Salvianolic Acid B Alleviates High Glucose-Induced Vascular Smooth Muscle Cell Inflammation by Upregulating the miR-486a-5p Expression.

The macrovascular complications of diabetes cause high mortality and disability in patients with type 2 diabetes mellitus (T2DM). The inflammatory response of vascular smooth muscle cell (VSMC) runs through its pathophysiological process. Salvianolic acid B (Sal B) exhibits beneficial effects on the cardiovascular system. However, its role and mechanism in diabetic vascular inflammatory response remain unclear. In this study, we found that Sal B reduced vascular inflammation in diabetic mice and high glucose- (HG-) induced VSMC inflammation. Subsequently, we found that Sal B reduced HG-induced VSMC inflammation by downregulating FOXO1. Furthermore, miR-486a-5p expression was obviously reduced in HG-treated VSMC. Sal B attenuated HG-induced VSMC inflammation by upregulating miR-486a-5p. Loss- and gain-of-function experiments had proven that the transfection of the miR-486a-5p mimic inhibited HG-induced VSMC inflammation whereas that of the miR-486a-5p inhibitor promoted HG-induced VSMC inflammation, thereby leading to the amelioration of vascular inflammation in the diabetic mice. Furthermore, studies had shown that miR-486a-5p inhibited FOXO1 expression by directly targeting its 3'-UTR. In conclusion, Sal B alleviates the inflammatory response of VSMC by upregulating miR-486a-5p and aggravating its inhibition of FOXO1 expression. Sal B exerts a significant anti-inflammatory effect in HG-induced VSMC inflammation by modulating the miR-486a-5p/FOXO1 axis.

Two new acorane-type sesquiterpenoids from an endophytic Trichoderma harzianum associated with Paeonia lactiflora Pall.

Two new acorane-type sesquiterpenoids, harzianes A and B (1 and 2), together with two known cyclonerodiol-type sesquiterpenoids (3-4) and four known sterols (5-8) were isolated from the endophytic Trichoderma harzianum, associated with the medicinal plant Paeonia lactiflora Pall. Compounds 1 and 2 were identified as a pair of heterotropic isomers by spectroscopic analysis (HR-ESI-MS, 1D and 2D NMR), and their absolute configurations were determined by ECD calculations. All compounds were tested for anti-inflammatory activity, however, none demonstrated such activity.

Associations between Borg's rating of perceived exertion and changes in urinary organic acid metabolites after outdoor weight-bearing hiking.

BACKGROUND: Developing methods to monitor exercise load and evaluate body fatigue and muscle injury over time in hiking training remains a key problem to be solved. A widely used psycho-physical tool to assess the subjective perception of effort during exercise is Borg's rating of perceived exertion (BRPE) scale. Data on the relationships and validity of the BRPE compared to objectively assessed metabolic criteria are still lacking, especially urinary organic acid concentrations. AIM: To verify whether the BRPE scale could be used in the prescription of outdoor hiking with weight-bearing and reveal the relationship between the BRPE scale and urinary physiological measures. METHODS: Eighty-nine healthy men (average age: 22 years) were enrolled in a 40 km (6 h) hiking training exercise with a 20 kg load. After training, the BRPE scale (6-20) was completed. All participants were divided into three groups according to the rating of the BRPE scale. Urine samples were collected before and after training. Urinary myoglobin levels were measured immediately using the fluorescent immunoassay method. The remaining urine was subpacked and frozen for the subsequent detection of urinary organic acids using gas chromatography and mass spectrometry. RESULTS: The contents of organic acids and myoglobin in urine were significantly increased after participants hiked 40 km (6 h) with a 20 kg load. Only orthogonal partial least-squares discrimination analysis performed well in separating the group with a BRPE score of 6-12 from the group with a BRPE score of 13-20. Significant differences in the urine levels of several organic acids were observed between the two groups, and the heatmap also presented different metabolic profiles based on BRPE. According to the standard of a variable importance in the projection > 1, fold change > 1.5 and P < 0.05, 19 different metabolites of urinary organic acids were screened and enriched in pathways mainly including the citrate cycle (tricarboxylic acid cycle) and alanine, aspartate and glucose metabolism. CONCLUSION: The BRPE scale identified significantly different urinary organic acid profiles between the higher and lower BRPE value groups, and, thus, could be used to monitor body fatigue in individuals participating in long-distance outdoor hiking with weight bearing.

