Search

Background: MicroRNAs (miRNAs) have been emerging as valuable prognostic biomarkers of breast cancer. We therefore summarized recent research into miRNAs involved in human breast cancer and, further, completed a meta-analysis to predict the role of specific miRNAs in the survival of breast cancer patients., Methods: Studies were identified by searching PubMed, Embase and Web of Science. Descriptive characteristics for studies were described, and an additional meta-analysis for specific miRNAs was performed. Pooled hazard ratios (HRs) and their corresponding 95% confidence intervals (CIs) were calculated., Results: A total of 41 articles including 27 types of miRNAs were found regarding prognostic biomarkers for breast cancer survival, of which, micRNA-21 (miR-21) was the most-studied specific miRNA that appeared repeatedly among the selected classifiers. For the studies evaluating miR-21's association with clinical outcomes, the median HR in the studies was 2.32 (interquartile range [IQR] = 1.04-3.40), and the pooled HR suggested that high expression of miR-21 has a negative impact on overall survival (OS; HR = 1.46, 95% CI, 1.25-1.70; p<0.05) and disease/recurrence-free survival in breast cancer (HR = 1.49, 95% CI, 1.17-1.90; p<0.01). We also found that higher expression levels of miR-210 significantly predicted poorer outcome, with median HR in the reported studies of 4.07 (IQR = 1.54-4.43) and a pooled HR of 2.94 (95% CI, 2.08-4.17; p<0.05)., Conclusions: These results indicate that miRNAs show promising associations with prognosis in breast cancer. Moreover, specific miRNAs such as miR-21 and miR-210 can predict poor survival rates in breast cancer patients.

BACKGROUND: Heat stress (HS) is known to exert negative effects on the poultry and breeding industry, resulting in severe economic losses. Bile acids (BAs), an important component of bile, play a crucial role in improving the production performance of livestock and poultry, alleviating stress injury, and ensuring the health of livestock and poultry. At present, porcine BAs are widely used because of their therapeutic effects on HS; however, it remains unclear whether the same effects are exerted by sheep BAs, which are different from porcine BAs and have different compositions. In this study, we compared the anti‐HS effects of porcine BAs and sheep BAs in the diet by establishing an HS model of chicks and investigating the chicken performance, HS‐related genes' expression, oxidative stress markers, jejunal histoarchitecture, inflammatory cytokines' expression, jejunal secreted immunoglobulin A concentration, and cecal bacterial flora. RESULTS: The results showed that the addition of sheep BAs to the diet increased the average daily weight gain and the feed conversion ratio of chicks. Under HS, sheep BAs were more effective than porcine BAs in improving the activities of lactate dehydrogenase and glutamic pyruvic transaminase in serum and the content/activity of malondialdehyde, superoxide dismutase, and reduced glutathione in serum and tissue, in reducing the messenger RNA (mRNA) expression of heat shock proteins (HSP60, HSP70, and HSP90) in the liver and jejunum, and in improving the histological structure and the expression of tight junction proteins (occludin and zonula occludens‐1) and enriching intestinal bacterial flora. However, porcine BAs were significantly inferior to sheep BAs in reducing the mRNA expression of inflammatory factors (interleukin‐6, interleukin‐1β, and tumor necrosis factor‐α). CONCLUSION: The effect of sheep BAs was more significant than porcine BAs was in alleviating HS injury in chicks, suggesting that sheep BAs have great potential as new feed nutrition and health additive to improve poultry production performance and prevent HS. © 2023 Society of Chemical Industry. [ABSTRACT FROM AUTHOR]

