MIRLET7I

Locus Summary

Gene:MIRLET7I; microRNA let-7i
Aliases: LET7I, let-7i, MIRNLET7I, hsa-let-7i
Location:12q14.1
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: 31 August, 2019

Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 31 August 2019 using data from PubMed using criteria.

Literature Analysis

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

Tag cloud generated 31 August, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (10)

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)MIRLET7I Function in CancerEffect
ovary (3)
-epithelial ovarian carcinoma (1)
-ovarian cancer (1)
-epithelial ovarian cancer (1)
PGRMC1 (1)
increase paclitaxel sensitivity (1)
inhibit cell proliferation (1)
induce apoptosis (1)
decrease cell survival (1)
increase cisplatin sensitivity (1)
tumor-suppressive (2)
colorectum (1)
-colorectal cancer (1)
inhibit cell proliferation (1)
inhibit cell migration (1)
inhibit cell invasion (1)
tumor-suppressive (1)

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

Latest Publications: MIRLET7I (cancer-related)

Wang TH, Hsueh C, Chen CC, et al.
Melatonin Inhibits the Progression of Hepatocellular Carcinoma through MicroRNA Let7i-3p Mediated RAF1 Reduction.
Int J Mol Sci. 2018; 19(9) [PubMed] Free Access to Full Article Related Publications
Melatonin is the main pineal hormone that relays light/dark-cycle information to the circadian system. Recent studies have examined the intrinsic antitumor activity of melatonin in various cancers, including hepatocellular carcinoma (HCC), the primary life-threatening malignancy in both sexes in Taiwan. However, the detailed regulatory mechanisms underlying melatonin's anti-HCC activity remain incompletely understood. Here, we investigated the mechanisms by which the anti-HCC activity of melatonin is regulated. Human hepatoma cell lines were treated with 1 and 2 mM melatonin, and functional assays were used to dissect melatonin's antitumor effect in HCC; small-RNA sequencing was performed to identify the microRNAs (miRNAs) involved in the anti-HCC activity of melatonin; and quantitative RT-PCR and Western blotting were used to elucidate how miRNAs regulate melatonin-mediated HCC suppression. Melatonin treatment at both doses strongly inhibited the proliferation, migration and invasion capacities of Huh7 and HepG2 cell lines, and melatonin treatment markedly induced the expression of the miRNA let7i-3p in cells. Notably, transfection of cells with a let7i-3p mimic drastically reduced RAF1 expression and activation of mitogen-activated protein kinase signaling downstream from RAF1, and rescue-assay results demonstrated that melatonin inhibited HCC progression by modulating let7i-3p-mediated RAF1 suppression. Our findings support the view that melatonin treatment holds considerable promise as a therapy for HCC.

Wang BG, Jiang LY, Xu Q
A comprehensive evaluation for polymorphisms in
Biosci Rep. 2018; 38(4) [PubMed] Free Access to Full Article Related Publications
miRNA polymorphisms had potential to be biomarkers for cancer susceptibility and prognosis. The mature

Zhao L, Fong AHW, Liu N, Cho WCS
Molecular subtyping of nasopharyngeal carcinoma (NPC) and a microRNA-based prognostic model for distant metastasis.
J Biomed Sci. 2018; 25(1):16 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Nasopharyngeal carcinoma (NPC) is a highly invasive and metastatic cancer, with diverse molecular characteristics and clinical outcomes. This study aims to dissect the molecular heterogeneity of NPC, followed by the construction of a microRNA (miRNA)-based prognostic model for prediction of distant metastasis.
METHODS: We retrieved two NPC datasets: GSE32960 and GSE70970 as training and validation cohorts, respectively. Consensus clustering was employed for cluster discovery, and support vector machine was used to build a classifier. Finally, Cox regression analysis was applied to constructing a prognostic model for predicting risk of distant metastasis.
RESULTS: Three NPC subtypes (immunogenic, classical and mesenchymal) were identified that are molecularly distinct and clinically relevant, of which mesenchymal subtype (~ 36%) is associated with poor prognosis, characterized by suppressing tumor suppressor miRNAs and the activation of epithelial--mesenchymal transition. Out of the 25 most differentially expressed miRNAs in mesenchymal subtype, miR-142, miR-26a, miR-141 and let-7i have significant prognostic power (P < 0.05).
CONCLUSIONS: We proposed for the first time that NPC can be stratified into three subtypes. Using a panel of 4 miRNAs, we established a prognostic model that can robustly stratify NPC patients into high- and low- risk groups of distant metastasis.

