Research IndicatorsGraph generated 13 March 2017 using data from PubMed using criteria.
Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic. Tag cloud generated 13 March, 2017 using data from PubMed, MeSH and CancerIndex
Specific Cancers (3)
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).
Numbers shown below represent number of publications held in OncomiRDB database for Oncogenic and Tumor-Suppressive MicroRNAs.
|Tissue||Target Gene(s)||Regulator(s)||MIR106A Function in Cancer||Effect|
-colorectal cancer (1)
|TGFBR2 (1)||promote cell migration (1)|
promote cell invasion (1)
-breast cancer (1)
|E2F1 (1)||inhibit cell proliferation (1)|
induce apoptosis (1)
Source: OncomiRDB Wang D. et al. Bioinformatics 2014, 30(15):2237-2238.
miRBase, University of Manchester
Annotated database entry including the location and sequence of the mature miRNA sequence.
miRCancer, East Carolina University
Search miRCancer for miR-106a associations with cancer and associated genes.
OMIM, Johns Hopkin University
Referenced article focusing on the relationship between phenotype and genotype.
International Cancer Genome Consortium.
Summary of gene and mutations by cancer type from ICGC
COSMIC, Sanger Institute
Somatic mutation information and related details
GEO Profiles, NCBI
Search the gene expression profiles from curated DataSets in the Gene Expression Omnibus (GEO) repository.
Latest Publications: MIR106A (cancer-related)
Shin SS, Park SS, Hwang B, et al.MicroRNA-106a suppresses proliferation, migration, and invasion of bladder cancer cells by modulating MAPK signaling, cell cycle regulators, and Ets-1-mediated MMP-2 expression.
Oncol Rep. 2016; 36(4):2421-9 [PubMed
] Related Publications
Despite the clinical significance of tumorigenesis, little is known about the cellular signaling networks of microRNAs (miRs). Here we report a new finding that mir‑106a regulates the proliferation, migration, and invasion of bladder cancer cells. Basal expression levels of mir‑106a were significantly lower in bladder cancer cells than in normal urothelial cells. Overexpression of mir‑106a suppressed the proliferation of bladder cancer cell line EJ. Transient transfection of mir‑106a into EJ cells led to downregulation of ERK phosphorylation and upregulation of p38 and JNK phosphorylation over their levels in the control. Flow cytometry analysis revealed that mir‑106a-transfected cells accumulated in the G1-phase of the cell cycle, and cyclin D1 and CDK6 were significantly downregulated. This G1-phase cell cycle arrest was due in part to the upregulation of p21CIP1/WAF1. In addition, mir‑106a overexpression blocked the wound-healing migration and invasion of EJ cells. Furthermore, mir‑106a transfection resulted in decreased expression of MMP-2 and diminished binding activity of transcription factor Ets-1 in EJ cells. Collectively, we report the novel mir‑106a-mediated molecular signaling networks that regulate the proliferation, migration, and invasion of bladder cancer cells, suggesting that mir‑106a may be a therapeutic target for treating advanced bladder tumors.
Chen L, Zhang F, Sheng XG, et al.MicroRNA-106a regulates phosphatase and tensin homologue expression and promotes the proliferation and invasion of ovarian cancer cells.
Oncol Rep. 2016; 36(4):2135-41 [PubMed
] Related Publications
Ovarian cancer is a leading cause of malignant gynecological tumor-related mortality among women. The treatment of ovarian cancer patients continues to be challenging. MicroRNA‑106a (miR‑106a) is widely expressed in diverse human tumors. In the present study, we investigated the biological and pathological roles of miR-106a in ovarian cancers. We found that miR-106a expression was significantly increased in primary ovarian cancer tissues and ovarian cancer cells compared with the level in normal tissues. Ectopic expression of an miR-106a inhibitor attenuated ovarian cancer cell proliferation and invasion. miR-106a promoted the growth and invasion of SKOV3 cells by targeting phosphatase and tensin homolog (PTEN). Furthermore, the present study revealed that IL-6 inhibited miR-106a expression by activating STAT3. Tocilizumab, a humanized anti-human IL-6R antibody, that competitively inhibits IL-6/IL-6R signaling, did not inhibit the proliferation and invasion of SKOV3 cells. In conclusion, our studies revealed that miR-106a was significantly increased in the ovarian cancer tissues and cell lines. Downregulation of the expression of miR-106a inhibited cell growth and metastasis of ovarian cancer cells. Together, the present study suggests that miR‑106a acts as an oncogene in ovarian cancers.
He QY, Wang GC, Zhang H, et al.miR-106a-5p Suppresses the Proliferation, Migration, and Invasion of Osteosarcoma Cells by Targeting HMGA2.
DNA Cell Biol. 2016; 35(9):506-20 [PubMed
] Related Publications
We aim to investigate the effect of miR-106a-5p on the proliferation, migration, and invasion of osteosarcoma (OS) cells by targeting high-mobility group AT-hook 2 (HMGA2). Real-time fluorescent quantitative polymerase chain reaction (RT-qPCR) was used for detecting the expressions of miR-106-5p and HMGA2 in 137 OS and adjacent normal bone tissues. Immunohistochemistry was applied for the HMGA2 protein expression detection. Luciferase reporter gene assay was conducted for verifying whether miR-106-5p targeted HMGA2. MG63 and U2SO cells were respectively divided into five groups: Blank, miR-106a-5p, scramble, HMGA2-siRNA, and miR-106a-5p+HMGA2 groups. RT-qPCR and western blot were applied for detecting the expressions of miR-106a-5p and HMGA2 in five groups. Proliferation rate, cell cycle, invasion, and migration ability of OS cells were detected using methyl thiazolyl-tetrazolium, 5-ethynyl-2'-deoxyuridine (Edu) assay, flow cytometry, and Transwell. Compared with adjacent normal tissues, OS tissues presented with decreased miR-106a-5p expressions, elevated HMGA2 mRNA, and positive expressions (all p < 0.05). The sensitivity and specificity of miR-106a-5p were 97.8%, 93.43%, and HMGA2 mRNA were 97.8%, 99.27%, separately. miR-106a-5p and HMGA2 expressions were associated with tumor size, Enneking stage, distant metastasis, and lung metastasis. Expressions of HMGA2 in OS cells in miR-106a-5p and HMGA2 siRNA groups were both significantly decreased with the same downregulation level, and the proliferation rates in both groups were obviously slowed down after 48 h (both p < 0.001). Edu positive cells, S phase cells (majority of cells blocked at G0/G1 phase), migratory and invasive cells were obviously decreased (all p < 0.05). Downregulation of miR-106a-5p was found in OS tissues, and upregulation of miR-106a-5p can inhibit the proliferation, migration, and invasion by targeting HMGA2 in OS cells.