Diagnostic value of matrix metalloproteinases 2, 7 and 9 in urine for early detection of colorectal cancer.

BACKGROUND: A noninvasive biomarker with high diagnostic performance is urgently needed for the early diagnosis of colorectal cancer (CRC). AIM: To evaluate the diagnostic value of matrix metalloproteinases (MMPs) 2, 7 and 9 in urine for CRC. METHODS: Of 59 healthy controls, 47 patients with colon polyps and 82 patients with CRC were included in this study. Carcinoembryonic antigen (CEA) in serum and MMP2, MMP7, and MMP9 in urine were detected. The combined diagnostic model of the indicators was established by binary logistic regression. The receiver operating characteristic curve (ROC) of the subjects was used to evaluate the independent and combined diagnostic value of the indicators. RESULTS: The MMP2, MMP7, MMP9, and CEA levels in the CRC group differed significantly from levels in the healthy controls (P < 0.05). The levels of MMP7, MMP9, and CEA also differed significantly between the CRC group and the colon polyps group (P < 0.05). The area under the curve (AUC) distinguishing between the healthy control and the CRC patients using the joint model with CEA, MMP2, MMP7 and MMP9 was 0.977, and the sensitivity and specificity were 95.10% and 91.50%, respectively. For early-stage CRC, the AUC was 0.975, and the sensitivity and specificity were 94.30% and 98.30%, respectively. For advanced stage CRC, the AUC was 0.979, and the sensitivity and specificity were 95.70% and 91.50%, respectively. Using CEA, MMP7 and MMP9 to jointly established a model distinguishing the colorectal polyp group from the CRC group, the AUC was 0.849, and the sensitivity and specificity were 84.10% and 70.20%, respectively. For early-stage CRC, the AUC was 0.818, and the sensitivity and specificity were 76.30% and 72.30%, respectively. For advanced stage CRC, the AUC was 0.875, and the sensitivity and specificity were 81.80% and 72.30%, respectively. CONCLUSION: MMP2, MMP7 and MMP 9 may exhibit diagnostic value for the early detection of CRC and may serve as auxiliary diagnostic markers for CRC.

Three new triterpenoid glycosides from Aronia melanocarpa (Michx.) Elliott.

Three new triterpenoid glycosides, 2α,3α,23,24-tetrahydroxyurs-12,19- dien-oic acid 28-O-ß- D -glucopyranoside (1), 2α,3ß,23,24-tetrahydroxyurs-12, 19(29) -dien-28-oic acid 28-O-ß- D -glucopyranoside (2), and 2α,3ß,23,24-tetrahydroxyurs-12, 18-dien-28-oic acid 28-O-ß- D -glucopyranoside (3) were isolated from Aronia melanocarpa (Michx.) Elliott. Their structures were elucidated by extensive spectroscopic methods. All the isolated compounds displayed moderate inhibitory activity against nitric oxide production in macrophages.

Effectiveness and Safety of Histamine H2 Receptor Antagonists: An Umbrella Review of Meta-Analyses.

Histamine H2 receptor antagonists (H2RAs) were widely used to inhibit gastric acid secretion, but its association with adverse events remains controversial and unclear. We conducted an umbrella review of meta-analyses to systematically assess the quality and credibility of the correlations between H2RA use with the risk of adverse outcomes through searching 4 major databases from inception to April 30, 2022. Forty-six individual meta-analyses were identified, including 29 meta-analyses of observation studies with 32 unique outcomes and 19 meta-analyses of randomized controlled trials with 3 unique outcomes for comparing the H2RA versus non-H2RA group. A Measurement Tool to Assess Systematic Reviews 2 rating for the included meta-analyses showed that 4 of 46 meta-analyses were assigned as high scores, 3 were assigned as "moderate," and 25 were assigned as low scores. Grading of Recommendations Assessment, Development and Evaluation assessment for combined results demonstrated that 6 outcomes were rated as "moderate," 9 outcomes were rated as "low," and 17 outcomes were rated as "very low." We confirmed significant associations of H2RA use with pneumonia, peritonitis, necrotizing enterocolitis, Clostridium difficile infection, liver cancer, gastric cancer, and hip fracture diseases. No associations for colorectal cancer, melanoma, kidney cancer, lung cancer, or common reproductive system cancer or renal, neurological, and cardiovascular system diseases were observed. We found a variety of evidence for the associations between H2RAs and adverse outcomes, which would give clinicians more positive guidance on prescription of H2RAs in clinical practice.

