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  1. MicroRNA let-7c | Cancer Genetics Web
  2. MicroRNA and Cancer
  3. Introduction
  4. MicroRNAs in cancer.

To analyze miRa expression in breast cancer, we first detected miRa levels in 25 pairs of human breast carcinoma tissues and their adjacent non-cancerous tissues. Next, we measured miRa levels in human breast cancer cell lines, and found significantly lower levels of miRa expression in the breast cancer cell lines than in the normal breast epithelial cell line MCFA Fig 1C.

MicroRNA let-7c | Cancer Genetics Web

BT cells are triple-negative breast cancer cells with high invasive ability. A Migration assay. B Invasion assay. C Wound healing assay. D Proliferation assay. E Colony formation assay. The mean was derived from the cell counts of five fields; each experiment was repeated three times.

MicroRNA and Cancer

Representative images of migrated, invaded, or proliferative cells are shown. Among the candidates, WT1 was selected for further study because it acts as an oncogene in human cancers. HEKT cells were cotransfected with the vectors with miRa mimics or negative control. However, the mutated putative miRa binding site almost abolished the decrease of luciferase activity Fig 3B. Results are representative of three independent experiments. Western blotting Fig 3C and immunofluorescence staining Fig 3D showed that in cells transfected with pLVXa, WT1 protein was downregulated as compared to transfected with the negative control.

WT1 expression was significantly upregulated in breast carcinoma tissues compared to that in the adjacent non-cancerous tissues Fig 3E. B Migration assay, C invasion assay, D wound healing assay, and E colony formation assay of miRa—WT1 interaction in regulating breast cancer cell migration, invasion, and proliferation. Representative images of proliferative cells are shown.

As metastasis was inhibited by miRa targeting of WT1 protein, we examined whether WT1 counteracts the anti-metastasis effect induced by miRa. WT1 overexpression also partially prevented the inhibition of motility induced by miRa Fig 4D , and similarly partially blocked the decreased colony formation induced by miRa Fig 4E. WT1 is a complex gene with 10 exons, and expresses at least 36 subtypes, each with four zinc fingers [ 20 ]. Different roles have been ascribed to WT1 in carcinogenesis. Its role in breast carcinogenesis is poorly understood.

In the early stage of breast cancer development, DNA hypermethylation occurs in the WT1 promoter and leads to the low WT1 expression in breast cancer [ 22 ]. In breast cancer, higher WT1 expression is associated with higher histological stage and worse prognosis, and WT1 acts as an oncogene in breast cancer progression [ 23 ].

Our study also shows that the adjacent non-cancerous tissues had low levels of WT1 as compared with the breast cancer tissue. Although the relationship between WT1 and breast cancer has been studied, the biological significance of WT1 signaling in breast cancer has not been completely elucidated. We, too, report reduced miRa-5p expression in breast cancer tissues compared with the adjacent non-cancerous tissues. Our experiments suggest that it is likely that miRa-5p is involved in carcinogenesis and acts as a tumor suppressor in breast cancer.

Consequently, miRa may target multiple genes other than WT1 , which may also have important roles in carcinogenesis. For example, in acute myeloid leukemia, miRa can repress c- KIT proto-oncogene expression and function as a tumor suppressor silenced by methylation [ 31 ].

They identified miR, miR, and miRa-3p as tumor suppressors that can inhibit breast cancer proliferation by regulating the cell cycle network protein driven by EGFR [ 30 ]. At this point, the most important question therefore is how important this new pathway is in breast carcinogenesis.

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Here, we found that miRa overexpression inhibited the proliferation, migration, and invasion of breast cancer cells. The enforced WT1 expression successfully, albeit partially, reversed the anti-proliferative, anti-migration, and anti-invasion effects of miRa on breast cancer cells, although there are many targets of miRa. Our results suggest that the targeting of WT1 is an important mechanism by which the tumor-suppressive function of miRa is exerted.