MicroRNAs (miRNAs) are aberrantly expressed in virtually all cancer types, including digestive cancers. Herein, we aggregated and systematically analyzed miRNA expression profiles of 1765 tumor samples, including esophageal, gastric, liver, pancreatic, colon and rectal cancers, obtained through small RNA sequencing by The Cancer Genome Atlas. We found that digestive cancers of different tissue origins could be differentiated according to their miRNA expression profiles. In particular, esophageal squamous cell carcinoma and esophageal adenocarcinoma exhibited distinct miRNA expression patterns. Thirteen (e.g. miR-135b, miR-182) and sixteen (e.g. miR-139, miR-133a-1, miR-490) miRNAs were commonly upregulated and downregulated in more than four cancer types, respectively. Pertinent to pathological features, low miR-181d expression was associated with microsatellite instability in colon and gastric cancers whereas low miR-106a expression was associated with hepatitis B virus infection in hepatocellular carcinoma. Progression in colon cancer could also be predicted by low let-7f-2 and high miR-106a expression. Molecular subtypes with distinct prognostic outcomes independent of tumor-node-metastasis staging were identified in hepatocellular carcinoma and colon cancer. In total, 4 novel and 6 reported associations between specific miRNAs and patients' survival were identified. Collectively, novel miRNA markers were identified to stratify digestive cancers with different pathological features and survival outcomes.
Validation of biomarkers is essential to advance the translational process to clinical application. Although there exists an increasing number of reports on small non-coding RNAs (microRNAs) as minimally-invasive markers from blood, serum or plasma, just a limited number is verified in follow-up studies. We used qRT-PCR to evaluate a known miRNA signature measured from blood that allowed for separation between patients with non-small cell lung cancer (NSCLC), COPD and healthy controls.From the data of our previous microarray studies we selected a panel of 235 miRNAs related to lung cancer and COPD. We observed a high concordance between the AUC values of our initial microarray screening and the qRT-PCR data (correlation of 0.704, p < 10-16). Overall, 90.3% of markers were successfully validated. Among the top markers that were concordant between both studies we found hsa-miR-20b-5p, hsa-miR-20a-5p, hsa-miR-17-5p, and hsa-miR-106a-5p. The qRT-PCR analysis also confirmed that non-small cell lung cancer patients could be accurately differentiated from unaffected controls: a subset of five markers was sufficient to separate NSCLC patients from unaffected controls with accuracy of 94.5% (specificity and sensitivity of 98% and 91%). Beyond differentiation from controls, we also succeeded in separating NSCLC patients from patients with COPD. MiRNAs that were identified as relevant for the separation between lung cancer and COPD by both qRT-PCR and the array-based studies included hsa-miR-26a-5p, hsa-miR-328-3p and hsa-miR-1224-3p. Although for differentiation between NSCLC patients from COPD patients more markers were required, still high accuracy rates were obtained (5 markers: 78.8%; 10 markers: 83.9%; 50 markers: 87.6%).
Gu R, Huang S, Huang W, et al.MicroRNA-17 family as novel biomarkers for cancer diagnosis: a meta-analysis based on 19 articles.
Tumour Biol. 2016; 37(5):6403-11 [PubMed
] Related Publications
Cancer remains as the leading cause of death all over the world due to the lack of efficient diagnostic techniques and therapeutic methods. Many studies have reported the potential diagnostic value of microRNA-17 (miRNA-17, miR-17) family members as biomarkers for cancer detection. However, inconsistent results were revealed from a wide range of studies. As a result of this, a meta-analysis based on 19 studies was conducted to assess the diagnostic performance of miR-17 family for cancer detection. A total of 1772 patients with certain types of cancer and 1320 healthy controls were involved in these studies. The overall diagnostic accuracy was measured by the following: sensitivity, 0.67 (95 % confidence interval (CI) 0.60-0.74); specificity, 0.83 (95 % CI 0.74-0.85); positive likelihood ratio (PLR), 3.9 (95 % CI 2.6-5.9); negative likelihood ratio (NLR), 0.40 (95 % CI 0.34-0.48); and diagnostic odds ratio (DOR), 10 (95 % CI 6-16), respectively. Additionally, the pooled area under the summary receiver operator characteristic (SROC) curve (area under the curve (AUC)) was 0.79 (95 % CI 0.75-0.82), indicating a relatively low accuracy of miR-17 family as biomarkers for cancer detection. Subgroup analysis further showed that miR-17 family had more reliable performance in cancer diagnosis for Asian than that for Caucasian. Moreover, multiple miRNAs containing miR-17, -20a/b, and -93 reflected higher diagnostic accuracy than both miR-106a/b (single miRNA) and the overall miR-17 family assay. Therefore, appropriate combinations of miR-17 family may be used as non-invasive screening biomarkers for cancer, and it is necessary to carry out a large-scale population-based study to further assess the potential diagnostic value of miR-17 family.
Guo W, Zhang Y, Zhang Y, et al.Decreased expression of miR-204 in plasma is associated with a poor prognosis in patients with non-small cell lung cancer.
