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Despite tremendous advances in modern medicine, effective prevention or therapeutic strategies for age-related neurodegenerative diseases such as Alzheimer's disease (AD) remain limited. Currently, accumulating evidence has demonstrated that microRNAs (miRNAs) are increasingly associated with age-related diseases and are emerging as promising therapeutic targets. Urolithin A, a metabolite compound resulting from the transformation of ellagitannins by gut bacteria, has been reported to have anti-oxidant, anti-inflammatory, and anti-apoptotic properties. The present study primarily focused on the ameliorative effect of urolithin A on aging mice and on the exploration of the potential mechanisms of such an ameliorative effect on cognitive impairment and brain aging. In this study, we first tested the neuroprotective effect of urolithin A using an in vitro H2O2-induced PC12 cell oxidative damage model. The in vivod-gal-induced brain aging model showed that urolithin A significantly suppressed the upregulation of miR-34a induced by d-gal. Moreover, target genes associated with miR-34a were also examined. Urolithin A supplementation ameliorated apoptosis induced by d-gal and rescued miR-34a overexpression–induced impaired autophagy in brain aging mice after a 2-month administration. Furthermore, urolithin A activated autophagy by upregulating the SIRT1 signaling pathway and downregulating the mTOR signaling pathway. In conclusion, urolithin A may exert neuroprotective effects and may aid in preventing d-gal-induced brain aging through activation of the miR-34a-mediated SIRT1/mTOR signaling pathway.

The microRNA(miRNA)-34a is a key regulator of tumor suppression. It controls the expression of a plethora of target proteins involved in cell cycle, differentiation and apoptosis, and antagonizes processes that are necessary for basic cancer cell viability as well as cancer stemness, metastasis, and chemoresistance. In this review, we focus on the molecular mechanisms of miR-34a-mediated tumor suppression, giving emphasis on the main miR-34a targets, as well as on the principal regulators involved in the modulation of this miRNA. Moreover, we shed light on the miR-34a role in modulating responsiveness to chemotherapy and on the phytonutrients-mediated regulation of miR-34a expression and activity in cancer cells. Given the broad anti-oncogenic activity of miR-34a, we also discuss the substantial benefits of a new therapeutic concept based on nanotechnology delivery of miRNA mimics. In fact, the replacement of oncosuppressor miRNAs provides an effective strategy against tumor heterogeneity and the selective RNA-based delivery systems seems to be an excellent platform for a safe and effective targeting of the tumor.

Backgroud Accumulating evidences indicate that circular RNAs (circRNAs), a class of non-coding RNAs, play important roles in tumorigenesis. However, the function of circRNAs in triple negative breast cancer (TNBC) is largely unknown. Methods We performed circRNA microarrays to identify circRNAs that are aberrantly expressed in TNBC cell lines. Expression levels of a significantly upregulated circRNA, circGFRA1, was detected by quantitative real-time PCR (qRT-PCR) in TNBC cell lines and tissues. Kaplan-Meier survival analysis was used to explore the significance of circGFRA1 in clinical prognosis. Then, we examined the functions of circGFRA1 in TNBC by cell proliferation, apoptosis and mouse xenograft assay. In addition, luciferase assay was used to explore the miRNA sponge function of circGFRA1 in TNBC. Results Microarray analysis and qRT-PCR verified a circRNA termed circGFRA1 that was upregulated in TNBC. Kaplan-Meier survival analysis showed that upregulated circGFRA1 was correlated with poorer survival. Knockdown of circGFRA1 inhibited proliferation and promoted apoptosis in TNBC. Via luciferase reporter assays, circGFRA1 and GFRA1 was observed to directly bind to miR-34a. Subsequent experiments showed that circGFRA1 and GFRA1 regulated the expression of each other by sponging miR-34a. Conclusions Taken together, we conclude that circGFRA1 may function as a competing endogenous RNA (ceRNA) to regulate GFRA1 expression through sponging miR-34a to exert regulatory functions in TNBC. circGFRA1 may be a diagnostic biomarker and potential target for TNBC therapy.