In this study, we have partly elucidated miRa regulation of WT1 in breast cancer, where the mechanism of miRa downregulation during carcinogenesis can accelerate cell growth and promote cancer cell diffusion. Although most studies indicate that miRa acts as a tumor suppressor, several other studies suggest that miRa is an oncogene and facilitates cancer cell proliferation. For example, knockdown of miRa-3p significantly inhibited cell proliferation and colony formation and induced cells into G1 phase arrest by directly targeting PTEN phosphatase and tensin homolog deleted on chromosome ten , indicating that miRa-3p functions as a tumor-promoting microRNA in renal cell carcinoma[ 33 ].

Also, Fisher et al. Single miRNAs present biological activity by targeting different proteins, which may be differently expressed in cancer cells, resulting in the contradictory activity observed in different cell types. These discrepancies suggest the important role of cellular context in the function of miRNAs. Therefore, more studies are required to shed light on the activity of miRa in breast cancer cells. Many studies have shown that the occurrence and development of breast cancer, including tumor metastasis, are complicated processes in which epithelial—mesenchymal transition EMT and mesenchymal—epithelial transition MET take place.

For example, in heart development, WT1 can activate the WNT4 gene specifically, subsequently controlling the interstitial cell epithelium. However, in kidney tissues, WT1 can specifically activate another gene and play a promoter role in MET. In the present study, breast carcinoma tissue samples with higher pathological stages had lower levels of miRa expression.

These findings imply that miRa levels are associated with the degree of tumor cell differentiation. Therefore, we speculate that, miRa can affect the specific regulatory factor WT1 in mammary gland cells, influencing cell transformation and differentiation. In future studies, we will elucidate the downstream of WT1. Identifying and characterizing miRa in breast cancer provides a better understanding of targeted therapy. The negative correlation between miRa expression and WT1 indicates that patients with breast cancer who have lower miRa expression may have higher WT1 expression, which might contribute to the activation of carcinogenesis and invasion.

These results favor a strong correlation between WT1 and miRa, indicating that restoration of miRa expression may be a promising strategy for breast cancer clinical therapies and that WT1 could be a novel biomarker of breast cancer prognosis and diagnosis, and a potential molecular therapeutic target.

Browse Subject Areas? Click through the PLOS taxonomy to find articles in your field. Introduction Breast cancer is a clinically heterogeneous disease. Materials and methods Patients and specimens We obtained breast tumor tissues and the paired normal adjacent tissues from patients without preoperative chemotherapy, hormone therapy, or radiotherapy who had undergone tumor resection at the Department of Surgical Oncology of the First Affiliated Hospital of Wenzhou Medical University between and Plasmid construction To construct the plasmid expressing miRa, we amplified the primary sequence of hsa-pre-miRa and its flanking regions using specific primer pairs S1 Table , and then cloned them into pcDNA3.

Western blotting We isolated total proteins from the cultured cells, and detected protein concentrations using a Pierce bicinchoninic acid protein assay kit BCA Protein Assay Kit. Cell migration assay The cell migration assay was performed in vitro using well Transwell chambers.

Cell invasion assay The cell invasion assay was performed using well Transwell chambers. Immunofluorescence assay We seeded 10 5 cells per mL breast cancer cells onto coverslips and cultured them in a 6-well culture plate for 24 h. Results Study subjects We enrolled 25 patients according to the inclusion criterion.

Clin Epigenetics. Background: Chronic lung diseases such as chronic obstructive pulmonary disease COPD and epigenetic events underlie lung cancer LC development. The study objective was that lung tumor expression levels of specific microRNAs and their downstream biomarkers may be differentially regulated in patients with and without COPD. Expression of downstream markers Conclusions: Biomarkers of mechanisms involved in tumor growth, angiogenesis, migration, and apoptosis were differentially expressed in tumors of patients with underlying respiratory disease.

These findings shed light into the underlying biology of the reported greater risk to develop LC seen in patients with chronic respiratory conditions. The presence of an underlying respiratory disease should be identified in all patients with LC as the differential biological profile may help determine tumor progression and the therapeutic response.