Int J Mol Med. 2015; 36(6):1720-6 [PubMed
] Related Publications
In order to identify novel non-invasive biomarkers with high accuracy for the screening of non-small cell lung cancer (NSCLC), we investigated the predictive power of 4 microRNAs (miR-146, miR-204, miR-106a and miR-124) in plasma samples obtained from patients with NSCLC and healthy controls (n=50; training phase) by reverse transcription-quantitative polymerase chain reaction (RT-qPCR). We found that the levels of miR-204 in the patients with NSCLC were significantly dysregulated compared with the healthy controls, and thus this miRNA was selected for further validation. For the validation phase, RT-qPCR was performed on plasma samples from patients with NSCLC and healthy controls (n=176) in order to examine the expression levels of the candidate miRNA, miR-204. The results revealed that the plasma levels of miR-204 were significantly downregulated in the patients with NSCLC compared with the healthy controls (p<0.001). The value of the area under the receiver operating characteristic (ROC) curve obtained for miR-204 was 0.809 (sensitivity, 76%; specificity, 82%), which was higher than the values obtained for carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9 (CA19-9). The expression of miR-204 in plasma significantly correlated with the tumor stage (p=0.009) and distant metastasis (p=0.048). A log-rank test revealed that lower plasma levels of miR-204 were associated with a shorter overall survival and disease-free survival (p=0.006 and 0.0065, respectively). Both univariate and multivariate Cox regression analyses indicated that a lower miR-204 expression level in plasma was a prognostic factor with a relative risk of death of 1.936 and 1.712, respectively. On the whole, our results suggest that the decreased expression of miR-204 in plasma is a promising biomarker for the detection of NSCLC and the prediction of poor survival in patients with the disease.
Recently, rapid advances in bioinformatics analysis have expanded our understanding of the transcriptome to a genome-wide level. miRNA-mRNA-lncRNA interactions have been shown to play critical regulatory role in cancer biology. In this study, we discussed the use of an integrated systematic approach to explore new facets of the oestrogen receptor (ER)-regulated transcriptome. The identification of RNAs that are related to the expression status of the ER may be useful in clinical therapy and prognosis. We used a network modelling strategy. First, microarray expression profiling of mRNA, lncRNA and miRNA was performed in MCF-7 (ER-positive) and MDA-MB-231 cells (ER- negative). A co-expression network was then built using co-expression relationships of the differentially expressed mRNAs and lncRNAs. Finally, the selected miRNA-mRNA network was added to the network. The key miRNA-mRNA-lncRNA interaction can be inferred from the network. The mRNA and non-coding RNA expression profiles of the cells with different ER phenotypes were distinct. Among the aberrantly expressed miRNAs, the expression levels of miR-19a-3p, miR-19b-3p and miR-130a-3p were much lower in the MCF-7 cells, whereas that of miR-148b-3p was much higher. In a cluster of miR-17-92, the expression levels of six of seven miRNAs were lower in the MCF-7 cells, in addition to miR-20b in the miR-106a-363 cluster. However, the levels of all the miRNAs in the miR-106a-25 cluster were higher in the MCF-7 cells. In the co-expression networking, CD74 and FMNL2 gene which is involved in the immune response and metastasis, respectively, had a stronger correlation with ER. Among the aberrantly expressed lncRNAs, lncRNA-DLEU1 was highly expressed in the MCF-7 cells. A statistical analysis revealed that there was a co-expression relationship between ESR1 and lncRNA-DLEU1. In addition, miR-19a and lncRNA-DLEU1 are both located on the human chromosome 13q. We speculate that miR-19a might be co-expressed with lncRNA-DLEU1 to co-regulate the expression of ESR1, which influences the occurrence and development of breast cancer cells with different levels of ER expression. Our findings reveal that the status of ER is mainly due to the differences in the mRNA and ncRNA profile between the breast cancer cell lines, and highlight the importance of studying the miRNA-mRNA-lncRNA interactions to completely illustrate the intricate transcriptome.
In recent years, not only has the role of miRNAs in cancer become increasingly clear but also their utilization as potential biomarkers and therapeutic targets has gained ground. Although the importance of dietary stilbenes such as resveratrol and pterostilbene as anti-cancer agents is well recognized, our understanding of their miRNA-targeting capabilities is still limited. In our previous study, we reported that resveratrol downregulates PTEN-targeting members of the oncogenic miR-17 family, which are overexpressed in prostate cancer. This study investigates the resveratrol and pterostilbene induced miRNA-mediated regulation of PTEN in prostate cancer. Here, we show that both compounds decrease the levels of endogenous as well as exogenously expressed miR-17, miR-20a and miR-106b thereby upregulating their target PTEN. Using functional luciferase reporter assays, we demonstrate that ectopically expressed miR-17, miR-20a and miR-106b directly target PTEN 3'UTR to reduce its expression, an effect rescued upon treatment with resveratrol and pterostilbene. Moreover, while stable lentiviral expression of miR-17/106a significantly decreased PTEN mRNA and protein levels and conferred survival advantage to the cells, resveratrol and more so pterostilbene was able to dramatically suppress these effects. Further, pterostilbene through downregulation of miR-17-5p and miR-106a-5p expression both in tumors and systemic circulation, rescued PTEN mRNA and protein levels leading to reduced tumor growth in vivo. Our findings implicate dietary stilbenes as an attractive miRNA-mediated chemopreventive and therapeutic strategy, and circulating miRNAs as potential chemopreventive and predictive biomarkers for clinical development in prostate cancer.
Aberrantly expressed long noncoding RNAs (lncRNAs) are associated with various cancers. However, the roles of lncRNAs in the pathogenesis of most cancers are unclear. Here, we report that the lncRNA FER1L4 (fer-1-like family member 4, pseudogene) acts as a competing endogenous RNA (ceRNA) to regulate the expression of PTEN (a well-known tumor suppressor gene) by taking up miR-106a-5p in gastric cancer. We observed that FER1L4 was downregulated in gastric cancer and that its level corresponded with that of PTEN mRNA. Both FER1L4 and PTEN mRNA were targets of miR-106a-5p. Further experiments demonstrated that FER1L4 downregulation liberates miR-106a-5p and decreases the abundances of PTEN mRNA and protein. More importantly, FER1L4 downregulation accelerated cell proliferation by promoting the G0/G1 to S phase transition. We conclude that one mechanism by which lncRNAs function in in tumorigenesis is as ceRNAs for tumor suppressor mRNAs.
de Melo Maia B, Ling H, Monroig P, et al.Design of a miRNA sponge for the miR-17 miRNA family as a therapeutic strategy against vulvar carcinoma.