Lundberg IV, Wikberg ML, Ljuslinder I, et al.
MicroRNA Expression in
Anticancer Res. 2018; 38(2):677-683 [PubMed] Related Publications
BACKGROUND/AIM: KRAS and BRAF are two genes commonly mutated in colorectal cancer (CRC). Even though BRAF is a downstream target of KRAS in the MAPK signalling pathway, KRAS- and BRAF-mutated CRCs are found to display several different clinical and histopathological features. We investigated whether a differential expression of microRNAs (miRNAs) could explain the clinicopathological differences seen between KRAS- and BRAF-mutated CRCs.
MATERIALS AND METHODS: Using a PCR array, we analyzed the expression of 84 different miRNAs in CRC cell lines wild-type in KRAS and BRAF, or mutated in KRAS or BRAF.
RESULTS: Ten miRNAs were selected for further analyses in tumor tissue specimens (let-7a, let-7i, miR-10a, miR-10b, miR-31, miR-100, miR-181a, miR-181b, miR-372, and miR-373). BRAF-mutated tumors were found to express significantly higher levels of miR-31 as well as significantly lower levels of miR-373, compared to wild-type tumors.
CONCLUSION: Our results suggest that KRAS- and BRAF-mutated CRCs may have different miRNA signatures compared to CRC tumors wild-type in KRAS and BRAF. However, no difference in expression levels between KRAS- and BRAF-mutated tumors was evident for the miRNAs analyzed in this study.

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.

Liu J, Ni S
Association between genetic polymorphisms in the promoters of let-7 and risk of cervical squamous cell carcinoma.
Gene. 2018; 642:256-260 [PubMed] Related Publications
Numerous reports showed low levels of let-7 family in cervical cancer, acting as tumor suppressors by regulating multiple target genes. Genetic variants in the promoter of miRNA have been reported to influence individuals' susceptibility to human diseases. We aimed to investigate the association of rs10877887 and rs13293512 polymorphisms in the promoters of let-7 with risk of cervical squamous cell carcinoma (CSCC). A total of 331 patients with CSCC and 358 controls were included. Genotyping of rs10877887 was done using polymerase chain reaction-restriction fragment length polymorphism analysis. Genotyping of rs13293512 was performed using Taqman allelic discrimination. Relative expression of let-7 family was determined using quantitative real-time polymerase chain reaction. The rs10877887CC genotype was significantly associated with an increased risk of CSCC compared with the rs10877887TT (adjusted OR=2.11, 95% CI, 1.31-3.40, p-value=0.002) or rs10877887 TT/CT genotypes (adjusted OR=2.11, 95% CI, 1.34-3.31, p-value<0.001). Similarly increased risk of CSCC was observed when compared rs10877887T with rs10877887C allele (adjusted OR=1.35, 95% CI, 1.08-1.69, p-value=0.008). Combined analysis showed that individuals carrying the genotypes of rs10877887CC+rs13293512CC had a 4.78-fold higher risk to develop CSCC compared with those carrying the genotypes of rs10877887CT/TT+rs13293512CT/TT (OR=4.78, 95% CI, 1.78-12.84, p-value=0.001). Additionally, patients harboring rs10877887CC genotype had a lower level of let-7i in CSCC tissues (p-value=0.02). This observation indicates that rs10877887 may be a useful biomarker for the etiology of CSCC.

Sun J, Pan LM, Chen LB, Wang Y
LncRNA XIST promotes human lung adenocarcinoma cells to cisplatin resistance via let-7i/BAG-1 axis.
Cell Cycle. 2017; 16(21):2100-2107 [PubMed] Free Access to Full Article Related Publications
Long noncoding RNAs (lncRNAs) have been identified as oncogenes or tumor suppressors that are involved in tumorigenesis and chemoresistance. LncRNA XIST expression is upregulated in several cancers, however, its biologic role in the development of the chemotherapy of human lung adenocarcinoma (LAD) has not been elucidated. This study aimed to observe the expression of LncRNA XIST in LAD and to evaluate its biologic role and clinical significance in the resistance of LAD cells to cisplatin. LncRNA XIST expression was markedly increased in cisplatin-resistant A549/DDP cells compared with parental A549 cells as shown by qRT-PCR. LncRNA XIST overexpression in A549 cells increased their chemosensitivity to cisplatin both in vitro and in vivo by protecting cells from apoptosis and promoting cell proliferation. By contrast, LncRNA XIST knockdown in A549/DDP cells decreased the chemoresistance. We revealed that XIST functioned as competing endogenous RNA to repress let-7i, which controlled its down-stream target BAG-1. We proposed that XIST was responsible for cisplatin resistance of LAD cells and XIST exerted its function through the let-7i/BAG-1 axis. Our findings suggested that lncRNA XIST may be a new marker of poor response to cisplatin and could be a potential therapeutic target for LAD chemotherapy.

Lim JH, Kim SG, Choi JM, et al.
Gut Liver. 2018; 12(1):58-66 [PubMed] Free Access to Full Article Related Publications
Background/Aims: To investigate whether
Methods: We examined expression and promoter methylation of
Results: In gastric cancer cell line,
Conclusions: This result suggests

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.

