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Breast cancer preferentially develops osteolytic bone metastasis, which makes patients suffer from pain, fractures and spinal cord compression. Accumulating evidences have shown that exosomes play an irreplaceable role in pre-metastatic niche formation as a communication messenger. However, the function of exosomes secreted by breast cancer cells remains incompletely understood in bone metastasis of breast cancer. Mouse xenograft models and intravenous injection of exosomes were applied for analyzing the role of breast cancer cell-derived exosomes . Effects of exosomes secreted by the mildly metastatic MDA231 and its subline SCP28 with highly metastatic ability on osteoclasts formation were confirmed by TRAP staining, ELISA, microcomputed tomography, histomorphometric analyses, and pit formation assay. The candidate exosomal miRNAs for promoting osteoclastogenesis were globally screened by RNA-seq. qRT-PCR, western blot, confocal microscopy, and RNA interfering were performed to validate the function of exosomal miRNA. Implantation of SCP28 tumor cells leads to increased osteoclast activity and reduced bone density, which contributes to the formation of pre-metastatic niche for tumor cells. We found SCP28 cells-secreted exosomes are critical factors in promoting osteoclast differentiation and activation, which consequently accelerates bone lesion to reconstruct microenvironment for bone metastasis. Mechanistically, exosomal miR-21 derived from SCP28 cells facilitates osteoclastogenesis through regulating PDCD4 protein levels. Moreover, miR-21 level in serum exosomes of breast cancer patients with bone metastasis is significantly higher than that in other subpopulations. Our results indicate that breast cancer cell-derived exosomes play an important role in promoting breast cancer bone metastasis, which is associated with the formation of pre-metastatic niche via transferring miR-21 to osteoclasts. The data from patient samples further reflect the significance of miR-21 as a potential target for clinical diagnosis and treatment of breast cancer bone metastasis.

Background Melanoma is a cancer that has a high mortality rate in the absence of targeted therapy. Conventional therapies such as surgery, chemotherapy, and radiotherapy are associated with poor prognosis. The expression of miR-21 appears to be of clinical importance, and the regulation of its expression appears to be an opportunity for treatment. Methods In this current study, we aimed to evaluate the effects of miR-21 inhibition in- vitro and in-vivo. In-vitro studies have investigated LNA-anti-miR-21 in mouse melanoma cells (B16F10), and in-vivo studies have proposed a model of melanoma in male C57BL/6 mice. To evaluate the anticancer effects of LNA-anti-miR-21, a QRT-PCR analysis was performed using the 2 −ΔΔCT method to determine the degree of inhibition of oncomiR-21. The MTT test, propidium iodide/AnnexinV in-vitro, and tumor volume measurement using the QRT-PCR test with the 2 −ΔΔCT method were used to estimate the inhibition of miR-21 and the expression of downstream genes including: SNAI1, Nestin (Nes), Oct-4 , and NF-kB following miR-21 inhibition. Finally, immunohistochemistry was conducted for an in-vivo animal study. Results MiR-21 expression was inhibited by 80% after 24 h of B16F10 cell line transfection with LNA-anti-miR-21. The MTT test showed a significant reduction in the number of transfected cells with LNA-anti-miR-21. The transfected cells showed a significant increase in apoptosis in comparison with the control and scrambled LNA groups. According to our in vivo findings, anti-miR-21 could reduce tumor growth and volume in mice receiving intraperitoneal anti-miR after 9 days. The expression of the SNAI1 gene was significantly reduced compared to the controls. Immunohistochemical analysis showed no change in CD133 and NF-kB markers. Conclusion Our findings suggest LNA-anti-miR-21 can be potentially used as an anticancer agent for the treatment of melanoma.

Oligonucleotide-based therapies are currently gaining attention as a new treatment option for relatively rare as well as common diseases such as cardiovascular disease. With the remarkable progression of new sequencing technologies, a further step towards personalized precision medicine to target a disease at a molecular level was taken. Such therapies may employ antisense oligonucleotides to modulate the expression of both protein coding and non-coding RNAs, such as microRNAs. The cardiorenal syndrome (CRS) is a complex and severe clinical condition where heart and renal dysfunction mutually affect one another. The underlying mechanisms remain largely unknown and current treatments of CRS are mainly supportive therapies which slow down the progression of the disease, but hardly improve the condition. The small non-coding RNA, microRNA-21 (miR-21), is dysregulated in various heart and kidney diseases and has been repeatedly suggested as therapeutic target for the treatment of CRS. Impressive preclinical results have been achieved by an antisense oligonucleotide-based therapy to effectively block the pro-fibrotic traits of miR-21. Since microRNA-mediated pathways are generally very well-conserved, there is considerable commercial interest with regards to clinical translation. In this review, we will summarize the role of miR-21 within the heart–kidney axis and discuss the advantages and pitfalls of miR-21 targeting therapeutic strategies in CRS.