Mol Cell Probes. 2015; 29(6):420-6 [PubMed
] Related Publications
Dysregulation of microRNAs has been studied thoroughly, and has been observed in a variety of tumors including vulvar carcinomas, a rare type of gynecological tumor with increasing incidence. However, very few therapeutic alternatives have reached the clinical setting, and there is an urgent unmet need to develop novel strategies for patients with this tumor type. Thus, a microRNA (miRNA) sponge for the miR-17 miRNA family was designed, synthesized and validated in vitro in order to explore a new therapeutic strategy based on inhibiting this oncogenic miRNA family in vulvar cancer. Members of the miR-17 family were evaluated for expression in a vulvar tumor cell line (SW954) and 20 HPV negative formalin-fixed paraffin-embedded (FFPE) samples by quantitative real-time PCR (qRT-PCR). Six in tandem, bulged sequences that were complementary to these miRNAs were designed, synthesized, cloned, and transfected into SW954 cells. A luciferase reporter assay with a psiCheck2 vector was used to test the specificity of the sponge sequences for miR-17 family miRNA binding. Taqman qRT-PCR was used to test how the sponges affected miRNA expression. In FFPE samples, higher expression of miR-20a and miR-106a correlated with deeper tumor invasion (P = 0.0187 and P = 0.0404, respectively). The luciferase reporter assay validated the specificity of the sponge for miR-17 family members. Using qRT-PCR, we confirmed this specificity with decreased expression in 5 (out of six) miRNAs of the miR-17 family in SW954 cells. Although our results are preliminary, these results demonstrate that these miRNA sponges are potent inhibitors of the miR-17 family of miRNAs in SW954. Therefore, this miRNA-specific sponge may be developed into a novel therapeutic treatment for patients with vulvar cancer.
We sought to identify a serum miRNA expression profile to improve disease surveillance and to predict post-operative disease recurrence for stage II/III colorectal cancer (CRC) patients. Using the TaqMan Low-Density Array (TLDA), we performed an initial survey to analyze 749 miRNAs in the pooled serum of 20 paired pre- and post-operative CRC patients and 20 matched normal subjects. Using individual RT-qPCR verification in 175 stage II/III CRC patients, we identified that miR-145, miR-106a and miR-17-3p were significantly differentially expressed between pre- and post-operative CRC patients and between pre-operative CRC patients and normal controls (P < 0.0001). The area under the ROC curve (AUC) for the three-miRNA panel was 0.886 (95% CI 0.850-0.921) for discriminating between pre-operative CRC patients and normal subjects and 0.850 (95% CI 0.809-0.891) for discriminating between pre- and post-operative CRC patients. Furthermore, using the Kaplan-Meier method and Cox proportional hazards analysis, we found that miR-17-3p and miR-106a were powerful and independent prognostic indicators and that high levels of these miRNAs were associated with shorter disease-free survival (DFS) (P < 0.0001 for miR-17-3p and P = 0.001 for miR-106a). The present study reveals novel serum-miRNA-based biomarkers for monitoring tumor dynamics as well as for predicting disease recurrence in patients with stage II/III CRC.
Novel long non-coding RNA Fer-1-like protein 4 (FER1L4) has been confirmed to play crucial regulatory roles in tumor progression. It exerts an impact on tumor suppression and functions as a competing endogenous RNA (ceRNA) by sponging miR-106a-5p in gastric cancer. However, its clinical significance in colon cancer is completely unknown. The aim of the present study was to annotate the role of FER1L4 and its clinical value in colon cancer. The results showed the aberrant expression of FER1L4 and miR-106a-5p in colon cancer tissues. In addition, significant negative correlation between FER1L4 and miR-106a-5p expression levels was observed. Among the colon cancer cell lines, FER1L4 levels were relatively lower, with concurrent high levels of miR-106a-5p. Restoration of FER1L4 decreased the expression of miR-106a-5p, and had a significant influence on colon cancer cell proliferation, migration and invasion. The FER1L4 expression was correlated with depth of tumor invasion, lymph node metastasis, vascular invasion and clinical stage. Moreover, striking differences in overall survival and disease-free survival were observed for the cases with both low FER1L4 expression and high miR-106a-5p expression compared with cases with high FER1L4 expression and low miR-106a-5p expression. Circulating FER1L4 and miR-106a-5p levels were decreased and increased, respectively, in colon cancer patients after surgery. Our findings indicated that FER1L4 could exert a tumor suppressive impact on colon cancer, which at least, in part, through suppressing miR-106a-5p expression, and depletion of FER1L4, alone or combined with overexpression of miR-106a-5p, is predictive of poor prognosis in colon cancer and may play a crucial role in cancer prevention and treatment.
BACKGROUND: Growing evidence suggests that microRNAs (miRNAs) play an important role in tumor development, progression and metastasis. Aberrant miR-106b expression has been reported in several cancers. However, the role and underlying mechanism of miR-106 in colorectal cancer (CRC) have not been addressed.
METHODS: Quantitative RT-PCR(qRT-PCR) was performed to evaluate miR-106b levels in CRC cell lines and patient specimens. Cell proliferation was detected using MTT assay, and cell migration and invasion ability were evaluated by wound healing assay and transwell assay. The target gene of miR-106b was determined by qRT-PCR, western blot and luciferase assays.
RESULTS: miR-106b was significantly up-regulated in metastatic CRC tissues and cell lines, and high miR-106b expression was associated with lymph node metastasis and advanced clinical stage. In addition, miR-106b overexpression enhances, whereas miR-106b depletion reduces CRC cell migration and invasion. Moreover, we identify DLC1 as a direct target of miR-106b, reveal its expression to be inversely correlated with miR-106b in CRC samples and show that its re-introduction reverses miR-106b-induced CRC cell migration and invasion. Furthermore, survival analyses showed the patients with high mi-106b/low DLC1 had shorter overall survival (OS) and disease-free survival (DFS) rates, and confirmed miR-106b may be an independent prognostic factor for OS and DFS in CRC patients.
CONCLUSIONS: Our findings indicate that miR-106b promotes CRC cell migration and invasion by targeting DLC1. This miRNA may serve as a potential prognostic biomarker and therapeutic target for CRC.