Proton Pump Inhibitors and Cancer Risk: An Umbrella Review and Meta-analysis of Observational Studies.

OBJECTIVES: Increasing evidence suggested that proton pump inhibitors (PPIs) use might affect the development of cancers, but previous conclusions remain controversial. Therefore, an umbrella review was performed to clarify the associations between PPIs and various types of cancer by summarizing the existing meta-analyses and systematic reviews. METHODS: We searched PubMed, Cochrane Library, Embase, CNKI, Wanfang, and VIP database up to June 2022 for eligible meta-analyses or systematic reviews. The summary effect size, 95% CI, heterogeneity, small study effect, and 95% prediction interval were considered in the present study. A Measurement Tool to Assess Systematic Review 2 and grading of recommendation, assessment, development, and evaluation were used to assess methodological quality and evidence. RESULTS: The umbrella review included 21 meta-analyses containing 65 studies and 10 cancer types with 6.8 million subjects. The results showed that PPI use was significantly associated with increased risks of certain types of cancer, including gastric cancer (odds ratio [OR]: 2.07; 95% CI, 1.30 to 3.29), pancreatic cancer (OR: 1.73; 95% CI, 1.23 to 2.44), colorectal cancer (OR: 1.84; 95% CI, 1.26 to 2.67), and liver cancer (OR: 1.80; 95% CI, 1.27 to 2.54), but was not associated with esophageal cancer. In addition, PPI use was associated with decreased risk of breast cancer (OR: 0.69; 95% CI, 0.50 to 0.96). CONCLUSIONS: These findings suggested that clinicians should pay more attention to the occurrence of gastric cancer, pancreatic cancer, colorectal cancer, and liver cancer in patients who used PPIs, and PPI prescription should be written only when an accurate specific diagnosis has been made. Furthermore, additional PPIs to the treatment regimen may be benefit for women with a higher-than-average risk of breast cancer.

17ß-estradiol reduces NF-κB expression induced by increased crosstalk between KLF5 and ERα in murine vascular smooth muscle cells.

Pathological vascular remodeling and cell proliferation play vital roles in many proliferative vascular diseases. Estrogen can protect the cardiovascular system, but its exact molecular mechanism is unknown. Here we report that 17ß-estradiol (E2) suppressed vascular smooth muscle cells (VSMCs) proliferation and inflammation. qRT-PCR and Western blot demonstrated that E2 decreased NF-κB p50 expression and reduced VSMCs proliferation and inflammation. Mechanistically, a dual luciferase reporter assay and chromatin immunoprecipitation suggested that KLF5 promoted NF-κB p50 expression by binding to the NF-κB p50 promoter, whereas E2 reduced the effect of KLF5 binding to the NF-κB p50 promoter and inhibited NF-κB p50 expression. Furthermore, a coimmunoprecipitation assay and immunofluorescence staining showed that the interaction between KLF5 and ERα increased in VSMCs treated with E2, which in turn decreased NF-κB p50 expression levels. Altogether, we reveal that E2 inhibits VSMCs proliferation and inflammation by reducing NF-κB expression induced by an increased interaction between KLF5 and ERα. These data provide further insights into how E2 inhibits vascular proliferation and inflammation.

17ß-Estradiol Inhibits Proliferation and Oxidative Stress in Vascular Smooth Muscle Cells by Upregulating BHLHE40 Expression.