Additionally, epigenetic events offer a niche for pharmacological therapeutic targets. Oncol Res. As a member of the miRNA family, let-7c has been identified as a tumor suppressor in many cancers. However, the molecular biological function of let-7c in glioma has not been elucidated. The aim of this study was to explore let-7c expression levels and evaluate its function in glioma cells. We first measured the expression of let-7c in four glioma cell lines and a normal cell line by quantitative real-time reverse transcription polymerase chain reaction qRT-PCR , and the results showed that let-7c was downregulated in glioma cells.

By applying gain-of-function and loss-of-function assays, the experiments suggested that dysregulation of let-7c could obviously affect cell proliferation, metastasis, and invasion. Based on online bioinformatics analysis and Dual-Luciferase Reporter assays, we found that E2F5 was a target gene of let-7c and contributed to the function of let-7c in glioma cells. Our investigations indicated that loss of let-7c contributed to the progression of glioma cells. Gene Ther.

Non-small cell lung cancer NSCLC is the leading cause of cancer-related mortalities worldwide, yet this condition remains a poorly understood malignancy, and the subgroup of cancer stem cells CSCs leading to therapeutic resistance and adverse prognosis have not been well studied. CSCs frequently undergo symmetric division, which facilitates expansion of the stem cell pool, contributing to long-term relapse and therapy failure. Analysis of the clinical data from a public database showed a significant decrease of the Wnt signalling repressor Let-7c.

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Using biological and informatics analyses, we hypothesized that CCAT1 stimulated the main factors of the Wnt signalling pathway, of which the three most deregulated genes were further confirmed by western blotting. Axitinib, a Wnt signalling inhibitor, effectively stimulated asymmetric division, similar to Let-7c.

CCAT1 inhibition decreased the ratio of symmetric division of stem cells, and both Let-7c and Axitinib significantly abolished CCAT1 induction of symmetric division by inhibiting Wnt signalling. Stimulation of stem cells to divide asymmetrically by delivering Let-7c or suppressive Axitinib could represent prospective strategies for curing lung cancer patients.

Breast cancer stem-like cells are sensitized to tamoxifen induction of self-renewal inhibition with enforced Let-7c dependent on Wnt blocking. Int J Mol Med.

Visualization of MicroRNA Sequence Data Analysis

Let-7 microRNAs have been reported to have tumor suppressive functions; however, the effect of Let-7 when used in combination with chemotherapies is uncertain, but may have potential for use in clinical practice. In this study, we used RT-qPCR, western blot analysis, cell proliferation assay, flow cytometry analysis, immunohistochemistry IHC staining, luciferase assays, cell sorting analysis and xenografted tumor model to explore the role of Let-7 in the chemotherapy sensitivity of breast cancer stem cells.

LIN28 proteins regulate let-7 biogenesis by binding to conserved sequences within the pre-miRNA structure. 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. 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. The present study aimed to investigate the mechanism underlying the effect of H19 on human epidermal growth factor receptor HER2 expression.

HER2 protein expression levels were examined using immunohistochemistry and western blot analyses. The potential of microRNAs as human prostate cancer biomarkers: A meta-analysis of related studies. J Cell Biochem. Prostate cancer PC is a very important kind of male malignancies. When PC evolves into a stage of hormone resistance or metastasis, the fatality rate is very high. Currently, discoveries and advances in miRNAs as biomarkers have opened the potential for the diagnosis of PC, especially early diagnosis. All of relevant records were selected via electronic databases: Pubmed, Embase, Cochrane, and CNKI based on the assessment of title, abstract, and full text.

Selected articles were published in According to the inclusion criteria, records were included for this meta-analysis. The detection of miRNAs is an effective way to control patient's prognosis and evaluate therapeutic efficacy. However, large-scale detections based on common clinical guidelines are still necessary to further validate our conclusions, due to the bias induced by molecular heterogeneity and differences in study design and detection methods.

Overexpression of microRNA let-7 correlates with disease progression and poor prognosis in hepatocellular carcinoma. Medicine Baltimore. The aim of the study was to explore the clinical significance of let-7 expression in hepatocellular carcinoma HCC. The clinical significance study revealed that elevated let-7a expression was significantly correlated with serosal and vein invasion, while elevated let-7c expression was significantly correlated with vein invasion and advanced TNM stage.