MicroRNAs are a class of small non-coding RNAs that play essential roles in cancer development and progression. Recent studies suggested that abnormal expression of miRNAs occurs frequently in non-small cell lung cancer (NSCLC) tissues compared to adjacent normal tissues. In this study, we investigated the expression and the biological roles of miR-106a in non-small cell lung cancer. Our results showed that miR-106a was up-regulated in NSCLC tissues and cell lines. Inhibition of miR-106a in NSCLC cells substantially inhibited cell proliferation, migration, and invasion. Phosphatase and tensin homolog (PTEN) was identified as a direct target of miR-106a, and over-expression of miR-106a suppressed PTEN by direct binding to its 3'-untranslated region (3'-UTR). Furthermore, the presence of miR-106a was inversely correlated with PTEN in NSCLC tissues. Overall, this study suggested that miR-106a inhibited the growth and metastasis of NSCLC cells by decreasing PTEN expression. These data provide novel insights with potential therapeutic applications for the treatment of NSCLC.
Tumor cells have developed advantages to acquire hallmarks of cancer like apoptosis resistance, increased proliferation, migration, and invasion through cell signaling pathway misregulation. The sequential activation of genes in a pathway is regulated by miRNAs. Loss or gain of miRNA expression could activate or repress a particular cell axis. It is well known that aberrant miRNA expression is well recognized as an important step in the development of cancer. Individual miRNA expression is reported without considering that miRNAs are grouped in clusters and may have similar functions, such as the case of clusters with anti-oncomiRs (23b~27b~24-1, miR-29a~29b-1, miR-29b-2~29c, miR-99a~125b-2, miR-99b~125a, miR-100~125b-1, miR-199a-2~214, and miR-302s) or oncomiRs activity (miR-1-1~133a-2, miR-1-2~133a-1, miR-133b~206, miR-17~92, miR-106a~363, miR183~96~182, miR-181a-1~181b-1, and miR-181a-2~181b-2), which regulated mitogen-activated protein kinases (MAPK), phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K), NOTCH, proteasome-culling rings, and apoptosis cell signaling. In this work we point out the pathways regulated by families of miRNAs grouped in 20 clusters involved in cervical cancer. Reviewing how miRNA families expressed in cluster-regulated cell path signaling will increase the knowledge of cervical cancer progression, providing important information for therapeutic, diagnostic, and prognostic methodology design.
Ma Y, Zhang H, He X, et al.miR-106a* inhibits the proliferation of renal carcinoma cells by targeting IRS-2.
Tumour Biol. 2015; 36(11):8389-98 [PubMed
] Related Publications
MicroRNAs play critical roles in the development and progression of human cancers. Although it has been reported that miR-106a* is downregulated in follicular lymphoma, its role in renal cell carcinoma (RCC) remains unknown. This study investigated the expression and role of miR-106a* in human RCC. Our results showed that the miR-106a* expression decreased dramatically in clinical RCC tissues and cell lines. In vitro, overexpression of miR-106a* suppressed RCC cell proliferation and S/G2 transition, whereas inhibition of miR-106a* promoted cell proliferation and S/G2 transition. It was also found that miR-106a* expression was inversely correlated with the expression of insulin receptor substrate 2 (IRS-2). IRS-2 was determined to be a direct target of miR-106a* by a luciferase reporter assay. Importantly, silencing IRS-2 resulted in the same biologic effects as those of miR-106a* overexpression in RCC cells, including inhibition of RCC cell proliferation and triggering of S/G2 cell cycle arrest with inhibition of the PI3K/Akt signaling pathway. These results indicate that miR-106a* affects RCC progression by targeting IRS-2 with suppression of the PI3K/Akt signaling pathway in RCC cells. The findings suggest miR-106a* as a novel strategy for RCC treatment.
Jha P, Agrawal R, Pathak P, et al.Genome-wide small noncoding RNA profiling of pediatric high-grade gliomas reveals deregulation of several miRNAs, identifies downregulation of snoRNA cluster HBII-52 and delineates H3F3A and TP53 mutant-specific miRNAs and snoRNAs.
Int J Cancer. 2015; 137(10):2343-53 [PubMed
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Pediatric high-grade gliomas (HGGs) are highly malignant tumors that remain incurable and relatively understudied. The crucial role of noncoding RNAs (ncRNAs) has been reported in various cancers. However, the study on miRNAs in pediatric HGGs is scant and there is no report till date on the status of other small ncRNAs. Genome-wide microarray analysis was performed to investigate small ncRNA expression in pediatric HGG (n = 14) and compared to adult glioblastoma (GBM) signature. The validation of miRNAs and small nucleolar RNAs (snoRNAs) was done by real-time polymerase chain reaction. TP53 and H3F3A mutation-specific miRNA and snoRNA profiles were generated and analyzed. Pediatric HGGs showed upregulation of miR-17/92 and its paralog clusters (miR106b/25 and miR-106a/363), whereas majority of downregulated miRNAs belonged to miR379/656 cluster (14q32). Unsupervised hierarchical clustering identified two distinct groups. Interestingly, Group 2 with downregulated 14q32 cluster showed better overall survival. The miRNAs unique to pediatric HGG as compared to adult GBM were predicted to affect PDGFR and SMAD2/3 pathways. Similarities were seen between pediatric HGG and TP53 mutant miRNA profiles as compared to wild types. Several of H3F3A mutation-regulated genes were found to be the targets of H3F3A mutant-specific miRNAs. Remarkably, a significant downregulation of HBII-52 snoRNA cluster was found in pediatric HGGs, and was specific to H3F3A nonmutants. This is the first genome-wide profiling study on miRNAs and snoRNAs in pediatric HGGs with respect to H3F3A and TP53 mutations. The comparison of miRNA profiles of pediatric HGGs and adult GBM reiterates the overlaps and differences as also seen with their gene expression and methylation signatures.
