the miR-99b/let-7e/miR-125a cluster, or of its paralog, upregulated in t(4;14), were connected with the specific transcription factors PBX1 and CEBPA and several target genes. These results were validated in two additional independent plasma cell tumor datasets. Then, we reconstructed a non-redundant miRNA-gene regulatory network in MM, linking miRNAs, such as let-7g, miR-19a, mirR-20a, mir-21, miR-29 family, miR-34 family, miR-125b, miR-155, miR-221 to pathways associated with MM subtypes, in particular the ErbB, the Hippo, and the Acute myeloid leukemia associated pathways.

Hu H, Zhang L, Teng G, et al.
A variant in 3'-untranslated region of KRAS compromises its interaction with hsa-let-7g and contributes to the development of lung cancer in patients with COPD.
Int J Chron Obstruct Pulmon Dis. 2015; 10:1641-9 [PubMed] Free Access to Full Article Related Publications
OBJECTIVE: The objective of the present study was to explore the molecular mechanism by which a single nucleotide polymorphism (rs712) interferes with interaction between 3'-untranslated region (3'-UTR) of KRAS and let-7g, and its association with development of lung cancer in the patients with COPD.
MATERIALS AND METHODS: In this study, we confirmed that KRAS is a target of let-7g in lung cancer cells, and that introduction of rs712 minor allele into 3'-UTR significantly compromised the miRNA/mRNA interaction by using a luciferase reporter system. Additionally, a total of 35 lung tissue samples were obtained (TT:17, TG:12, GG:6), and let-7g and KRAS expression levels were determined.
RESULTS: We showed that let-7g level was similar between groups, and the concentration of KRAS in GG genotype group was significantly higher than in TT or GT genotype group. Meanwhile, we found COPD patients with GG genotype had significantly higher risk for lung cancer (odds ratio OR =6.83, P=0.0081), compared with TT and GT genotypes.
CONCLUSION: Our study demonstrated that KRAS 3'-UTR rs712 polymorphism interfered with miRNA/mRNA interaction, and showed that the minor allele was associated with an elevated risk for development of lung cancer in COPD.

Rice J, Roberts H, Rai SN, Galandiuk S
Housekeeping genes for studies of plasma microRNA: A need for more precise standardization.
Surgery. 2015; 158(5):1345-51 [PubMed] Related Publications
INTRODUCTION: Plasma microRNAs (miRNAs) are promising biomarkers for many forms of cancer in humans; however, a fundamental concern is the lack of standardization in current data acquisition and reporting. Part of this problem lies in the use of numerous, different housekeeping genes (HKG) for the acquisition of real-time polymerase chain reaction data. This existing practice of using different HKGs generally is accepted, but reproducibility of data for comparison and validation between different laboratories calls for improvement. The need for data reproducibility standardization is crucial. An ideal plasma HKG (1) should be expressed in all samples, (2) have medium-to-high levels of expression, and (3) have consistently measurable levels of expression.
METHODS: Total RNA was extracted from 200-μL plasma samples via a modified miRNeasy (QIAGEN) extraction technique with yeast carrier. Total RNA purity was assessed with a Nanodrop 2000 spectrophotometer (Thermo Scientific). The cycle threshold (Ct) was fixed at 0.03 for all samples. We investigated 10 potential HKGs based both on reports in the literature and our previous data. The potential HKGs were Let-7a, Let-7d, Let-7g, miR-16, RNU6, RNU48, miR-191, miR-223, miR-484, and miR-520d-5p. Once all samples were run for each potential HKG, the mean Ct and SD was calculated for all sample groups, allowing for comparison among HKGs.
RESULTS: We screened 380 miRNAs by using microfluidic array technology (Applied Biosystems) in a discovery cohort of 20 colorectal cancer (CRC) patients, 10 patients each with breast cancer (BC), lung cancer (LC), pancreatic cancer (PC), 11 patients with colorectal adenoma, and 12 controls. The mean Ct and SD was calculated for RNU6, miR-520d-5p, miR-16, miR-191, miR-223, and miR-484, which were expressed in all samples. Let-7a, Let-7d, Let-7g, and RNU48 were only expressed in 26%, 7%, 10%, and 8% of samples, respectively, and therefore were deemed to be insufficiently reliable HKGs. Only miRNAs with >50% expression were included in this statistical analysis. U6 and miR-520d-5p had the most consistent Ct as well as the least SD. The use of both RNU6 and 520d-5p as HKGs provided reliable results.
CONCLUSION: Among HKGs that were expressed in all samples, we suggest that RNU6 and miR-520d-5p were the best candidates for HKGs for studies of plasma miRNA because of the consistent and high Ct in all samples and a very narrow, reproducible SD.