Background Thyroid cancer is one of the most prevalent malignancies in endocrine system. Further understanding and revealing the molecular mechanism underlying thyroid cancer are indispensable for the development of effective diagnosis and treatments. In the present study, we attempted to provide novel basis for targeted therapy for thyroid cancer from the aspect of lncRNA-miRNA-mRNA interaction. Methods The expression and cellular function of XIST (X-inactive specific transcript) was determined. miRNAs which may be direct targets of XIST were screened for from online GEO database and miR-34a was selected. Next, the predicted binding between XIST and miR-34a, and the dynamic effect of XIST and miR-34a on downstream MET (hepatocyte growth factor receptor)-PI3K (phosphoinositide 3-kinase)-AKT (α-serine/threonine-protein kinase) signaling was evaluated. Results XIST was significantly up-regulated in thyroid cancer tissues and cell lines; XIST knockdown suppressed the cell proliferation in vivo and the tumor growth in vitro. Based on online database and online tool prediction results, miR-34a was underexpressed in thyroid cancer and might be a direct target of XIST. Herein, we confirmed the negative interaction between XIST and miR-34a; moreover, XIST knockdown could reduce the protein levels of MET, a downstream target of miR-34a, and the phosphorylation of PI3K and AKT. In thyroid cancer tissues, MET mRNA and protein levels of MET were up-regulated; MET was positively correlated with XIST while negatively correlated with miR-34a, further confirming that XIST serves as a ceRNA for miR-34a through sponging miR-34a, competing with MET for miR-34a binding, and finally modulating thyroid cancer cell proliferation and tumor growth. Conclusion In the present study, we provided novel experimental basis for targeted therapy for thyroid cancer from the aspect of lncRNA-miRNA-mRNA interaction.

Background Triple-negative breast cancer (TNBC) is a poor prognostic breast cancer with the highest mutations and limited therapeutic choices. Cytokine networking between cancer cells and the tumor microenvironment (TME) maintains the self-renewing subpopulation of breast cancer stem cells (BCSCs) that mediate tumor heterogeneity, resistance and recurrence. Immunotherapy of those factors combined with targeted therapy or chemoagents may advantage TNBC treatment. Results We found that the oncogene M ultiple C opies in T -cell Malignancy 1 (MCT-1/MCTS1) expression is a new poor-prognosis marker in patients with aggressive breast cancers. Overexpressing MCT-1 perturbed the oncogenic breast epithelial acini morphogenesis and stimulated epithelial-mesenchymal transition and matrix metalloproteinase activation in invasive TNBC cells, which were repressed after MCT-1 gene silencing. As mammary tumor progression was promoted by oncogenic MCT-1 activation, tumor-promoting M2 macrophages were enriched in TME, whereas M2 macrophages were decreased and tumor-suppressive M1 macrophages were increased as the tumor was repressed via MCT-1 knockdown. MCT-1 stimulated interleukin-6 (IL-6) secretion that promoted monocytic THP-1 polarization into M2-like macrophages to increase TNBC cell invasiveness. In addition, MCT-1 elevated the soluble IL-6 receptor levels, and thus, IL-6R antibodies antagonized the effect of MCT-1 on promoting M2-like polarization and cancer cell invasion. Notably, MCT-1 increased the features of BCSCs, which were further advanced by IL-6 but prevented by tocilizumab, a humanized IL-6R antibody, thus MCT-1 knockdown and tocilizumab synergistically inhibited TNBC stemness. Tumor suppressor miR-34a was induced upon MCT-1 knockdown that inhibited IL-6R expression and activated M1 polarization. Conclusions The MCT-1 pathway is a novel and promising therapeutic target for TNBC.