Chemotherapy resistance is one of the major obstacles to effective glioma therapy. Currently, the mechanism underlying chemotherapy resistance is unclear. A recent study showed that miR-106a is an important molecule involved in chemotherapy resistance. To explore the effects and mechanisms of miR-106a on multidrug resistance reversal in human glioma cells, we silenced miR-106a expression in the cisplatin-resistant U87 (U87/DDP) and the gefitinib-resistant U251 (U251/G) glioma cell lines and measured the resulting drug sensitivity, cell apoptosis rate and rhodamine 123 content. In addition, we detected decreased expression of P-glycoprotein, MDR1, MRP1, GST-π, CDX2, ERCC1, RhoE, Bcl-2, Survivin and Topo-II, as well as reduced production of IL-6, IL-8 and TGF-β in these cell lines. Furthermore, we found decreased expression of p-AKT and transcriptional activation of NF-κB, Twist, AP-1 and Snail in these cell lines. These results suggest that miR-106a is a promising therapeutic target for the treatment of human multidrug resistant glioma.
Fallah P, Amirizadeh N, Poopak B, et al.Expression pattern of key microRNAs in patients with newly diagnosed chronic myeloid leukemia in chronic phase.
Int J Lab Hematol. 2015; 37(4):560-8 [PubMed
] Related Publications
INTRODUCTION: Chronic myeloid leukemia (CML) is caused by reciprocal translocation in hematopoietic stem cells (HSCs). This translocation forms the BCR-ABL1 oncogene, which alters several signaling pathways that control malignancy. CML has three phases: chronic, accelerated, and blast crisis. The microRNAs (miRNAs or miRs) are noncoding RNAs that downregulate their target gene by targeting 3' UTR of mRNA or through translational inhibition. It has been shown that miRNAs regulate many biological processes, and dysregulation of these regulatory RNAs is involved in disease development, particularly in cancer. The important role of miRNAs as therapeutic agents and biomarkers has been demonstrated in CML patients at different phases of the disease.
METHODS: Stem-loop reverse transcription polymerase chain reaction was used to characterize differentially expressed miRNAs of leukocytes in the peripheral blood of 50 newly diagnosed CML patients in chronic phase.
RESULTS: Some onco-miRNAs were found to be downregulated (miR-155 and miR-106), and some tumor suppressor miRs (miR-16-1, miR-15a, miR-101, miR-568) were upregulated.
CONCLUSION: These results show that very few miRNAs alone would be good candidates for CML diagnosis independently of conflicting results, but together could be an additional tool for CML diagnosis. Moreover, miRNAs might be good candidates for prognosis prediction and CML therapy.
Feng M, Luo X, Gu C, et al.Systematic analysis of berberine-induced signaling pathway between miRNA clusters and mRNAs and identification of mir-99a ∼ 125b cluster function by seed-targeting inhibitors in multiple myeloma cells.
RNA Biol. 2015; 12(1):82-91 [PubMed
] Free Access to Full Article Related Publications
BACKGROUND: Berberine (BBR) is a natural alkaloid derived from a traditional Chinese herbal medicine. However, the exact mechanisms underlying the different effects of berberine on MM cells have not been fully elucidated.
METHODS: A systematic analysis assay integrated common signaling pathways modulated by the 3 miRNA clusters and mRNAs in MM cells after BBR treatment. The role of the mir-99a ∼ 125b cluster, an important oncomir in MM, was identified by comparing the effects of t-anti-mirs with complete complementary antisense locked nucleic acids (LNAs) against mature mir-125b (anti-mir-125b).
RESULTS: Three miRNAs clusters (miR-99a ∼ 125b, miR-17 ∼ 92 and miR-106 ∼ 25) were significantly down-regulated in BBR-treated MM cells and are involved in multiple cancer-related signaling pathways. Furthermore, the top 5 differentially regulated genes, RAC1, NFκB1, MYC, JUN and CCND1 might play key roles in the progression of MM. Systematic integration revealed that 3 common signaling pathways (TP53, Erb and MAPK) link the 3 miRNA clusters and the 5 key mRNAs. Meanwhile, both BBR and seed-targeting t-anti-mir-99a ∼ 125b cluster LNAs significantly induced apoptosis, G2-phase cell cycle arrest and colony inhibition.
CONCLUSIONS: our results suggest that BBR suppresses multiple myeloma cells, partly by down-regulating the 3 miRNA clusters and many mRNAs, possibly through TP53, Erb and MAPK signaling pathways. The mir-99a ∼ 125b cluster might be a novel target for MM treatment. These findings provide new mechanistic insight into the anticancer effects of certain traditional Chinese herbal medicine compounds.
MicroRNAs (miRNAs) enable colonic epithelial cells to acquire malignant characteristics and metastatic capabilities. Recently, cancer relevant miRNAs deregulated during disease progression have also been identified in tumor-associated stroma.By combining laser-microdissection (LMD) with high-throughput screening and high-sensitivity quantitation techniques, miRNA expression in colorectal cancer (CRC) specimens and paired normal colonic tissue was independently characterized in stromal and epithelial tissue compartments. Notably, deregulation of the key oncogene miR-21 was identified exclusively as a stromal phenomenon and miR-106a, an epithelial phenomenon in the malignant state.MiRNAs identified in this study successfully distinguished CRC from normal tissue and metastatic from non-metastatic tumor specimens. Furthermore, in a separate cohort of 50 consecutive patients with CRC, stromal miR-21 and miR-556 and epithelial miR-106a expression predicted short disease free survival (DFS) and overall survival (OS) in stage II disease: miR-21 (DFS: HR = 2.68, p = 0.015; OS: HR = 2.47, p = 0.029); miR-556 (DFS: HR = 2.60, p = 0.018); miR-106a (DFS: HR = 2.91, p = 0.008; OS: HR = 2.25, p = 0.049); combined (All High vs. All Low. DFS: HR = 5.83, p = 0.002; OS: HR = 4.13, p = 0.007).These data support the notion that stromal as well as epithelial miRNAs play important roles during disease progression, and that mapping patterns of deregulated gene expression to the appropriate tumor strata may be a valuable aid to therapeutic decision making in CRC.
Qiu ZL, Shen CT, Song HJ, et al.Differential expression profiling of circulation microRNAs in PTC patients with non-131I and 131I-avid lungs metastases: a pilot study.