Zhou H, Li Y, Liu B, et al.
Downregulation of miR-224 and let-7i contribute to cell survival and chemoresistance in chronic myeloid leukemia cells by regulating ST3GAL IV expression.
Gene. 2017; 626:106-118 [PubMed] Related Publications
Acquired resistance to imatinib is frequently associated with poor clinical outcome of chronic myeloid leukemia (CML) patient. To date, evidence indicates that protein glycosylation and its upstream regulators might be implicated in tumorigenesis and chemoresistance occurrence. In current study we initially explored N-glycan profiles on the surface of CML cell lines and bone marrow mononuclear cells (BMMC) of CML patients by using mass spectrometry (MS) analysis. An elevated sialylation was detected in K562R cells (CML cells with imatinib resistance phenotype) compare to K562 cells. By quantitative real time-PCR (qRT-PCR) and western blotting analysis we observed that imatinib resistant K562R cells exhibited marked high levels of CMP-N-acetylneuraminate-beta-galactosamide-alpha-2,3-sialyltransferase (ST3Gal IV) as compared to imatinib sensitive K562 cells. Further studies revealed that manipulated expression of ST3GAL IV led to the significant alterations of cell cycle distribution, apoptotic signal, cell proliferation and the effectiveness of imatinib treatment. Using microRNA array, miRNA database searching and luciferase reporter assay, we identified that miR-224 and let-7i directly regulate the expression of ST3GAL IV gene. Moreover, engineered expression of miR-224 and let-7i in K562 and K562R cells could significantly affect ST6Gal IV-induced proliferation rate and drug-resistance. Thus we propose that miR-224 and let-7i regulate the proliferation and chemosensitivity of CML cells probably via targeting ST3GAL IV.

Elkhadragy L, Chen M, Miller K, et al.
A regulatory BMI1/let-7i/ERK3 pathway controls the motility of head and neck cancer cells.
Mol Oncol. 2017; 11(2):194-207 [PubMed] Free Access to Full Article Related Publications
Extracellular signal-regulated kinase 3 (ERK3) is an atypical mitogen-activated protein kinase (MAPK), whose biological activity is tightly regulated by its cellular abundance. Recent studies have revealed that ERK3 is upregulated in multiple cancers and promotes cancer cell migration/invasion and drug resistance. Little is known, however, about how ERK3 expression level is upregulated in cancers. Here, we have identified the oncogenic polycomb group protein BMI1 as a positive regulator of ERK3 level in head and neck cancer cells. Mechanistically, BMI1 upregulates ERK3 expression by suppressing the tumor suppressive microRNA (miRNA) let-7i, which directly targets ERK3 mRNA. ERK3 then acts as an important downstream mediator of BMI1 in promoting cancer cell migration. Importantly, ERK3 protein level is positively correlated with BMI1 level in head and neck tumor specimens of human patients. Taken together, our study revealed a molecular pathway consisting of BMI1, miRNA let-7i, and ERK3, which controls the migration of head and neck cancer cells, and suggests that ERK3 kinase is a potential new therapeutic target in head and neck cancers, particularly those with BMI1 overexpression.

Chang JT, Wang F, Chapin W, Huang RS
Identification of MicroRNAs as Breast Cancer Prognosis Markers through the Cancer Genome Atlas.
PLoS One. 2016; 11(12):e0168284 [PubMed] Free Access to Full Article Related Publications
Breast cancer is the second-most common cancer and second-leading cause of cancer mortality in American women. The dysregulation of microRNAs (miRNAs) plays a key role in almost all cancers, including breast cancer. We comprehensively analyzed miRNA expression, global gene expression, and patient survival from the Cancer Genomes Atlas (TCGA) to identify clinically relevant miRNAs and their potential gene targets in breast tumors. In our analysis, we found that increased expression of 12 mature miRNAs-hsa-miR-320a, hsa-miR-361-5p, hsa-miR-103a-3p, hsa-miR-21-5p, hsa-miR-374b-5p, hsa-miR-140-3p, hsa-miR-25-3p, hsa-miR-651-5p, hsa-miR-200c-3p, hsa-miR-30a-5p, hsa-miR-30c-5p, and hsa-let-7i-5p -each predicted improved breast cancer survival. Of the 12 miRNAs, miR-320a, miR-361-5p, miR-21-5p, miR-103a-3p were selected for further analysis. By correlating global gene expression with miRNA expression and then employing miRNA target prediction analysis, we suggest that the four miRNAs may exert protective phenotypes by targeting breast oncogenes that contribute to patient survival. We propose that miR-320a targets the survival-associated genes RAD51, RRP1B, and TDG; miR-361-5p targets ARCN1; and miR-21-5p targets MSH2, RMND5A, STAG2, and UBE2D3. The results of our stringent bioinformatics approach for identifying clinically relevant miRNAs and their targets indicate that miR-320a, miR-361-5p, and miR-21-5p may contribute to breast cancer survival.

Lin LT, Chang CY, Chang CH, et al.
Involvement of let-7 microRNA for the therapeutic effects of Rhenium-188-embedded liposomal nanoparticles on orthotopic human head and neck cancer model.
Oncotarget. 2016; 7(40):65782-65796 [PubMed] Free Access to Full Article Related Publications
Human head and neck squamous cell carcinoma (HNSCC) is usually treated by surgical resection with adjuvant radio-chemotherapy. In this study, we examined whether the radiopharmaceutical 188Re-liposome could suppress the growth of HNSCC followed by an investigation of molecular mechanisms. The orthotopic HNSCC tumor model was established by human hypopharyngeal FaDu carcinoma cells harboring multiple reporter genes. The drug targeting and therapeutic efficacy of 188Re-liposome were examined using in vivo imaging, bio-distribution, pharmacokinetics, and dosimetry. The results showed that 188Re-liposome significantly accumulated in the tumor lesion compared to free 188Re. The circulation time and tumor targeting of 188Re-liposome were also longer than that of free 188Re in tumor-bearing mice. The tumor growth was suppressed by 188Re-liposome up to three weeks using a single dose treatment. Subsequently, microarray analysis followed by Ingenuity Pathway Analysis (IPA) showed that tumor suppressor let-7 microRNA could be an upstream regulator induced by 188Re-liposome to regulate downstream genes. Additionally, inhibition of let-7i could reduce the effects of 188Re-liposome on suppression of tumor growth, suggesting that let-7 family was involved in 188Re-liposome mediated suppression of tumor growth in vivo. Our data suggest that 188Re-liposome could be a novel strategy for targeting HNSCC partially via induction of let-7 microRNA.