Background: Intimal hyperplasia is a major complication of restenosis after angioplasty. The abnormal proliferation and oxidative stress of vascular smooth muscle cells (VSMCs) are the basic pathological feature of neointimal hyperplasia. 17ß-Estradiol can inhibit VSMCs proliferation and inflammation. However, it is still unclear whether and how 17ß-Estradiol affects intimal hyperplasia. Methods: The neointima hyperplasia was observed by hematoxylin/eosin staining. The expression of PCNA, cyclin D1, NOX1, NOX4 and p47phox in neointima hyperplasia tissues and VSMCs was determined by qRT-PCR and Western blotting. MTS assay, cell counting and EdU staining were performed to detect cells proliferation. The oxidative stress was assessed by ROS staining. Results: 17ß-Estradiol suppressed carotid artery ligation-induced intimal hyperplasia, which is accompanied by an increase of BHLHE40 level. Furthermore, loss- and gain-of-function experiments revealed that BHLHE40 knockdown promotes, whereas BHLHE40 overexpression inhibits TNF-α-induced VSMC proliferation and oxidative stress. 17ß-Estradiol inhibited TNF-α-induced VSMC proliferation and oxidative stress by promoting BHLHE40 expression, thereby suppressing MAPK signaling pathways. In addition, enforcing the expression of BHLHE40 leads to amelioration of intimal hyperplasia. Conclusions: Our study demonstrates that 17ß-Estradiol inhibits proliferation and oxidative stress in vivo and in vitro by promotion of BHLHE40 expression.

17ß-Estradiol Attenuates LPS-Induced Macrophage Inflammation In Vitro and Sepsis-Induced Vascular Inflammation In Vivo by Upregulating miR-29a-5p Expression.

Excessive release of cytokines such as IL-1ß and other inflammatory mediators synthesized and secreted by macrophages is the fundamental link of uncontrolled inflammatory response in sepsis. 17ß-Estradiol (E2) plays anti-inflammatory and vascular protective effects by regulating leukocyte infiltration and the expression of chemokines or cytokines induced by injury. However, the role of E2 in the inflammatory response of macrophages in sepsis and its mechanism are still not fully understood. In the present study, we show that E2 alleviates vascular inflammation in sepsis mice induced by cecal ligation puncture (CLP). E2 significantly decreases RAW 264.7 cell inflammation response by downregulating the expression of NLRP3. Furthermore, we found that miR-29a-5p was significantly downregulated in LPS-treated macrophages. Treating RAW 264.7 cells with E2 markedly upregulated the miR-29a-5p expression level. More importantly, we demonstrated that miR-29a-5p repressed NLRP3 expression by directly targeting its 3'-UTR. Loss- and gain-of-function experiments revealed that transfection of the miR-29a-5p mimic abrogates LPS-induced macrophage inflammation. Moreover, depletion of miR-29a-5p by its inhibitor largely promotes LPS-induced macrophage inflammation. In summary, miR-29a-5p upregulation induced by E2 alleviated RAW 264.7 cell inflammation response by aggravating miR-29a-5p repression of NLRP3 expression. E2 exerts significant anti-inflammatory efficacy in macrophages by regulating the miR-29a-5p/NLRP3 axis. Targeting miR-29a-5p may be a novel therapeutic strategy to suppress sepsis-induced vascular inflammation.

Imbalance of Molecular Module of TINCR-miR-761 Promotes the Metastatic Potential of Early Triple Negative Breast Cancer and Partially Offsets the Anti-Tumor Activity of Luteolin.

BACKGROUND: Triple negative breast cancer (TNBC) poses a great threat to patient prognosis. LncRNA-miRNA is a molecular module formed by a long non-coding RNA (LncRNA) and a microRNA (miRNA) that mediates the metastatic potential of tumours such as TNBC, and luteolin (LU) is a natural compound with anti-TNBC activity. OBJECTIVE: We aim to explore the regulatory mechanism of terminal differentiation-induced non-coding RNA (TINCR)-miR-761 molecular module in early TNBC, as well as its influence on anti-tumor activity of LU. METHODS: The serum was collected from TNBC patients in early stage to detect the expression of TINCR and miR-761 using RT-PCR. Transwell method was applied for the determination of cell migration and invasion, Western blot for epithelial-mesenchymal transition (EMT), flow cytometry (FCM) for cell apoptosis, and dual luciferase reporter and RNA pull-down experiment for the verification of the targeted relationship between TINCR and miR-761. RESULTS: Both TINCR and miR-761 were up-regulated in the serum of patients with early TNBC and the area under the curve (AUC) of the two for distinguishing TNBC from BC was not less than 0.850. In the cell function tests, down-regulation of TINCR or miR-761 notably suppressed the metastatic potentials (cell migration, invasion and EMT) of TNBC cells were remarkably inhibited, while up-regulation of TINCR or miR-761 notably promoted the metastatic potentials. We also confirmed that TINCR acts as the molecular sponge of miR-761, and has positive regulation on it. Besides, LU can significantly down-regulate TINCR and miR-761, and partially offset the anti-TNBC activity of LU when they were abnormally up-regulated, which was mainly reflected in the decrease of anti-proliferation and pro-apoptotic ability of LU against TNBC. CONCLUSION: There is an imbalance of TINCR-miR-761 molecular module in early TNBC, which may be a potential new therapeutic target of TNBC.