Although mesenchymal stem cells (MSCs) transplantation into the IVD (intervertebral disc) may be beneficial in inhibiting apoptosis of nucleus pulposus cells (NPCs) and alleviating IVD degeneration, the underlying mechanism of this therapeutic process has not been fully explained. The purpose of this study was to explore the protective effect of MSC‐derived exosomes (MSC‐exosomes) on NPC apoptosis and IVD degeneration and investigate the regulatory effect of miRNAs in MSC‐exosomes and associated mechanisms for NPC apoptosis. MSC‐exosomes were isolated from MSC medium, and its anti‐apoptotic effect was assessed in a cell and rat model. The down‐regulated miRNAs in apoptotic NPCs were identified, and their contents in MSC‐exosomes were detected. The target genes of eligible miRNAs and possible downstream pathway were investigated. Purified MSC‐exosomes were taken up by NPCs and suppressed NPC apoptosis. The levels of miR‐21 were down‐regulated in apoptotic NPCs while MSC‐exosomes were enriched in miR‐21. The exosomal miR‐21 could be transferred into NPCs and alleviated TNF‐α induced NPC apoptosis by targeting phosphatase and tensin homolog (PTEN) through phosphatidylinositol 3‐kinase (PI3K)‐Akt pathway. Intradiscal injection of MSC‐exosomes alleviated the NPC apoptosis and IVD degeneration in the rat model. In conclusion, MSC‐derived exosomes prevent NPCs from apoptotic process and alleviate IVD degeneration, at least partly, via miR‐21 contained in exosomes. Exosomal miR‐21 restrains PTEN and thus activates PI3K/Akt pathway in apoptotic NPCs. Our work confers a promising therapeutic strategy for IVD degeneration.

Background 5-Fluorouracil (5-FU) has been commonly prescribed for patients with colorectal cancer (CRC), but resistance to 5-FU is one of the main reasons for failure in CRC. Recently, microRNAs (miRNAs) have been established as a means of reversing the dilemma by regulating signaling pathways involved in initiation and progression of CRC. However, how to safely and effectively deliver miRNA to target cells becomes a main challenge. Results In this study, Engineered exosomes were exploited to simultaneously deliver an anticancer drug 5-FU and miR-21 inhibitor oligonucleotide (miR-21i) to Her2 expressing cancer cells. Purified engineered exosomes from the donor cells loaded with 5-FU and miR-21i via electroporation to introduce into 5-FU-resistant colorectal cancer cell line HCT-116 5FR . Furthermore, systematic administration of 5-FU and miR-21i loaded exosomes in tumor bearing mice indicated a significantly anti-tumor effect. The results showed that the engineered exosome-based 5-FU and miR-21i co-delivery system could efficiently facilitate cellular uptake and significantly down-regulate miR-21 expression in 5-FU resistant HCT-116 5FR cell lines. Consequently, the down-regulation of miR-21 induced cell cycle arrest, reduced tumor proliferation, increased apoptosis and rescued PTEN and hMSH2 expressions, regulatory targets of miR-21. Of particular importance was the significant reduction in tumor growth in a mouse model of colon cancer with systematic administration of the targeting miR-21i. More excitedly, the combinational delivery of miR-21i and 5-FU with the engineered exosomes effectively reverse drug resistance and significantly enhanced the cytotoxicity in 5-FU-resistant colon cancer cells, compared with the single treatment with either miR-21i or 5-FU. Conclusion The strategy for co-delivering the functional small RNA and anticancer drug by exosomes foreshadows a potential approach to reverse the drug resistance in CRC and thus to enhance the efficacy of the cancer treatment.

miR-21 is one of the most highly expressed members of the small non-coding microRNA family in many mammalian cell types. Its expression is further enhanced in many diseased states including solid tumors, cardiac injury, and inflamed tissue. While the induction of miR-21 by inflammatory stimuli cells has been well documented in both hematopoietic cells of the immune system (particularly monocytes/macrophages but also dendritic and T-cells) and non-hematopoietic tumorigenic cells, the exact functional outcome of this elevated miR-21 is less obvious. Recent studies have confirmed a key role for miR-21 in the resolution of inflammation and in negatively regulating the pro-inflammatory response induced by many of the same stimuli that trigger miR-21 induction itself. In particular, miR-21 has emerged as a key mediator of the anti-inflammatory response in macrophages. This suggests that miR-21 inhibition in leukocytes will promote inflammation and may enhance current therapies for defective immune responses such as cancer, mycobacterial vaccines, or Th2-associated allergic inflammation. At the same time, miR-21 has been shown to promote inflammatory mediators in non-hematopoietic cells resulting in neoplastic transformation. This review will focus on functional studies of miR-21 during inflammation, which is complicated by the numerous molecular targets and processes that have emerged as miR-21 sensitive. It may be that the exact functional outcome of miR-21 is determined by multiple features including the cell type affected, the inducing signal, the transcriptomic profile of the cell, which ultimately affect the availability and ability to engage different target mRNAs and bring about its unique responses. Reviewing this data may illustrate that RNA-based oligonucleotide therapies for different diseases based upon miR-21 may have to target the unique and operative miRNA:mRNA interactions' functionally active in disease.