Nucl Med Biol. 2015; 42(5):499-504 [PubMed
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INTRODUCTION: Loss of the ability to concentrate (131)I is one of the important causes of radioiodine-refractory disease in papillary thyroid carcinoma (PTC). Recent advantages of serum microRNAs (miRNAs) open a new realm of possibilities for noninvasive diagnosis and prognosis of many cancers. The aim of the current study was to identify differential expression profiling of circulation miRNAs in PTC patients with non-(131)I and (131)I-avid lungs metastases.
METHODS: The expressions of miRNAs were examined using miRNA microarray chip. The most significantly changed miRNAs from microarray were verified by using qRT-PCR. The potential miRNAs regulating target genes and their preliminary biological functions were forecasted by Bioinformatic analysis.
RESULTS: Compared to (131)I-avid lung metastases, 13 kinds of significantly differential serum miRNAs including 5 upregulated miRNAs (miR-1249, miR-106a, miR-503, miR-34c-5p, miR-1281) and 8 downregulated miRNAs (miR-1915, miR-2861, miR-3196, miR-500, miR-572, miR-33b, miR-554, miR-18a) in PTC patients with non-(131) I-avid lung metastases were identified. Bioinformatic analysis demonstrated that miR-106a was the core miRNA regulating 193 genes in the network. The results of validation confirmed the up-regulation of miR-106a in non-(131)I-avid lungs metastatic PTC patients.
CONCLUSION: Differentially expressed serum miRNA profiles between PTC patients with non-(131)I and (131)I-avid lungs metastases were analyzed. These findings in our present study could represent new clues for the diagnostic and therapeutic strategy in PTC patients with non-(131)I-avid metastatic disease.
Gastric cancer is one of the most common malignant diseases and has one of the highest mortality rates worldwide. Its molecular mechanisms are poorly understood. Recently, the functions of non-coding RNAs (ncRNAs) in gastric cancer have attracted wide attention. Although the expression levels of various ncRNAs are different, they may work together in a network and contribute to gastric carcinogenesis by altering the expression of oncogenes or tumor suppressor genes. They affect the cell cycle, apoptosis, motility, invasion, and metastasis. Dysregulated microRNAs (miRNAs) and long non-coding RNAs (lncRNAs), including miR-21, miR-106, H19, and ANRIL, directly or indirectly regulate carcinogenic factors or signaling pathways such as PTEN, CDK, caspase, E-cadherin, Akt, and P53. Greater recognition of the roles of miRNAs and lncRNAs in gastric carcinogenesis can provide new insight into the mechanisms of tumor development and identify targets for anticancer drug development.
Battistella M, Romero M, Castro-Vega LJ, et al.The High Expression of the microRNA 17-92 Cluster and its Paralogs, and the Downregulation of the Target Gene PTEN, Is Associated with Primary Cutaneous B-Cell Lymphoma Progression.
J Invest Dermatol. 2015; 135(6):1659-67 [PubMed
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The oncogenic microRNA (miR) 17-92 cluster has a causative role in the lymphomagenesis of nodal B-cell lymphomas, by activating proliferation and inhibiting apoptosis. Here we analyzed primary cutaneous B-cell lymphomas for the miR-17-92 cluster and its paralogs miR-106a-363 and miR-106b-25. In 22 primary cutaneous diffuse large B-cell lymphomas, leg type (PCLBCL-LT) compared with 22 primary cutaneous follicle center lymphomas (PCFCLs), we found that miR-20a and miR-106a were overexpressed. Multivariate Cox analysis showed that higher miR-20a and miR-20b expression levels were associated with shorter disease-free and overall survival, independently from histological type. Gene expression profiling also showed a downregulation of 8 candidate target genes of miR-20a, miR-20b, and miR-106a in PCLBCL-LT compared with PCFCL. Among the candidate target genes, PTEN, NCOA3, and CAPRIN2 were confirmed to be underexpressed in PCLBCL-LT using quantitative reverse transcriptase-PCR on CD20-positive laser-microdissected tumor cells. In multivariate Cox analysis, lower PTEN mRNA expression level was associated with shorter disease-free survival (DFS), independently from the histological type. Altogether, this molecular and bioinformatic study of 44 patient skin biopsy samples showed that the oncogenic miR-17-92 cluster and its paralogs were involved in cutaneous B-cell lymphoma progression, and that the downregulation of the target gene PTEN was associated with shorter DFS.
Ozgur A, Tutar L, Tutar YRegulation of Heat Shock Proteins by miRNAs in human breast cancer.
Microrna. 2014; 3(2):118-35 [PubMed
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Metabolic rates of cancer cells are faster compared to normal cells. This faster rate yields aberrant protein folding and causes loss of protein function. Therefore, cancer cells need more Heat Shock Proteins (HSPs) for proper substrate- protein folding on oncogenic pathways. Pseudogenes regulate tumor suppressors and oncogenes, and pseudogenes are deregulated in cancer progression. Further, alterations in miRNA expression have been identified in different cancer types. MiRNAs also have both oncogenic and tumour-suppressive roles in breast cancer post-transcriptional gene regulation. Breast cancer is a genetic disease and we performed miRNA analysis in human breast cancer cell lines to identify miRNAs in association with HSPs and pseudogenes by employing CellMiner; a web-based suite. CellMiner integrates several databases and help analysing microarray metadata. The experimental data provide a platform for researchers to compare macromolecules' relationships in NCI-60 cell lines. Breast cancer associated miRNAs gathered from literature and analyzed by employing this suite, significantly correlated HSP genes and pseudogenes in the breast cancer are determined as; HSPA13, HSP90AB1, TRAP1, HSPB1, DNAJB4, HSPD1 and HSP90AA4P, HSPB1P1, DNAJC8P1, HSPD1P9 respectively. HSPs involved in breast cancer are regulated by several miRNAs and miRNA regulators from CellMiner data found as hsa-miR-17, hsa-miR-22, hsa-miR-93, hsa-miR-106a, hsa-miR-125b, hsa-miR-130a, and hsamiR- 141. Cross check of the determined miRNAs and target HSPs was performed by target site prediction software. Comparison of the experimental data from CellMiner and software predicted data indicate differences. CellMiner data provide a vast miRNA types compared to prediction softwares-web tools data and reported miRNAs in the literature. Therefore, reported key miRNAs in this work that are not studied earlier may help cancer researchers to uncover novel posttranslational regulation mechanisms. Cancer cells use HSP network as an escape mechanism from apoptosis, therefore inhibition of associated HSPs by modulating miRNAs may provide a novel therapy for the tumorigenesis.