Keloids are benign dermal tumors that arise from abnormal wound healing processes following skin lesions. Surgical excision followed by radiotherapy plays an important role in the treatment of keloids. Nevertheless, radioresistance remains a serious impediment to treatment efficacy. Investigation of the molecular response of keloids to radiation may contribute to radiosensitizing strategies. Primary keloid fibroblasts from human keloids were isolated and irradiated with X-ray. The expression profiles of messenger RNA (mRNA) in nonradiated and irradiated primary keloid fibroblasts were measured by mRNA sequencing analysis. Then, we identified common motifs and corresponding transcription factors of dysregulated mRNAs by using bioinformatic analysis of the proximal promoters. Whereafter, GO and KEGG were used to analyze the functional enrichment of the differentially expressed genes. We found that radiation not only suppressed proliferation but also increased cell senescence of primary keloid fibroblasts. There were 184 mRNAs and 204 mRNAs that showed significant changes in 4 and 8 Gy irradiated primary keloid fibroblasts, respectively. Among them, 8 upregulated and 30 downregulated mRNAs showed consistent alterations in 4 and 8 Gy irradiated primary keloid fibroblasts. More importantly, the xForkhead box O1 (FOXO1) signaling pathway was involved in the irradiation response. Pretreatment with the FOXO1 signaling inhibitor AS1842856 significantly promoted LDH release, apoptosis and senescence of primary keloid fibroblasts following irradiation. Our findings illustrated the molecular changes in human keloid fibroblasts in response to radiation, and FOXO1 pathway inhibition is expected to provide a novel strategy for the radiosensitization of keloids. [ABSTRACT FROM AUTHOR]

The p.Thr61Ile (p.T61I) mutation in coiled‐coil‐helix–coiled‐coil‐helix domain containing 2 (CHCHD2) was deemed a causative factor in Parkinson's disease (PD). However, the pathomechanism of the CHCHD2 p.T61I mutation in PD remains unclear. Few existing mouse models of CHCHD2‐related PD completely reproduce the features of PD, and no transgenic or knock‐in (KI) mouse models of CHCHD2 mutations have been reported. In the present study, we generated a novel CHCHD2 p.T61I KI mouse model, which exhibited accelerated mortality, progressive motor deficits, and dopaminergic (DA) neurons loss with age, accompanied by the accumulation and aggregation of α‐synuclein and p‐α‐synuclein in the brains of the mutant mice. The mitochondria of mouse brains and induced pluripotent stem cells (iPSCs)‐derived DA neurons carrying the CHCHD2 p.T61I mutation exhibited aberrant morphology and impaired function. Mechanistically, proteomic and RNA sequencing analysis revealed that p.T61I mutation induced mitochondrial dysfunction in aged mice likely through repressed insulin‐degrading enzyme (IDE) expression, resulting in the degeneration of the nervous system. Overall, this CHCHD2 p.T61I KI mouse model recapitulated the crucial clinical and neuropathological aspects of patients with PD and provided a novel tool for understanding the pathogenic mechanism and therapeutic interventions of CHCHD2‐related PD. [ABSTRACT FROM AUTHOR]

Background:PLOD1 (procollagen-lysine, 2-oxoglutarate 5-dioxygenase 1) is important for extracellular matrix formation and is involved in various diseases, including cancer; however, its role in gastrointestinal cancer is unclear. In this study, the expression of PLOD1 in gastrointestinal carcinoma and its relationships with patient survival were examined. Materials and Methods: Sample expression profiles were downloaded from the Gene Expression Omnibus database and methylation data were obtained from the Cancer Genome Atlas. Correlations between PLOD1 expression and clinicopathological features were analyzed by chi-square tests. Patient survival was evaluated by a Kaplan–Meier analysis. Results:PLOD1 expression was upregulated in gastric cancer and colorectal cancer compared with that in normal tissues. High PLOD1 levels indicated a poor prognosis. The high methylation group had a significantly lower level of PLOD1 expression. Conclusion: These results indicated that PLOD1 is highly expressed in gastrointestinal carcinoma and is a potential prognostic marker and therapeutic target. The data also indicate that hypomethylation contributes to PLOD1 upregulation in gastric and colon cancers. [ABSTRACT FROM AUTHOR]