Fawzy IO, Hamza MT, Hosny KA, et al.
Abrogating the interplay between IGF2BP1, 2 and 3 and IGF1R by let-7i arrests hepatocellular carcinoma growth.
Growth Factors. 2016; 34(1-2):42-50 [PubMed] Related Publications
IGF2BP 1, 2 and 3 control the fate of many transcripts. Immunoprecipitation studies demonstrated the IGF2BPs to bind to IGF1R mRNA, and our laboratory has recently shown them to post-transcriptionally regulate IGF1R. This study sought to identify a microRNA regulating the IGF2BPs and consequently IGF1R. All three IGF2BPs were among the top-ranked predicted targets of let-7i. Let-7i was downregulated in HCC tissues, and transfection of HuH-7 with let-7i inhibited malignant cell behaviors and decreased IGF2BPs transcripts. Direct binding of let-7i to IGF2BP2 and IGF2BP3 3'UTRs was confirmed, and the effect of let-7i caused a decrease in the IGF2BPs' target gene, the IGF1R. IGF1R mRNA was inversely correlated with let-7i in HCC tissues and was reduced upon let-7i transfection into HuH-7. Reporter assays validated IGF1R as a target of let-7i. Therefore, let-7i may control HCC tumorigenesis by regulating IGF1R directly and indirectly by interrupting the interplay between IGF1R and the IGF2BPs.

Xiao D, Barry S, Kmetz D, et al.
Melanoma cell-derived exosomes promote epithelial-mesenchymal transition in primary melanocytes through paracrine/autocrine signaling in the tumor microenvironment.
Cancer Lett. 2016; 376(2):318-27 [PubMed] Free Access to Full Article Related Publications
The tumor microenvironment is abundant with exosomes that are secreted by the cancer cells themselves. Exosomes are nanosized, organelle-like membranous structures that are increasingly being recognized as major contributors in the progression of malignant neoplasms. A critical element in melanoma progression is its propensity to metastasize, but little is known about how melanoma cell-derived exosomes modulate the microenvironment to optimize conditions for tumor progression and metastasis. Here, we provide evidence that melanoma cell-derived exosomes promote phenotype switching in primary melanocytes through paracrine/autocrine signaling. We found that the mitogen-activated protein kinase (MAPK) signaling pathway was activated during the exosome-mediated epithelial-to-mesenchymal transition (EMT)-resembling process, which promotes metastasis. Let-7i, an miRNA modulator of EMT, was also involved in this process. We further defined two other miRNA modulators of EMT (miR-191 and let-7a) in serum exosomes for differentiating stage I melanoma patients from non-melanoma subjects. These results provide the first strong molecular evidence that melanoma cell-derived exosomes promote the EMT-resembling process in the tumor microenvironment. Thus, novel strategies targeting EMT and modulating the tumor microenvironment may emerge as important approaches for the treatment of metastatic melanoma.

Ottley EC, Nicholson HD, Gold EJ
Activin A regulates microRNAs and gene expression in LNCaP cells.
Prostate. 2016; 76(11):951-63 [PubMed] Related Publications
BACKGROUND: Prostate cancer (PCa) is an increasing health issue worldwide. For patients with advanced castration-resistant PCa (CRPC) treatment options are limited and overall survival is relatively short. Paired with this, non-invasive diagnostic options are yet to be established. Activins are members of the TGF-β superfamily and have been linked to prostate physiology. For instance, activin A is an inhibitor of growth in the prostate. A novel class of non-coding RNA, microRNAs (miRNAs) have been intrinsically linked to a range of cellular processes and carcinogenesis. No studies have investigated the impact of activin A on miRNA expression in PCa cell lines. Hence, the objective of this study was to determine the effect of activin A on miRNA expression and downstream target genes in PCa.
METHODS: Activin-sensitive (LNCaP) and insensitive (PC3) prostate cells were treated with 50 ng/ml of activin A for 72 hr. To examine miRNA expression following treatment, SYBR RT-qPCR miRNA arrays were used in conjunction with TaqMan RT-qPCR. MiRPath-TarBase analysis was conducted using the miRNAs that were significantly altered following activin A treatment of LNCaP cells to highlight enriched target genes within biological pathways. Highlighted target genes were assessed using pathway-focused TGF-β and cell cycle SYBR RT-qPCR arrays.
RESULTS: Activin A treatment altered nine miRNAs in LNCaP cells: miR-222-3p, miR-15b-5p, miR-93-5p, miR-18a-5p, and let-7i-5p were significantly decreased, while miR-30a/30d-5p, let-7c, and miR-196b-5p were significantly increased versus media control. In PC3 cells five miRNAs were altered: miR-130a-3p, miR-7-5p, and miR-140-3p were significantly decreased while miR-191-5p and miR-26a-5p were significantly increased versus media control. MiRPath-TarBase analysis highlighted that the miRNAs significantly altered in LNCaP cells targeted genes contained in activin A-related KEGG pathways. Furthermore, when LNCaP cells were treated with activin A the expression of the targeted genes was the inverse of the expression of activin A-mediated miRNAs.
CONCLUSIONS: This study demonstrated the ability of activin A to modulate miRNA expression in PCa cell lines and suggests a correlative relationship between miRNA expression and downstream target genes in LNCaP cells. This study provides impetus for further studies into activin A and miRNAs in PCa. Prostate 76:951-963, 2016. © 2016 Wiley Periodicals, Inc.