Regulatory Effect of miR497-5p-CCNE1 Axis in Triple-Negative Breast Cancer Cells and Its Predictive Value for Early Diagnosis.

OBJECTIVE: To explore the regulatory role of miR497-5p-CCNE1 axis in triple-negative breast cancer (TNBC) cells and its predictive value for early diagnosis. METHODS: Cancer tissue and adjacent tissue samples were collected from 86 patients with TNBC.RT-PCR was used to detect the expression of miR497-5p and CCNE1 (target gene) mRNA, determined by biological prediction in tissue and TNBC cells. ROC was used to analyze the diagnostic value of miR497-5p in TNBC. MTT, invasion, and flow cytometry were used to detect the proliferation, invasion, cycle, apoptosis rate, and expression of related proteins of TNBC cells with overexpression of miR497-5p or knockdown of CCNE1. RESULTS: RT-qPCR results showed that miR497-5p levels were significantly downregulated in TNBC tissue and cells, while CCNE1 expression was significantly upregulated, and miR497-5p expression was negatively correlated with that of CCNE1 (P<0.001). ROC analysis showed that the AUC of miR497-5p for TNBC was >0.9, which had better diagnostic value. The cell tests revealed that miR497-5p played a role in tumor inhibition, including inhibiting proliferation and invasion of TNBC cells, blocking the cell cycle, and promoting apoptosis. Bioinformatic prediction and subsequent experiments revealed that CCNE1 was the direct target of miR497-5p. Furthermore, after knocking down the expression of CCNE1 in TNBC cells, the proliferation and invasion of TNBC cells were significantly inhibited, the cell cycle blocked, and the apoptosis rate significantly increased (P<0.001), and expression of the proapoptosis-related proteins Bax and caspase 3 (cleaved) were upregulated, while expression of the antiapoptosis-related protein BCL2 was downregulated (P<0.001). CONCLUSION: miR497-5p inhibited the proliferation and invasion of TNBC cells by targeting CCNE1, blocked the cell cycle and promoted the apoptosis of TNBC cells, and had better diagnostic value for TNBC. miR497-5p can be used as a new potential target for the treatment of TNBC.

Comparative genomic analysis of three geographical isolates from China reveals high genetic stability of Plutella xylostella granulovirus.

In this study, the genomes of three Plutella xylostella granulovirus (PlxyGV) isolates, PlxyGV-W and PlxyGV-Wn from near Wuhan and PlxyGV-B from near Beijing, China were completely sequenced and comparatively analyzed to investigate genetic stability and diversity of PlxyGV. PlxyGV-W, PlxyGV-B and PlxyGV-Wn consist of 100,941bp, 100,972bp and 100,999bp in length with G + C compositions of 40.71-40.73%, respectively, and share nucleotide sequence identities of 99.5-99.8%. The three individual isolates contain 118 putative protein-encoding ORFs in common. PlxyGV-W, PlxyGV-B and PlxyGV-Wn have ten, nineteen and six nonsynonymous intra isolate nucleotide polymorphisms (NPs) in six, fourteen and five ORFs, respectively, including homologs of five DNA replication/late expression factors and two per os infectivity factors. There are seventeen nonsynonymous inter isolate NPs in seven ORFs between PlxyGV-W and PlxyGV-B, seventy three nonsynonymous NPs in forty seven ORFs between PlxyGV-W and PlxyGV-Wn, seventy seven nonsynonymous NPs in forty six ORFs between PlxyGV-B and PlxyGV-Wn. Alignment of the genome sequences of nine PlxyGV isolates sequenced up to date shows that the sequence homogeneity between the genomes are over 99.4%, with the exception of the genome of PlxyGV-SA from South Africa, which shares a sequence identity of 98.6-98.7% with the other ones. No events of gene gain/loss or translocations were observed. These results suggest that PlxyGV genome is fairly stable in nature. In addition, the transcription start sites and polyadenylation sites of thirteen PlxyGV-specific ORFs, conserved in all PlxyGV isolates, were identified by RACE analysis using mRNAs purified from larvae infected by PlxyGV-Wn, proving the PlxyGV-specific ORFs are all genuine genes.