Hu H, Zhao X, Jin Z, Hou M
Hsa-let-7g miRNA regulates the anti-tumor effects of gastric cancer cells under oxidative stress through the expression of DDR genes.
J Toxicol Sci. 2015; 40(3):329-38 [PubMed] Related Publications
Oxidative stress is linked to increased risk of gastric cancer (GC). Recent reports have found that hsa-let-7 g microRNA (miRNA) has properties of anti-tumor and resistance to damages induced by oxidized low-density lipoprotein (ox-LDL). Dysregulation of hsa-let-7 g was present in GC in vivo and in vitro under exogenous stress. However, we didn't know whether there are regulatory mechanisms of hsa-let-7 g in GC under oxidative stress. This study was aimed at investigating the effects of hsa-let-7 g microRNA (miRNA) on GC under oxidative stress. The results showed that H2O2 induced the increase of DNA damage response (DDR) genes (ATM, H2AX and Chk1) and downregulation of hsa-let-7 g in GC cells. Further study confirmed Hsa-let-7 g caused the apoptosis and loss of proliferation in GC cells exposed to H2O2 associated with repression of DDR system. Yet, we found let-7 g didn't target DDR genes (ATM, H2AX and Chk1) directly. In addition, data revealed hsa-let-7 g miRNA increased the sensitivity of GC to X-rays involving in ATM regulation as well according to application of X-rays (another DDR inducer). In conclusion, Hsa-let-7 g miRNA increased the sensitivity of GC to oxidative stress by repression activation of DDR indirectly. Let-7 g improved the effects of X-rays on GC cells involving in DDR regulation as well.

Reddemann K, Gola D, Schillert A, et al.
Dysregulation of microRNAs in angioimmunoblastic T-cell lymphoma.
Anticancer Res. 2015; 35(4):2055-61 [PubMed] Related Publications
BACKGROUND: Angioimmunoblastic T-cell lymphomas (AITLs) are the second most frequent peripheral T-cell lymphomas in humans worldwide and histomorphologically well characterized. MicroRNAs are a group of small non-coding RNAs that can negatively regulate gene expression on a posttranscriptional level. Their dysregulation has been shown to be of importance in numerous tumour entities.
MATERIALS AND METHODS: As a first step towards understanding the possible influence of microRNA-dysregulation in AITL, we analyzed the expression signatures of 760 microRNAs in 30 nodal AITLs in comparison to reactive lymphadenitis with T-zone hyperplasia.
RESULTS: We found miR-34a, miR-146a and miR-193b to be up-regulated, as well as miR-140-3p, let-7g, miR-30b and miR-664 to be down-regulated in AITL to a significant level.
CONCLUSION: The microRNA-signatures of AITL reveal some overlap to autoimmune diseases, virus-triggered lymphomas and angiogenic factors that, coupled with future studies, will potentially provide better understanding of this disease.

Jamali Z, Asl Aminabadi N, Attaran R, et al.
MicroRNAs as prognostic molecular signatures in human head and neck squamous cell carcinoma: a systematic review and meta-analysis.
Oral Oncol. 2015; 51(4):321-31 [PubMed] Related Publications
The aim of this study was to systematically review the articles investigating the prognostic value of different microRNAs (miRs) in human head and neck squamous cell carcinoma (HNSCC). Following the guidelines of the Meta-analysis of Observational Studies in Epidemiology group (MOOSE), we performed a broad and sensitive search on online databases to identify the studies that examined associations between different miRs expression and HNSCC prognosis. In this study, we considered clinical endpoints such as overall survival (OS) and disease specific survival (DFS) as acceptable outcomes. The prognostic value was demonstrated using hazard ratio (HR) with 95% confidence interval (CI). A total of 21 studies involving 1685 subjects analyzed the relationship between miRNA and prognosis of HNSCC. Our findings showed that significant elevated expressions of miR-21, miR-18a, miR-134a, miR-210, miR-181a, miR-19a, and miR-155 were associated with poor survival in human HNSCC. Conversely, decreased expressions of miR-153, miR-200c, miR-363, miR-203, miR-17, miR-205, miR-Let-7d, Let-7g, miR-34a, miR-126a, miR-375, miR-491-p5, miR 218, miR-451 and miR-125b were associated with poor prognosis. Alteration in miR-193b expression level does not show any significant association with cancer survival. We performed meta-analysis on the articles choosing miR-21 as prognostic marker. After excluding the study causing heterogeneity, a fixed model was applied, which showed an association between increased expression of miR-21 and poor survival (Pooled HR=1.57-95% CI: 1.22-2.02, P<0.05). Based on the results, it can be concluded that miRs specifically miR-21 may be promising markers for prognosis prediction in HNSCC.

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