Lin Z, Li JW, Wang Y, et al.
Abnormal miRNA-30e Expression is Associated with Breast Cancer Progression.
Clin Lab. 2016; 62(1-2):121-8 [PubMed] Related Publications
BACKGROUND: microRNAs (miRNAs) are involved in the regulation of various cellular processes, such as differentiation, proliferation, metabolism, and apoptosis, and they have been implicated in several diseases, including cancers.
METHODS: To assess the role of miRNA in the progression of breast cancer, we performed TaqMan-based miRNA profiling for plasma from patients with breast cancer (n = 53), unrelated diseases (n = 40), or matched healthy controls (n = 40), and for breast tumors or adjacent non-tumors (n = 41).
RESULTS: We selected 18 miRNAs with predicted roles in breast cancer and demonstrated that let-7i (p = 0.019), let-7a (p = 0.02), and miR-650 (p = 0.008) were significantly up-regulated in plasma; miR-21 (p < 0.001) is up-regulated in breast cancer tissue, and miR-30e was down-regulated in both plasma (p < 0.001) and breast cancer tissues (p = 0.004). Plasma miR-30e expression was shown to be statistically associated with age (p = 0.0402) and clinical stage (p = 0.007). However, receiver-operating characteristic curve analyses suggested that miR-30e expression cannot significantly differentiate breast cancer from healthy tissue or plasma. Consistent with a potential role for miR-30e in breast cancer, three predicted targets of miR-30e (RAB11A, BNIP3L, and RAB32) are up-regulated in breast cancer tissue.
CONCLUSIONS: These findings suggest that reduced miR-30e correlates with the clinical stage of breast cancer. It is worthwhile to further explore that the potential role of miR-30e as a tumor suppressor in breast cancer, as well as its potential therapeutic utility.

Tavano F, Copetti M, Piepoli A, et al.
Support Vector Machine Based on microRNA Expression Profiles to Predict Histological Origin of Ampullary Carcinoma: Case Report of a Patient Affected From Adenocarcinoma of the Papilla of Vater With Lynch Syndrome.
Pancreas. 2016; 45(4):626-9 [PubMed] Related Publications
Adenocarcinomas of Vater's papilla (PVAC) may originate from either the pancreatic duct or the intestinal epithelium. Conflicting data have been reported about the frequency of the 2 anatomical entities and their influence on patients' prognosis. To ascertain the anatomical origin of PVAC in a family member of a Lynch syndrome kindred, we searched for microRNA (miRNA) expression profiles on resected tumor specimens. The support vector machine was trained on our previous miRNAs expression data sets of pancreatic and colorectal tissue samples and used to classify the site of origin of the tumor in our patient. The support vector machine worked by contrasting the profiles of miRNAs in patients with pancreatic ductal and colorectal cancers to that of our patient, which was finally classified as pancreatic ductal adenocarcinoma accordingly to alterations of 55 miRNAs. The PVAC might be originated from ductal epithelium rather than from the intestinal mucosa of the papilla in the case at issue. Alteration of miR-548b-3p, miR-551a, miR-21, miR-92a, miR-let-7i, and miR-181a* emerged as potentially associated with cancer genetic susceptibility in PVAC.

Treece AL, Duncan DL, Tang W, et al.
Gastric adenocarcinoma microRNA profiles in fixed tissue and in plasma reveal cancer-associated and Epstein-Barr virus-related expression patterns.
Lab Invest. 2016; 96(6):661-71 [PubMed] Free Access to Full Article Related Publications
MicroRNA expression in formalin-fixed paraffin-embedded tissue (FFPE) or plasma may add value for cancer management. The GastroGenus miR Panel was developed to measure 55 cancer-specific human microRNAs, Epstein-Barr virus (EBV)-encoded microRNAs, and controls. This Q-rtPCR panel was applied to 100 FFPEs enriched for adenocarcinoma or adjacent non-malignant mucosa, and to plasma of 31 patients. In FFPE, microRNAs upregulated in malignant versus adjacent benign gastric mucosa were hsa-miR-21, -155, -196a, -196b, -185, and -let-7i. Hsa-miR-18a, 34a, 187, -200a, -423-3p, -484, and -744 were downregulated. Plasma of cancer versus non-cancer controls had upregulated hsa-miR-23a, -103, and -221 and downregulated hsa-miR-378, -346, -486-5p, -200b, -196a, -141, and -484. EBV-infected versus uninfected cancers expressed multiple EBV-encoded microRNAs, and concomitant dysregulation of four human microRNAs suggests that viral infection may alter cellular biochemical pathways. Human microRNAs were dysregulated between malignant and benign gastric mucosa and between plasma of cancer patients and non-cancer controls. Strong association of EBV microRNA expression with known EBV status underscores the ability of microRNA technology to reflect disease biology. Expression of viral microRNAs in concert with unique human microRNAs provides novel insights into viral oncogenesis and reinforces the potential for microRNA profiles to aid in classifying gastric cancer subtypes. Pilot studies of plasma suggest the potential for a noninvasive addition to cancer diagnostics.