Superoxide dismutase 1 (SOD1) is ubiquitously expressed and the predominant dismutase in the cytoplasm. Whereas transcriptional regulation of the SOD 1 gene has been well characterized, posttranscriptional regulation of the gene remains largely unknown in eukaryotes. In this study, a full-length 3′UTR of the SOD 1 transcript was cloned and characterized for its ability to regulate SOD 1 gene expression in human cancer cells. Inclusion of the SOD 1 3′UTR in the pGL3 reporter construct dramatically enhanced the reporter activity by 10- to 220-fold in various cell lines. RT-PCR analysis, however, indicated that the reporter gene mRNA levels were only modestly altered by the SOD 1 3′UTR, suggesting that the SOD 1 3′UTR enhances the reporter gene activity not simply by stabilizing the mRNA but primarily by promoting translation of the protein. Bioinformatics analysis showed multiple stem and loop structures of the SOD 1 3′UTR, and alterations in this secondary structure led to remarkably reduced reporter gene activity. Importantly, introducing the SOD 1 3′UTR into cancer cells attenuated endogenous SOD1 expression in a concentration-dependent manner, indicating the involvement of RNA trans -acting factors in this process. Using siRNA and RNA immunoprecipitation techniques, we identified AUF-1, an RNA-binding protein, as a positive regulator of SOD1 expression through its 3′UTR. Consequently, AUF-1 was found to regulate redox balance in our cell model systems. Furthermore, in human ovarian, esophageal, and pancreatic cancer tissues, the expression of SOD1 was significantly correlated with that of AUF-1, further supporting the importance of AUF-1 in regulating SOD 1 gene expression. [ABSTRACT FROM AUTHOR]

Background/Aims: This study investigated the clinical relevance and biological function of paired box gene 2 (PAX2) in esophageal squamous cell carcinoma (ESCC). Methods/Results: Results showed that PAX2 expression was significantly increased in tumor tissues and that its expression correlated with the ESCC stage (P = 0.001), lymph node metastasis (pN, P = 0.019) and lymphatic invasion (P = 0.005) in 120 ESCC tissue specimens by immunohistochemistry. Furthermore, PAX2 overexpression resulted in markedly reduced cell proliferation but increased metastasis capacity in ESCC TE-1 and Eca-109 cells. Knockdown of PAX2 expression with a short hairpin RNA confirmed a role in the promotion of metastasis in ESCC cells. mRNA microarray screening revealed that PAX2 overexpression affected multiple genes that function in multiple pathways. Interleukin-5 (IL-5), which was induced by PAX2 and has been shown to promote tumor metastasis, was further studied in greater detail. Two PAX2 binding sites were identified in the IL-5 promoter, and PAX2 was observed to stimulate IL-5 promoter activity and IL-5 expression in esophageal cancer cells. Chromatin immunoprecipitation (ChIP) confirmed the direct binding of PAX2 in the IL-5 promoter. The expression of PAX2 mRNA significantly correlated with that of IL-5 in normal esophageal and ESCC tissues. Conclusion: These findings demonstrate that PAX2 is overexpressed in esophageal carcinoma and IL-5 is identified as PAX2's effector for metastasis. © 2015 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Epigallocatechin-3-gallate (EGCG), the major polyphenolic constituent of green tea, is a potent antioxidant that may have potential therapeutic applications for the treatment of many disorders, including cancer. Peroxisome proliferator-activated receptor-α (PPARα) has been shown to play a key role in diverse metabolic and cellular functions. PPARα modulates target gene expression by binding to specific regions on the DNA of target genes. The effects and mechanisms of PPARα activation on EGCG efficacy have not yet been analyzed in cancer cells. We found that when cancer cells were exposed to EGCG, the expression of PPARα was increased at the protein level in a dose-dependent manner. The PPARα agonist clofibrate blocked cytoprotective heme oxygenase-1 (HO-1) induction and sensitized multiple types of cancer cells to EGCG-induced cell death. Conversely, the PPARα inhibitor G6471 and PPARα siRNA increased HO-1 expression. Electro-mobility shift assays (EMSA) and in vivo chromatin immunoprecipitation (ChIP) confirmed that PPARα interacts with the peroxisome proliferator-responsive element of theHO-1promoter. Moreover, cell death induced by EGCG plus clofibrate was partially reversed by HO-1 overexpression in PANC1 cells. These results indicate that PPARα is a direct and negative regulator of HO-1 induced by EGCG and confers cell susceptibility to EGCG. [ABSTRACT FROM AUTHOR]