Summary Purpose Naturally occurring tumor suppressor microRNA-34a (miR-34a) downregulates the expression of >30 oncogenes across multiple oncogenic pathways, as well as genes involved in tumor immune evasion, but is lost or under-expressed in many malignancies. This first-in-human, phase I study assessed the maximum tolerated dose (MTD), safety, pharmacokinetics, and clinical activity of MRX34, a liposomal miR-34a mimic, in patients with advanced solid tumors. Patients and Methods Adult patients with solid tumors refractory to standard treatment were enrolled in a standard 3 + 3 dose escalation trial. MRX34 was given intravenously twice weekly (BIW) for three weeks in 4-week cycles. Results Forty-seven patients with various solid tumors, including hepatocellular carcinoma (HCC; n  = 14), were enrolled. Median age was 60 years, median prior therapies was 4 (range, 1–12), and most were Caucasian (68%) and male (57%). Most common adverse events (AEs) included fever (all grade %/G3%: 64/2), fatigue (57/13), back pain (57/11), nausea (49/2), diarrhea (40/11), anorexia (36/4), and vomiting (34/4). Laboratory abnormalities included lymphopenia (G3%/G4%: 23/9), neutropenia (13/11), thrombocytopenia (17/0), increased AST (19/4), hyperglycemia (13/2), and hyponatremia (19/2). Dexamethasone premedication was required to manage infusion-related AEs. The MTD for non-HCC patients was 110 mg/m 2 , with two patients experiencing dose-limiting toxicities of G3 hypoxia and enteritis at 124 mg/m 2 . The half-life was >24 h, and C max and AUC increased with increasing dose. One patient with HCC achieved a prolonged confirmed PR lasting 48 weeks, and four patients experienced SD lasting ≥4 cycles. Conclusion MRX34 treatment with dexamethasone premedication was associated with acceptable safety and showed evidence of antitumor activity in a subset of patients with refractory advanced solid tumors. The MTD for the BIW schedule was 110 mg/m 2 for non-HCC and 93 mg/m2 for HCC patients. Additional dose schedules of MRX34 have been explored to improve tolerability.

Introduction: LncRNA FEZF1-AS1 has been reported to be an oncogene in many types of cancer, while its role in glioblastoma (GBM) is unknown. This study aimed to investigate the potential involvement of FEZF1-AS1 in GBM. Methods: FEZF1-AS1 expression in paired GBM and non-tumor tissues from GBM patients was determined by RT-qPCR. A 2-year follow-up was performed to analyze the prognostic value of FEZF1-AS1 for GBM. Cell transfections were performed to analyze the interactions between FEZF1-AS1, miR-34a and Notch-1. Transwell assay was performed to analyze the role of FEZF1-AS1, miR-34a and Notch-1 in regulating GBM cell invasion and migration. Results: In this study, analysis of TCGA dataset revealed the upregulation of FEZF1-AS1 in GBM, and the overexpression of FEZF1-AS1 in GBM was further confirmed using GBM tissues from GBM patients included in this study. High levels of FEZF1-AS1 were correlated with poor survival. FEZF1-AS1 was predicted to form base pairing with miR-34a. However, overexpression of FEZF1-AS1 and miR-34a failed to affect the expression of each other. However, upregulation of Notch-1, a target of miR-34a, was observed after FEZF1-AS1 in GBM cells. Moreover, increased invasion and migration rates of GBM cells were observed after FEZF1-AS1 and Notch-1 overexpression. MiR-34a played an opposite role and reduced the effects of FEZF1-AS1 and Notch-1 overexpression. Conclusion: FEZF1-AS1 may sponge miR-34a to upregulate Notch-1 in GBM, thereby promoting cancer cell invasion and migration. Keywords: glioblastoma, FEZF1-AS1, miR-34a, Notch-1

Previous reports have revealed that down-regulation of miR-34a expression can promote colorectal cancer (CRC) cell growth by targeting cell cycle-related transcriptional factor E2F1. To date, the function of the single nucleotide polymorphism (SNP) located in the mature region of miR-34a has not been investigated. We performed a case-control study including 685 CRC patients and 618 cancer-free controls. Genotyping, real-time PCR assay, cell transfection, and the dual luciferase reporter assay were used in our study. Cell proliferation and cell cycle analysis were measured in CRC cells including Hct-116 and SW480. The overall survival of different genotypes was also investigated. We found that the rs35301225 polymorphism in miR-34a was involved in the occurrence of CRC by acting as a tumor suppressor by down-regulation of tumor-promoting gene E2F1. C/A SNP of miR-34a could promote CRC cell proliferation by up-regulation of E2F1. Also, C/A genotype can change the cell cycle by increasing the S phase percentage. Moreover, the SNP in rs35301225 of miR-34a was associated with tumor size and tumor differentiation, as well as metastasis in CRC patients; C/A SNP was related to the significantly enhanced expression of E2F1 and shorter survival in post-surgery CRC patients. rs35301225 in miR-34a was highly associated with a decreased risk of CRC in a Chinese population and might serve as a novel biomarker for colon cancer.