Li L, Chen J, Chen X, et al.
Serum miRNAs as predictive and preventive biomarker for pre-clinical hepatocellular carcinoma.
Cancer Lett. 2016; 373(2):234-40 [PubMed] Free Access to Full Article Related Publications
The extremely poor prognosis of patients with symptomatic hepatocellular carcinoma (HCC) diagnosed clinically at advanced stages suggests an urgent need for biomarkers that can be used for prospective surveillance and pre-clinical screening for early presence of pre-malignant lesions and tumors. In a retrospective longitudinal phase 3 biomarker study in seven medical centers of China, time-series and 6 months interval-serum samples were collected from chronic hepatitis B virus infected (CHB) patient cohorts at the pre-malignant or pre-clinical stages (average 6 months prior to clinical diagnosis) and CHB patients that did not develop cancer, and circulating miRNAs measured. A set of serum miRNAs including miR-193a-3p, miR-369-5p, miR-672, miR-429 and let-7i* were identified in pre-clinical HCC patients and have the potential to screen for CHB patients at high risk to develop HCC 6-12 months after miRNAs measurement. These circulating miRNAs combined with the conventional screening tools using α-fetoprotein and ultrasound, may have great promise for the prediction and prevention of HCC in high-risk populations.

Zhang Y, Hu Y, Fang JY, Xu J
Gain-of-function miRNA signature by mutant p53 associates with poor cancer outcome.
Oncotarget. 2016; 7(10):11056-66 [PubMed] Free Access to Full Article Related Publications
Missense mutation of p53 not only impairs its tumor suppression function, but also causes oncogenic gain of function (GOF). The molecular underpinning of mutant p53 (mutp53) GOF is not fully understood, especially for the potential roles of non-coding genes. Here we identify the microRNA expression profile (microRNAome) of mutp53 on Arg282 by controlled microarray experiments, and clarify the prognostic significance of mutp53-regulated miRNAs in cancers. A predominant repression effect on miRNA expression was found for mutant p53, with 183 significantly downregulated and only 12 upregulated miRNAs. Mutp53 and wild-type (wtp53) commonly upregulate let-7i, and other two miRNAs were upregulated by wtp53 but repressed by mutp53 (miR-610 and miR-3065-3p). Based the mutp53-regulated miRNA signature, a non-negative matrix factorization (NMF) model classified gastric cancer (GC) cases into subgroups with significantly different Disease-free survival (Kaplan-Meier test, P = 0.013). In contrast, the NMF model based on all miRNAs did not associate with cancer outcome. The mutp53 miRNA signature associated with the outcomes of breast cancer (P = 0.024) and hepatocellular cancer (P = 0.012). The miRPath analysis revealed that mutp53-suppressed miRNAs associate with Hippo, TGF-β and stem cell signaling pathways. Taken together, our results highlight a miRNA-mediated GOF mechanism of mutant p53 on Arg282, and suggest the prognostic potential of mutp53-associated miRNA signature.

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.

Chen C, Hu Y, Li L
NRP1 is targeted by miR-130a and miR-130b, and is associated with multidrug resistance in epithelial ovarian cancer based on integrated gene network analysis.
Mol Med Rep. 2016; 13(1):188-96 [PubMed] Free Access to Full Article Related Publications
Multidrug resistance (MDR) in epithelial ovarian cancer (EOC) remains a public health issue for women worldwide, and its molecular mechanisms remain to be fully elucidated. The present study aimed to predict the potential genes involved in MDR, and examine the mechanisms underlying MDR in EOC using bioinformatics techniques. In the present study, four public microarray datasets, including GSE41499, GSE33482, GSE15372 and GSE28739, available in Gene Expression Omnibus were downloaded, and 11 microRNAs (miRNA; miRs), including miR‑130a, miR‑214, let‑7i, miR‑125b, miR‑376c, miR‑199a, miR‑93, miR‑141, miR‑130b, miR‑193b* and miR‑200c, from previously published reports in PubMed were used to perform a comprehensive bioinformatics analysis through gene expression analysis, signaling pathway analysis, literature co‑occurrence and miRNA‑mRNA interaction networks. The results demonstrated that the expression of neuropilin 1 (NRP1) was upregulated, thereby acting as the most important hub gene in the integrated gene network. NRP1 was targeted by miR‑130a and miR‑130b at the binding site of chromosome 10: 33466864‑3466870, which was involved in the axon guidance signaling pathway. These results suggested that alteration of the gene expression levels of NRP1 expression may contribute to MDR in EOC. These data provide important information for further experimental investigations of the drug resistance‑associated functions of NRP1 in EOC.

