Explore the vast range of titles available.

Extracellular vesicles (EVs) are nanometer-sized membranous vesicles used for primitive cell-to-cell communication. We previously reported that colon cancer-derived EVs contain abundant miR-92a-3p and have a pro-angiogenic function. We previously identified Dickkopf-3 (Dkk-3) as a direct target of miR-92a-3p; however, the pro-angiogenic function of miR-92a-3p cannot only be attributed to downregulation of Dkk-3. Therefore, the complete molecular mechanism by which miR-92a-3p exerts pro-angiogenic effects is still unclear. Here, we comprehensively analyzed the gene sets affected by ectopic expression of miR-92a-3p in endothelial cells to elucidate processes underlying EV-induced angiogenesis. We found that the ectopic expression of miR-92a-3p upregulated cell cycle- and mitosis-related gene expression and downregulated adhesion-related gene expression in endothelial cells. We also identified a novel target gene of miR-92a-3p, claudin-11. Claudin-11 belongs to the claudin gene family, which encodes essential components expressed at tight junctions (TJs). Disruption of TJs with a concomitant loss of claudin expression is a significant event in the process of epithelial-to-mesenchymal transition. Our findings have unveiled a new EV-mediated mechanism for tumor angiogenesis through the induction of partial endothelial-to-mesenchymal transition in endothelial cells.

Cancer‐related microRNAs (miRNAs) are emerging as promising and noninvasive biomarkers for colorectal cancer (CRC). This study aimed to investigate the usefulness of postoperative changes in plasma miR21‐5p levels for recurrence and progressive disease (PD) after surgical resection. This study was a prospective study of 103 CRC patients who underwent surgical resection. Self‐paired plasma samples collected pre‐operation (Pre), 7 days post‐operation (POD7), 1 month post‐operation (POM1), and 6 months post‐operation (POM6) were analyzed. The miRNA levels were evaluated by quantitative reverse transcription PCR. Among the enrolled patients, ten cases (9.7%) of postoperative recurrence and six cases (5.8%) of postoperative PD occurred at POM6. In the recurrence and PD group, plasma miR21‐5p levels significantly increased (POM1: P < .01, POM6: P < .01, respectively). The area under the curve (AUC) value for postoperative changes in plasma miR21‐5p levels at POM1 and POM6 to discriminate recurrence and PD were 0.675 and 0.715, respectively. Combined analysis with postoperative carcinoembryonic antigen (CEA) level in discriminating recurrence and PD increased AUC values (POM1: 0.715 and POM6: 0.789). Furthermore, multivariate analysis for recurrence and PD after surgical resection showed that postoperative changes in the plasma miR21‐5p level at POM1 and POM6 were independent prognostic factors (POM1: P = .03, POM6: P < .01). The postoperative changes in plasma miR21‐5p level could be a useful noninvasive biomarker for monitoring and predicting recurrence and PD after surgical resection of CRC patients. Furthermore, plasma miR21‐5p can predict recurrence and PD after surgical resection. Postoperative changes in plasma miR21‐5p level could be a useful noninvasive biomarker for monitoring and predicting recurrence and progressive disease after surgical resection of CRC patients.

Mutations in K/H/N-RAS occur in approximately 30% of human cancers, yet most RAS mutants remain undruggable in clinical settings. Here, we describe a protein-based pan-RAS inhibitor, RRSP-RBD, that combines a RAS/Rap1A-specific endopeptidase (RRSP) with a RAS-binding domain (RBD). This engineered fusion protein localizes to RAS on the plasma membrane, where it cleaves RAS, disrupts RAS-effector interactions, and effectively inhibits downstream RAS signaling. To achieve intracellular delivery of RRSP-RBD in vivo, we engineer two cell-permeable variants. The diphtheria toxin-based version (RRSP-RBD-DTB) demonstrates femtomolar anti-tumor potency and induces tumor regression in a xenograft mouse model. The cell-permeable peptide-based version (RRSP-RBD-TAT) exhibits robust anti-tumor activity in syngeneic models without inducing irreversible toxicity in normal tissues. Interestingly, anti-tumor efficacy of RRSP-RBD-TAT critically depends on the tumor microenvironment, requiring infiltration by IFNγ +  CD8 +  T cells to mediate tumor regression. Pharmacokinetic and toxicity evaluations indicate that RRSP-RBD is tolerated under the conditions tested and support further investigation as a protein-based pan-RAS inhibitor (all mouse studies were performed in female mice). Many cancers depend on RAS signaling, but blocking diverse RAS mutants remains challenging. Here, authors engineer a protein-based pan-RAS inhibitor that induces tumor regression in mouse models and reveals an immune-dependent mechanism of action