Background As an important means of communication, exosomes play an important role in the development of hepatocellular carcinoma (HCC). Methods Bioinformatics analysis, dual-luciferase reporter assays, methylation-specific quantitative PCR, and ChIP-PCR analysis were used to gain insight into the underlying mechanism of miR-21 in HCC. Results The detection of miRNAs in exosomes of HCC showed that miR-21 expression in exosomes was positively correlated with the expression level of miR-21 in cells and negatively correlated with the expression of its target genes PTEN, PTENp1 and TETs. HCC cell-derived exosomes could increase miR-21 and p-Akt expression in HCC cells and downregulate the expression of PTEN, PTENp1 and TETs. MiR-21 inhibitors or PTENp1 overexpression vectors could weaken the effect of the abovementioned exosomes and simultaneously weaken their role in promoting cell proliferation and migration and inhibiting apoptosis. Further studies showed that miR-21 not only directly regulated the expression of PTEN, PTENp1 and TETs but also increased the methylation level of the PTENp1 promoter by regulating the expression of TETs, thereby inhibiting the expression of PTENp1 and further downregulating the expression of PTEN. Conclusions Exosomal miR-21 can regulate the expression of the tumor suppressor genes PTEN and PTENp1 in various ways and affect the growth of HCC cells.

Breast cancer (BrCa) relies on specific microRNAs to drive disease progression. Oncogenic miR-21 is upregulated in many cancers, including BrCa, and is associated with poor survival and treatment resistance. We sought to determine the role of miR-21 in BrCa tumor initiation, progression and treatment response. In a triple-negative BrCa model, radiation exposure increased miR-21 in both primary tumor and metastases. In vitro, miR-21 knockdown decreased survival in all BrCa subtypes in the presence of radiation. The role of miR-21 in BrCa initiation was evaluated by implanting wild-type miR-21 BrCa cells into genetically engineered mouse models where miR-21 was intact, heterozygous or globally ablated. Tumors were unable to grow in the mammary fat pads of miR-21−/− mice, and grew in ~50% of miR-21+/− and 100% in miR-21+/+ mice. The contribution of miR-21 to progression and metastases was tested by crossing miR-21−/− mice with mice that spontaneously develop BrCa. The global ablation of miR-21 significantly decreased the tumorigenesis and metastases of BrCa, while sensitizing tumors to radio- and chemotherapeutic agents via Fas/FasL-dependent apoptosis. Therefore, targeting miR-21 alone or in combination with various radio or cytotoxic therapies may represent novel and efficacious therapeutic modalities for the future treatment of BrCa patients.

While coronary artery disease (CAD) has become a major threat worldwide, the timely biomarker-based early diagnosis of CAD remains a major unmet clinical challenge. We aimed towards assessing the level of circulatory microRNAs as candidates of novel biomarkers in patients with CAD. A total of 147 subjects were recruited which includes 78 subjects with angiographically proven CAD, 15 pre-atherosclerotic normal coronary artery (NCA) subjects and 54 healthy individuals. Quantitative real-time PCR assays were performed. MiR-133b was downregulated by 4.6 fold (p < 0.0001) whereas miR-21 was upregulated by ~2 fold (p < 0.0001) in plasma samples of CAD patients. Importantly, both the miRNAs showed association with disease severity as miR-133b was downregulated by 8.45 fold in acute coronary syndrome (ACS), 3.38 fold in Stable angina (SA) and 2.08 fold in NCA. MiR-21 was upregulated by 2.46 fold in ACS, 1.90 fold in SA and 1.12 fold in NCA. Moreover, miR-133b could significantly differentiate subjects with ST-elevation myocardial infarction (STEMI) from Non-STEMI. Area under the curve (AUC) for miR-133b was 0.80 with >75.6% sensitivity and specificity, AUC for miR-21 was 0.79 with >69.4% sensitivity and specificity. Our results suggest that miR-133b and miR-21 could be possible candidates of novel biomarkers in early prediction of CAD.