Wang W, Corrigan-Cummins M, Barber EA, et al.
Aberrant Levels of miRNAs in Bone Marrow Microenvironment and Peripheral Blood of Myeloma Patients and Disease Progression.
J Mol Diagn. 2015; 17(6):669-78 [PubMed] Free Access to Full Article Related Publications
The bone marrow (BM) microenvironment of multiple myeloma (MM) is reported to play a role in the biology of disease. In this study, we found that the extracellular BM microenvironment in MM contains a unique miRNA signature detectable by miRNA microarray and quantitative real-time PCR, which is partially represented in the peripheral blood. Eleven miRNAs were significantly decreased in both BM and serum of MM patients in comparison with controls. Evaluation of these miRNAs in plasma of a separate cohort of MM patients and controls confirmed significantly aberrant levels of let-7a, let-7b, let-7i, miR-15b, miR-16, and miR-20a in both serum and plasma. We then studied the myeloma precursor diseases and found that a subset of the MM miRNAs exhibited aberrant expression in monoclonal gammopathy of undetermined significance and smoldering myeloma. miRNA analysis of enriched CD138(+) plasma cells from MM and monoclonal gammopathy of undetermined significance found that most of the validated MM BM signature miRNAs were significantly decreased in MM plasma cells. Gene expression profiling indicated that multiple targets of the decreased miRNAs found increased expression in MM plasma cells, including ATF2, HRAS, HDAC4, TGFB1, TGFBR1, and mitogen-activated protein kinases. The findings suggest that these miRNAs are detectable in aberrant levels in the peripheral blood of patients with plasma cell proliferation and may play a role in aberrant plasma cell proliferation and disease progression.

Yang WH, Su YH, Hsu WH, et al.
Imipramine blue halts head and neck cancer invasion through promoting F-box and leucine-rich repeat protein 14-mediated Twist1 degradation.
Oncogene. 2016; 35(18):2287-98 [PubMed] Free Access to Full Article Related Publications
The unique characteristic of head and neck squamous cell carcinoma (HNSCC) is that local invasion rather than distant metastasis is the major route for dissemination. Therefore, targeting the locally invasive cancer cells is more important than preventing systemic metastasis in HNSCC and other invasive-predominant cancers. We previously demonstrate a specific mechanism for HNSCC local invasion: the epithelial-mesenchymal transition (EMT) regulator Twist1 represses microRNA let-7i expression, leading to the activation of the small GTPase Rac1 and engendering the mesenchymal-mode movement in three-dimensional (3D) culture. However, targeting the EMT regulator is relatively difficult because of its transcription factor nature and the strategy for confining HNSCC invasion to facilitate local treatment is limited. Imipramine blue (IB) is a newly identified anti-invasive compound that effectively inhibits glioma invasion. Here we demonstrate that in HNSCC cells, a noncytotoxic dose of IB represses mesenchymal-mode migration in two-and-a-half-dimensional/3D culture system. IB suppresses EMT and stemness of HNSCC cells through inhibition of Twist1-mediated let-7i downregulation and Rac1 activation and the EMT signalling. Mechanistically, IB inhibits reactive oxygen species-induced nuclear factor-κB pathway activation. Importantly, IB promotes degradation of the EMT inducer Twist1 by enhancing F-box and leucine-rich repeat protein 14 (FBXL14)-mediated polyubiquitination of Twist1. Together, this study demonstrates the potent anti-invasion and EMT-inhibition effect of IB, suggesting the potential of IB in treating local invasion-predominant cancers.

Li M, Song Q, Song Q, et al.
Circulating miR-25-3p and miR-451a May Be Potential Biomarkers for the Diagnosis of Papillary Thyroid Carcinoma.
PLoS One. 2015; 10(7):e0132403 [PubMed] Free Access to Full Article Related Publications
OBJECTIVE: There is no effective and reliable biomarker to distinguish benign thyroid nodules from papillary thyroid carcinomas (PTC). This study aimed at examining the levels of plasma miRNAs in patients with PTC or benign nodules to explore the potential miRNA biomarkers for PTC.
PATIENTS AND METHODS: Genome-wide plasma miRNA expression profiles were determined by the miRNA Microarray and the significantly higher levels of miRNAs were validated in plasma and tissues by quantitative RT-PCR. The levels of two miRNAs were further tested in seven patients before and after tumor excision and the potential values for the diagnosis of PTC were evaluated by receiver operating characteristic curve (ROC).
RESULTS: In comparison with that in the patients with benign nodules, eight significantly higher and three lower levels of plasma miRNAs were detected in the PTC patients. Further validation indicated that the levels of plasma miR-25-3p, miR-451a, miR-140-3p and let-7i were significantly higher in the PTC cases than in those with benign nodules or the healthy controls. Significantly higher levels of miR-25-3p and miR-451a were detected in the thyroid tissues from the PTC patients. The levels of plasma miR-25-3p and miR-451a in seven patients significantly decreased after tumor excision. ROC analyses revealed that the levels of plasma miR-25-3p at cut-off 1.41 and miR-451a at 1.38 had sensitivity of 92.8% and 88.9%, and specificity of 68.8% and 66.7% for distinguishing PTC from benign nodules, respectively.
CONCLUSION: Our findings suggest that the levels of plasma miR-25-3p and miR-451a may be valuable for the diagnosis of PTC.