Elevated let-7e expression was significantly correlated with vein invasion in HCC. Significantly shorter postoperative overall survival was observed in HCC patients with high let-7c expression. The upregulation of let-7 expression is associated with the progression and poor prognosis of HCC, and further mechanistic studies are warranted. Let-7c-5p inhibits cell proliferation and induces cell apoptosis by targeting ERCC6 in breast cancer. Oncol Rep. In this study, we found that let-7c-5p expression was clearly downregulated in breast cancer tissues compared with that of corresponding adjacent tissues.

Furthermore, overexpression of let-7c-5p in MCF-7 breast cancer cells could significantly inhibit cell proliferation and induce cell apoptosis. Collectively, the present study suggested that let-7c-5p acted as a tumor suppressor in breast cancer possibly by negatively regulating ERCC6, which took an important part in nucleotide excision repair and it may provide a new potential strategy for breast cancer therapy.

Detection of let-7 miRNAs in urine supernatant as potential diagnostic approach in non-metastatic clear-cell renal cell carcinoma. Biochem Med Zagreb. The aim of this study was to evaluate whether let-7 family miRNAs differ in their urinary concentrations between renal cell carcinoma RCC cases and healthy controls. Total RNA was purified from cell-free supernatant of the first morning urine specimens. H2Bub1 influences many aspects of chromatin function, including transcription regulation and DNA repair.

Cancer cells often display reduced levels of H2Bub1, and this reduction may contribute to cancer progression. The let-7 family of microRNAs miRNAs comprises multiple members with reported tumor-suppressive features, whose expression is frequently downregulated in cancer.


We now report that let-7b and let-7c can positively regulate cellular H2Bub1 levels. Overexpression of let-7b and let-7c in a variety of non-transformed and cancer-derived cell lines results in H2Bub1 elevation. The positive effect of let-7b and let-7c on H2Bub1 levels is achieved through targeting of multiple mRNAs, coding for distinct components of the H2B deubiquitylation machinery. RNF20 knockdown KD strongly reduces H2Bub1 levels and increases the migration of non-transformed mammary epithelial cells and breast cancer-derived cells.

Together, our findings uncover a novel function of let-7 miRNAs as regulators of H2B ubiquitylation, suggesting an additional mechanism whereby these miRNAs can exert their tumor-suppressive effects. A recent, novel approach used nanoparticle-encapsulated peptide nucleic acids in a mouse lymphoma model This method allowed the antimiRs to target the acidic tumor microenvironment, while evading hepatic clearance and facilitating entry into the tumor cells by a nonendocytic pathway.

The approach should be widely applicable to ensure targeted delivery of antimiRs against any oncomiR under investigation. In contrast to the use of antimiRs, an alternative therapeutic approach makes use of reintroducing tumor-suppressive miRNAs that have been downregulated in the target cells. Thus, miRNA shows considerable promise as a therapeutic agent for a variety of cancers.

However, it remains to be seen whether these results from model systems can be translated into clinical trials, while addressing concerns about efficacy and safety. At the time of writing, a Phase I trial of miR-RX34 a mimic of miR, which is downregulated in a variety of cancers through a pmediated pathway was underway in patients with liver cancer Although our knowledge of the precise mechanisms by which miRNAs contribute to transcriptional regulation is incomplete, strong evidence supports a causal link between miRNA dysregulation and the development of many types of cancer.

Gene expression studies, particularly those powered by next-generation sequencing, offer predictive power to enable the development of miRNA-based diagnostic assays that can assist with early detection of cancer and inform physicians about personalized treatment options. Therapeutic approaches, designed to silence oncogenic miRNAs using antisense miRNA or to introduce high levels of tumor-suppressive miRNAs, have shown encouraging results in animal models. The extension of these approaches to comprehensive, randomized controlled trials that evaluate the safety, specificity, and effectiveness of miRNA across multiple cancer types can provide a potential new weapon in the arsenal of therapeutic tools being deployed in the clinic.

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MicroRNAs in cancer.

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