We investigated whether miR143#12, a synthesized chemically modified miR-143-3p derivative, exerts therapeutic effects on acute myocardial infarction (AMI). Sprague–Dawley rats and Japanese white rabbits underwent 30 min of coronary occlusion followed by 2 weeks of reperfusion. The rat AMI model was intravenously administered with control miRNA (9 μg/kg), 3 μg/kg or 9 μg/kg of miR143#12 1 h after reperfusion, while the rabbit AMI model was intravenously administered with control miRNA (9 μg/kg) or 9 μg/kg of miR143#12. In the rat and rabbit AMI models, 9 μg/kg of miR143#12 significantly reduced infarct sizes and significantly improved cardiac function including LVEF and LVFS at 2 weeks. The tissue miR143 levels in infarct areas significantly decreased after AMI in both models. Electron microscopic study and immunohistochemistry suggested that miR143#12 suppressed autophagic cell death caused by AMI and induced neoangiogenesis in the infarct border. In cultured rat H9c2 cells, miR143#12 significantly inhibited H 2 O 2 -induced autophagic cell death by decreasing ROS levels and increased viable cell numbers more than the control by silencing COX-1 , - 2 , and ATG7 . Replacement treatment with miR143#12 in the infarct areas, where the expression levels of miR143 were significantly decreased, has a beneficial effect on AMI by silencing COX-1 and - 2 .

It has been well established that microRNA (miR)‐143 is downregulated in human bladder cancer (BC). Recent precision medicine has shown that mutations in BC are frequently observed in FGFR3, RAS and PIK3CA genes, all of which correlate with RAS signaling networks. We have previously shown that miR‐143 suppresses cell growth by inhibiting RAS signaling networks in several cancers including BC. In the present study, we showed that synthetic miR‐143 negatively regulated the RNA‐binding protein Musashi‐2 (MSI2) in BC cell lines. MSI2 is an RNA‐binding protein that regulates the stability of certain mRNAs and their translation by binding to the target sequences of the mRNAs. Of note, the present study clarified that MSI2 positively regulated KRAS expression through directly binding to the target sequence of KRAS mRNA and promoting its translation, thus contributing to the maintenance of KRAS expression. Thus, miR‐143 silenced KRAS and MSI2, which further downregulated KRAS expression through perturbation of the MSI2/KRAS cascade. MiR‐143 directly impacts KRAS and RNA‐binding protein MSI2. MSI2 enhances translation of KRAS through directly binding to mRNA of KRAS. KRAS controls the maintenance of KRAS signaling networks through the novel MSI2/KRAS cascade.

The ethanol extract from the wood of Taxus Yunnanensis (TY) induced apoptosis in all cancer cell lines tested, which was mainly due to activation of an extrinsic pathway in human colon cancer DLD-1 cells. The extrinsic pathway was activated by the upregulation of the expression levels of Fas and TRAIL/DR5, which led to the activation of caspase-8. Of note, the machinery of this increase in expression was promoted by the upregulation of MIR32a expression, which silenced MIR34a-targeting E2F3 transcription factor. Furthermore, ectopic expression of MIR32a or siR-E2F3 silencing E2F3 increased Fas and TRAIL/DR5 expression. Thus, the extract activated the extrinsic pathway through the MIR34a/E2F3 axis, resulting in the autocrine and paracrine release of TRAIL, and upregulated expression of death receptors Fas and DR5 in the treated DLD-1 cells, which were functionally validated by Fas immunocytochemistry, and using anti-Fas and anti-TRAIL antibodies, respectively. In vivo, TY showed significant anti-tumor effects on xenografted and syngeneic model mice. The extract may also aid in chemoprevention by selectively making marked tumor cells susceptible to the tumor immunosurveillance system.

Background Although melanoma brain metastases (MBM) tend to respond to systemic therapy concordantly with extracranial metastases, little is known about differences in immune cell and vascular content between the brain and other metastatic sites. Here we studied infiltrating immune cell subsets and microvessel density (MVD) in paired intracerebral and extracerebral melanoma metastases. Methods Paired intracerebral and extracerebral tumor tissue was obtained from 37 patients with metastatic melanoma who underwent craniotomy between 1997 and 2014. A tissue microarray was constructed to quantify subsets of tumor-infiltrating T-cell, B-cell, and macrophage content, PD-L1 expression, and MVD using quantitative immunofluorescence. Results MBM had lower CD3+ (p = 0.01) and CD4+ (p = 0.003) T-cell content, lower MVD (p = 0.006), and a trend for lower CD8+ (p = 0.17) T-cell content compared to matched extracerebral metastases. There were no significant differences in CD20+ B-cell or CD68+ macrophage content, or tumor or stroma PD-L1 expression. Low MVD (p = 0.008) and high CD68+ macrophage density (p = 0.04) in intracerebral metastases were associated with improved 1-year survival from time of first MBM diagnosis. Conclusions Although responses to immune-modulating drugs in the body and the brain tend to be concordant, differences were found in MVD and T-cell content between these sites. Studies of these markers should be incorporated into prospective therapeutic clinical trials to determine their prognostic and predictive value.