MicroRNAs (miRNAs), which regulate gene expression by partial complementarity to the 3′ untranslated region of their target genes, have been implicated in cancer initiation and progression. However, the molecular mechanism underlying the regulation of miRNA expression during pancreatic tumorigenesis has not been extensively reported. In this study, we first compared the miRNA expression in human pancreatic cancers and adjacent normal tissues by miRNA array and identified 12 differentially expressed miRNAs. miR-132, which is downregulated in tumors, was further studied in greater detail. Decreased expression of miR-132 was confirmed in 16 of 20 pancreatic carcinomas (P < 0.0001), compared with their respective benign tissues by TaqMan miRNA assays. miR-132 expression was remarkably influenced by promoter methylation in PANC1 and SW1990 cells. Promoter hypermethylation was observed in tumor samples but not in the normal counterparts, and the expression of miR-132 negatively correlated with its methylation status (P = 0.013). miR-132 was transcribed by RNA polymerase II, and Sp1 played a major role in miR-132 transcription. The expression of Sp1 correlated with that of miR-132 in tissues. Moreover, cancerous tissues showed significantly lower Sp1-binding affinity to the miR-132 promoter, relative to non-tumor samples. Proliferation and colony formation of pancreatic cancer cells were suppressed in cells transfected with miR-132 mimics and enhanced in cells transfected with miR-132 inhibitor by negatively regulating the Akt-signaling pathway. Our present findings illustrate the mechanism driving miR-132 downregulation and the important role of miR-132 in pancreatic cancer development. [ABSTRACT FROM PUBLISHER]

Abstract: MicroRNAs (miRNAs) have emerged as important regulators in the development of pancreatic cancer and may be a valuable therapeutic application. DPC4/Smad4 is a critical tumor suppressor involved in the progression of pancreatic cancer, but few studies have been conducted to determine its relationship with miRNAs. In this study, we identify miR-421 as a potential regulator of DPC4/Smad4. We find that in human clinical specimens of pancreatic cancer miR-421 is aberrantly upregulated while DPC4/Smad4 is strongly repressed, and their levels of expression are inversely correlated. Moreover, ectopic expression of miR-421 significantly decreases DPC4/Smad4 protein level in pancreatic cancer cell lines and simultaneously promotes cell proliferation and colony formation in vitro. Our findings identify miR-421 as a potent regulator of DPC4/Smad4, which may provide a novel therapeutic strategy for treatment of DPC4/Smad4-driven pancreatic cancer. [Copyright &y& Elsevier]

Abstract: Both deregulation of tumor-suppressor genes and misexpression of microRNAs (miRNAs) have been implicated in the development of pancreatic cancer, but their relationship during this process remains less clear. Here, we report that the expression of miR-483-3p is strongly enhanced in pancreatic cancer tissues compared to side normal tissues using a miRNA-array differential analysis. Furthermore, DPC4/Smad4 is identified as a target of miR-483-3p and their expression levels are inversely correlated in human clinical specimens. Ectopic expression of miR-483-3p significantly represses DPC4/Smad4 protein levels in pancreatic cancer cell lines, and simultaneously promotes cell proliferation and colony formation in vitro. Our findings identify miR-483-3p as a potent regulator of DPC4/Smad4, which may provide a novel therapeutic strategy for the treatment of DPC4/Smad4-driven pancreatic cancer. [ABSTRACT FROM AUTHOR]

Radiation-induced esophageal injury remains a limitation for the process of radiotherapy for lung and esophageal cancer patients. Esophageal epithelial cells are extremely sensitive to irradiation, nevertheless, factors involved in the radiosensitivity of esophageal epithelial cells are still unknown. Terminal uridyl transferase 4 (TUT4) could modify the sequence of miRNAs, which affect their regulation on miRNA targets and function. In this study, we used transcriptome sequencing technology to identify mRNAs that were differentially expressed before and after radiotherapy in esophageal epithelial cells. We further explored the mRNA expression profiles between wild-type and TUT4 knockout esophageal epithelial cells. Volcano and heatmap plots unsupervised hierarchical clustering analysis were performed to classify the samples. Enrichment analysis on Gene Ontology functional annotations and Kyoto Encyclopedia of Genes and Genomes pathways was performed. We annotated differential genes from metabolism, genetic information processing, environmental information processing, cellular processes, and organismal systems human diseases. The aberrantly expressed genes are significantly enriched in irradiation-related biological processes, such as DNA replication, ferroptosis, and cell cycle. Moreover, we explored the distribution of transcription factor family and its target genes in differential genes. These mRNAs might serve as therapeutic targets in TUT4-related radiation-induced esophageal injury. [ABSTRACT FROM AUTHOR]