Yuan R, Zhi Q, Zhao H, et al.Upregulated expression of miR-106a by DNA hypomethylation plays an oncogenic role in hepatocellular carcinoma.
Tumour Biol. 2015; 36(4):3093-100 [PubMed
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Aberrant microRNA (miRNA) expression has been widely recognized to play an extremely important role in several cancers, including hepatocellular carcinoma (HCC). According to the previous studies, abnormal miR-106a expression was closely related to various cancer occurrences. However, the miR-106a expression in HCC remains unclear. In our study, we firstly detected the miR-106a expression levels in 36 pairs of HCC tissues. The results showed that miR-106a expression in HCC tissues was apparently higher than the level in the adjacent tissues. Then, we used quantitative real-time PCR (qPCR) and BSP to analyze miR-106a expression and promoter methylation in HCC cell lines. There came to a conclusion that the methylation status of the miR-106a promoter region was inversely correlated with the expression of miR-106a. After prediction with online software, we further used dual-luciferase reporter gene assay to ensure that TP53INP1 and CDKN1A might be the direct targets of miR-106a. At last, we explored the functions of miR-106a in HCC cells in vitro. Our results manifested that high-miR-106a cell line had stronger invasiveness, faster cell cycle progression, and more resistance to apoptosis compared with the low-miR-106a cell line. Therefore, our study suggested that upregulated expression of miR-106a by its promoter hypomethylation might contribute to the progression of HCC, which might be considered as a potentially effective biomarker and therapeutic approach in the future.
ZBTB4 is a transcriptional repressor and examination of publically-available microarray data sets demonstrated an inverse relationship in the prognostic value and expression of ZBTB4 and the histone methyltransferase EZH2 in tumors from breast cancer patients. The possibility of functional interactions between EZH2 and ZBTB4 was investigated in breast cancer cells and the results showed that EZH2 is directly suppressed by ZBTB4 which in turn is regulated (suppressed) by miR-106b and other paralogues from the miR-17-92, miR-106b-25 and miR-106a-363 clusters that are highly expressed in breast and other tumors. ZBTB4 also acts a suppressor of specificity protein (Sp) transcription factors Sp1, Sp3 and Sp4, and RNA interference studies show that Sp proteins are required for EZH2 expression. The prediction analysis results from breast cancer patient array data sets confirm an association of Sp1-dependent EZH2 gene signature with decreased survival of breast cancer patients. Disruption of oncogenic miR-ZBTB4 signaling axis by anticancer agent such as betulinic acid that induce down-regulation of Sp proteins in breast cancer cells resulted in inhibition of tumor growth and colonization of breast cancer cells in a mouse model. Thus, EZH2 is reciprocally regulated by a novel signaling network consisting of Sp proteins, oncogenic miRs and ZBTB4, and modulation of this gene network is a novel therapeutic approach for treatment of breast cancer and possibly other cancers.
Ma Y, Li X, Cheng S, et al.MicroRNA-106a confers cisplatin resistance in non-small cell lung cancer A549 cells by targeting adenosine triphosphatase-binding cassette A1.
Mol Med Rep. 2015; 11(1):625-32 [PubMed
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MicroRNAs (miRNAs) have been discovered to have pivotal roles in regulating the drug resistance of various types of human cancer, including cisplatin (DDP) resistance in non-small cell lung cancer (NSCLC). Fewer studies have explored the roles of miR-106a in NSCLC-cell resistance to DDP and its precise molecular mechanism has remained elusive. In the present study, whether miR-106a was able to mediate resistance of the lung cancer cell line A549 to DDP was investigated. Reverse transcription quantitative polymerase chain reaction was used to analyze miR-106a mRNA expression levels. miR-106a expression levels were upregulated in the DDP-resistant cell line A549/DDP compared with its parental cell line, A549. miR-106a-transfection induced DDP-resistance in A549 cells, while repression of miR-106a by anti-miR-106a in A549/DDP resulted in enhanced DDP cytotoxicity. Furthermore, it was discovered that the mechanism of miR-106a-induced DDP resistance involved the expression of adenosine triphosphatase-binding cassette, sub-family A, member 1 (ABCA1), as indicated by transfection of cells with short interfering RNA-ABCA1. The results of the present study suggested a novel mechanism underlying DDP-resistance in NSCLC.
BACKGROUND: Circulating microRNAs (miRNAs) are emerging as promising biomarkers for human cancer. In the current study, we investigated the potential use of serum miRNAs as biomarkers for diagnosis and prognosis in a cohort of Chinese astrocytoma patients.
METHODS: An initial screening of the circulating miRNA expression profile was performed on pooled serum samples from 10 preoperative patients and 10 healthy controls using a TaqMan low-density array. The selected serum miRNAs were then validated in 90 preoperative patients and 110 healthy controls who were randomly divided into a training set and a validation set. An additional double-blind test was performed in 50 astrocytomas and 50 controls to assess the serum miRNA-based biomarker accuracy in predicting astrocytoma. The differentially expressed miRNAs were evaluated in paired preoperative and postoperative serum samples from 73 astrocytoma patients. The correlation of the miRNA levels with survival in astrocytoma samples was estimated.
RESULTS: Nine serum miRNAs were significantly increased in the astrocytoma patients. The biomarker composed of these 9 miRNAs had high sensitivity, specificity, and accuracy. These 9 miRNAs were markedly decreased in the serum after operation. The upregulation of miR-20a-5p, miR-106a-5p, and miR-181b-5p was associated with advanced clinical stages of astrocytoma. Kaplan-Meier survival analysis showed that the high expression of miR-19a-3p, miR-106a-5p, and miR-181b-5p was significantly associated with poor patient survival. Finally, the combined 3-miRNAs panel was an important prognostic predictor, independent of other clinicopathological factors.
CONCLUSIONS: The results indicated the potential of serum miRNAs as novel diagnostic and prognostic biomarkers for human astrocytoma.