Rhabdomyosarcoma (RMS) is a soft tissue sarcoma most frequently found in children. In RMS, there are two major subtypes, embryonal RMS (ERMS) and alveolar RMS (ARMS). ARMS has the worse prognosis of the two owing to the formation of the chimeric PAX3–FOXO1 gene. A novel therapeutic method is required for treating ARMS. In our previous study, we found that the ectopic expression of chemically modified MIR143-3p#12 (CM-MIR143#12), which is RNase-resistant and shows the highest anti-proliferation activity among the synthesized MIR143 derivatives that were tested, induces significant cell growth suppression by targeting KRAS, AKT, and ERK in colorectal cancer cells. The expression of MIR143-3p in RMS was dramatically downregulated compared with that of normal tissue. Ectopic expression of CM-MIR143#12 in RMS cells resulted in a significant growth inhibitory effect through the induction of apoptosis and autophagy. Interestingly, we found that CM-MIR143#12 also silenced the expression of chimeric PAX3–FOXO1 directly and, using siR-KRAS or siR-AKT, that KRAS networks regulated the expression of PAX3–FOXO1 in ARMS cells. In ERMS harboring NRAS mutation, CM-MIR143#12 silenced mutated NRAS. These findings indicate that CM-MIR143#12 efficiently perturbed the RAS signaling pathway, including the ARMS-specific KRAS/PAX3–FOXO1 networks.

Therapy based on targeted inhibition of BCR‐ABL tyrosine kinase has greatly improved the prognosis for patients with Philadelphia chromosome (Ph)‐positive leukemia and tyrosine kinase inhibitors (TKI) have become standard therapy. However, some patients acquire resistance to TKI that is frequently associated with point mutations in BCR‐ABL. We previously reported that a medium‐chain fatty‐acid derivative AIC‐47 induced transcriptional suppression of BCR‐ABL and perturbation of the Warburg effect, leading to growth inhibition in Ph‐positive leukemia cells. Herein, we showed that AIC‐47 had anti‐leukemic effects in either wild type (WT)‐ or mutated‐BCR‐ABL‐harboring cells. AIC‐47 suppressed transcription of BCR‐ABL gene regardless of the mutation through downregulation of transcriptional activator, c‐Myc. Reprogramming of the metabolic pathway has been reported to be associated with resistance to anti‐cancer drugs; however, we found that a point mutation of BCR‐ABL was independent of the profile of pyruvate kinase muscle (PKM) isoform expression. Even in T315I‐mutated cells, AIC‐47 induced switching of the expression profile of PKM isoforms from PKM2 to PKM1, suggesting that AIC‐47 disrupted the Warburg effect. In a leukemic mouse model, AIC‐47 greatly suppressed the increase in BCR‐ABL mRNA level and improved hepatosplenomegaly regardless of the BCR‐ABL mutation. Notably, the improvement of splenomegaly by AIC‐47 was remarkable and might be equal to or greater than that of TKI. These findings suggest that AIC‐47 might be a promising agent for overcoming the resistance of Ph‐positive leukemia to therapy. Hematoxylin and eosin‐stained spleens of normal and leukemic mice. Medium‐chain fatty‐acid derivative AIC‐47 treatment eliminated the leukemia cells from the spleen. Spleens of mice treated with AIC‐47 had intact structures of white and red pulp.

Circulating microRNAs in the blood may provide diagnostic and prognostic information about canine neoplastic diseases, and their profiles may be conserved between human and canine species. We performed RT-qPCR to obtain the profiles of circulating plasma microRNA-214 and -126 in total 181 cases of canine neoplastic diseases and healthy controls. MicroRNA-214 levels were high in 2 epithelial tumours (thyroid and mammary carcinomas) and 4 non-epithelial tumours (osteosarcoma, histiocytic sarcoma, chondrosarcoma, and hemangiosarcoma). In contrast, microRNA-126 levels were high in 6 epithelial tumours (mammary, hepatocellular, squamous cell, thyroid, transitional cell carcinomas, and adenocarcinoma) and 4 non-epithelial tumours (osteosarcoma, mast cell tumour, melanoma, and hemangiosarcoma). The diagnostic potential of microRNA-214 was relatively high in sarcomas, whereas that of microR-126 was high in most types of the tumours. MicroRNA-214 and -126 were prognostic predictors in 2 groups (adenocarcinoma and non-epithelial tumours except for osteosarcoma) and 3 groups (epithelial tumours, adenocarcinoma, and melanoma), respectively. Additionally, the microRNA levels did not show a strong correlation with the other clinical parameters. In conclusion, circulating microRNA-214 and -126 have the potential to be diagnostic and prognostic biomarkers for canine neoplastic diseases. Furthermore, their profiles may be key references as well for exploring novel biomarkers for human cancers.