Nerve injury often leads to severe dysfunction because of the lack of axon regeneration in adult mammal. Intriguingly a series of extracellular vesicles (EVs) have the obvious ability to accelerate the nerve repair. However, the detailed molecular mechanisms to describe that EVs switch neuron from a transmitter to a regenerative state have not been elucidated. This study elucidated the microRNA (miRNA) expression profiles of two types of EVs that promote nerve regeneration. The functions of these miRNAs were screened in vitro. Among the 12 overlapping miRNAs, miR-25-3p was selected for further analysis as it markedly promoted axon regeneration both in vivo and in vitro. Furthermore, knockdown experiments confirmed that PTEN and Klf4 , which are the major inhibitors of axon regeneration, were the direct targets of miR-25-3p in dorsal root ganglion (DRG) neurons. The utilization of luciferase reporter assays and functional tests provided evidence that miR-25-3p enhances axon regeneration by targeting Tgif1. Additionally, miR-25-3p upregulated the phosphorylation of Erk. Furthermore, Rapamycin modulated the expression of miR-25-3p in DRG neurons. Finally, the pro-axon regeneration effects of EVs were confirmed by overexpressing miR-25-3p and Tgif1 knockdown in the optic nerve crush model. Thus, the enrichment of miR-25-3p in EVs suggests that it regulates axon regeneration, proving a potential cell-free treatment strategy for nerve injury. • miR-25-3p promotes axon regeneration by targeting Tgif1. • miR-25-3p up-regulate p-Erk expression level in DRG neuron. • SKP-SC-EVs containing miR-25-3p was a potential treatment strategy for nerve injury. [ABSTRACT FROM AUTHOR]

• An immune-related ceRNA network was constructed in RIEI. • Potential immune-related mechanisms and therapeutic agents for RIEI were identified. Radiation-induced esophageal injury (RIEI) is an adverse reaction of radiation therapy in patients with esophageal cancer, lung cancer and other malignant tumors. Competitive endogenous RNA (ceRNA) network is known to play a significant role in the onset and progression of many diseases, but the exact mechanism of ceRNA in RIEI has not been fully elucidated. In this study, rat esophaguses were obtained after conducting irradiation under different doses (0 Gy, 25 Gy, 35 Gy). Total RNA was extracted and mRNA, lncRNA, circRNA, and miRNA sequencing was performed. Multiple dose-dependent differentially expressed RNAs (dd-DERs), including 870 lncRNAs, 82 miRNAs, 2478 mRNAs, were obtained through the integration of differential expression analysis and dose-dependent screening (35 Gy ≥ 25 Gy > 0 Gy, or 35 Gy ≤ 25 Gy < 0 Gy). Co-expression analysis and prediction of the binding site in dd-DER were conducted and 27 lncRNAs, 20 miRNAs, and 168 mRNAs were selected to construct a ceRNA network. As the immune microenvironment is crucial for RIEI progression, we constructed an immune-related ceRNA network consisting of 11 lncRNAs, 9 miRNAs, and 9 mRNAs. The expression levels of these immune-related RNAs were verified by RT-qPCR. Immune infiltration analysis showed that the RNAs in the immune-related ceRNA network were mainly associated with the proportion of monocytes, M2 macrophages, activated NK cells, and activated CD4+ memory T cells. Drug sensitivity analysis was conducted based on the expression levels of mRNAs in the immune-related ceRNA network, and small molecule drugs with preventive and therapeutic effects on RIEI were identified. In summary, an immune-related ceRNA network associated with RIEI progression was constructed in this study. The findings provide useful information on new potential targets for the prevention and treatment of RIEI. [ABSTRACT FROM AUTHOR]