Zhang GM, Long XH, Liu JM, et al.
Let-7i inhibits the malignant phenotype of osteosarcoma cells by targeting Aurora-B.
Mol Med Rep. 2015; 12(3):3543-3548 [PubMed] Related Publications
Our previous study indicated that Aurora-B is involved in osteosarcoma (OS) cell invasion and metastasis; however, the mechanism underlying Aurora-B overexpression in OS remains unknown. In the present study, significantly downregulated let-7i expression in OS tissues and OS cells was observed compared with that in normal adjacent tumorous tissues and human osteoblast cell lines. Bioinformatic predictions have revealed a conserved binding site in a microRNA locus on Aurora‑B, suggesting the potential of let‑7i targeting the Aurora‑B gene. To validate this, a luciferase reporter assay was performed on OS cells. The results indicated that Aurora‑B is a likely to be a direct target negatively regulated by let‑7i. The expression of let‑7i in OS cells was restored by infection with let‑7i mimics. Results revealed that Aurora‑B mRNA and protein expression levels were significantly decreased. Furthermore, the proliferation, migration and invasion abilities of OS cells were significantly suppressed by infection with let‑7i mimics. Notably, the inhibitory effect of silencing Aurora‑B by LV‑shAurora‑B on cell proliferation, migratory and invasive ability was significantly lower than that by let‑7i mimics, which indicated that let‑7i inhibits cell malignant phenotypes partially by targeting Aurora‑B in OS cells. All data suggested that let‑7i may be a novel potential target for OS treatment.

Yan W, Liu Y, Yang P, et al.
MicroRNA profiling of Chinese primary glioblastoma reveals a temozolomide-chemoresistant subtype.
Oncotarget. 2015; 6(13):11676-82 [PubMed] Free Access to Full Article Related Publications
Accumulating evidence demonstrates that defining molecular subtypes based on objective genetic alterations may permit a more rational, patient-specific approach to molecular targeted therapy across various cancers. The objective of this study was to subtype primary glioblastoma (pGBM) based on MicroRNA (miRNA) profiling in Chinese population. Here, miRNA expression profiles from 82 pGBM samples were analyzed and 78 independent pGBM samples were used for qRT-PCR validation. We found that two distinct subgroups with different prognosis and chemosensitivities to temozolomide (TMZ) in Chinese pGBM samples. One subtype is TMZ chemoresistant (termed the TCR subtype) and confers a poor prognosis. The other subtype is TMZ-chemosensitive (termed the TCS subtype) and confers a relatively better prognosis compared with the TCR subtype. A classifier consisting of seven miRNAs was then identified (miR-1280, miR-1238, miR-938 and miR-423-5p (overexpressed in the TCR subtype); and let-7i, miR-151-3p and miR-93 (downregulated in the TCR subtype)), which could be used to assign pGBM samples to the corresponding subtype. The classifier was validated using both internal and external samples. Meanwhile, the genetic alterations of the TCR and TCS subtypes were also analyzed. The TCR subtype was characterized by no IDH1 mutation, and EGFR and Ki-67 overexpression. The TCS subtype displayed the opposite situation. Taken together, the results indicate a distinct subgroup with poor prognosis and TMZ-chemoresistance.

Li FQ, Xu B, Wu YJ, et al.
Differential microRNA expression in signet-ring cell carcinoma compared with tubular adenocarcinoma of human gastric cancer.
Genet Mol Res. 2015; 14(1):739-47 [PubMed] Related Publications
Gastric cancer is a disease with a heterogeneous pathology; its pathological mechanisms remain unclear because there is a poor understanding of its etiology. In this study, we identified differentially expressed microRNAs (miRNAs) among various gastric cancer subtypes. miRNA microarray analysis and bioinformatic analysis were used to compare miRNA expression between the signet-ring cell carcinoma and tubular adenocarcinoma subtypes of gastric cancer. Thirteen dysregulated miRNAs were identified in signet-ring cell carcinoma compared with tubular adenocarcinoma: miR-30a, miR-26b, miR-381, let-7i, miR-29c, miR-543, miR-499-3p, miR-628-3p, miR-524-5p, miR-181b, miR-1914, miR-663b, and miR-676. This is the first time that miR-499-3p, miR-628-3p, miR-524-5p, and miR-1914 have been identified in gastric cancer tissues. Bioinformatic analysis using target prediction algorithms indicated that these miRNAs are directly involved in gastric cancer pathogenesis and have different pathological mechanisms in various subtypes of signet-ring cell carcinoma and tubular adenocarcinoma. The miRNA expression patterns in different gastric adenocarcinoma subtypes may help discriminate between signet-ring cell and tubular gland cancer or other gastric cancer subtypes that would otherwise be difficult to identify using routine histological and immunohistochemical analyses. These preliminary data should be verified in further prospective studies.

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