MicroRNA-488 inhibits proliferation and motility of tumor cells via downregulating FSCN1, modulated by Notch3 in breast carcinomas.

As important modulators in multiple physiological processes, microRNAs (miRNAs) have been reported in various malignant tumors, including breast cancer. The current study investigated the function of a new tumor suppressor microRNA, miR-488, and its molecular mechanism of metastasis in breast cancers. CCK8 and transwell assays revealed that the upregulated miR-488 level significantly inhibited the proliferation and migration of breast cancer cells. As a potential downstream gene, the mRNA and protein level of FSCN1 was suppressed by increased miR-488 and vice versa. Luciferase assay showed that miR-488 directly bind to the 3'UTR of FSCN1 and suppressed the translation process of FSCN1. The promoter region of miR-488 was directly bound by Notch3 and promoted the expression of miR-488 transcriptionally. Immunohistochemistry results revealed that in patients with breast cancer, the expression of Notch3 and were negatively correlated with the FSCN1 levels significantly. Therefore, the current finding predicted miR-488 as a tumor suppressor molecule in breast cancer, and demonstrated that Notch3/miR-488/FSCN1 axis is established and involved in regulating the metastasis of breast cancers, providing novel therapeutic targets for patients with breast cancers.

Long non-coding RNAs engender drug resistance to different subtypes of treatments of breast cancers and may provide a "next generation" therapy option.

The dysfunction of long non-coding RNAs (lncRNAs), without protein-coding potential, has been implicated in drug resistance against treatment in various human diseases, especially in malignant tumors. As the most common-diagnosed female malignancy worldwide, breast cancer is also the second-leading cause of cancer-related mortality in women. Despite the improvement in neo-adjuvant therapy, endocrine therapy, molecular-targeted treatment, and chemotherapy, drug resistance to various treatment regimens is still quite prevalent. This article focused on the lncRNAs and their functions in drug resistance against breast cancer therapeutic agents, in order to develop new precise treatment strategies for patients with breast cancers. The discovery of lncRNA opened new doors to the molecular mechanisms of the biological processes, and has provided new pathways to regulate biochemical events. Thus, lncRNAs may be developed as a biomarker for the detection and/or prevention of breast cancer. Additionally, lncRNA-based approaches may provide an additional treatment modality in personalized medicine alone or in combination with existing tumor-directed interventions to improve patient outcomes. In conclusion, lncRNAs molecules may represent the "next generation" therapy option for breast cancer patients.

Involvement of glutathione peroxidases in the occurrence and development of breast cancers.

Glutathione peroxidases (GPxs) belong to a family of enzymes that is important in organisms; these enzymes promote hydrogen peroxide metabolism and protect cell membrane structure and function from oxidative damage. Based on the establishment and development of the theory of the pathological roles of free radicals, the role of GPxs has gradually attracted researchers' attention, and the involvement of GPxs in the occurrence and development of malignant tumors has been shown. On the other hand, the incidence of breast cancer in increasing, and breast cancer has become the leading cause of cancer-related death in females worldwide; breast cancer is thought to be related to the increased production of reactive oxygen species, indicating the involvement of GPxs in these processes. Therefore, this article focused on the molecular mechanism and function of GPxs in the occurrence and development of breast cancer to understand their role in breast cancer and to provide a new theoretical basis for the treatment of breast cancer.

Fanconi Anemia Pathway: Mechanisms of Breast Cancer Predisposition Development and Potential Therapeutic Targets.

The maintenance of genomic stability is crucial for species survival, and its failure is closely associated with tumorigenesis. The Fanconi anemia (FA) pathway, involving 22 identified genes, plays a central role in repairing DNA interstrand cross-links. Importantly, a germline defect in any of these genes can cause Fanconi's anemia, a heterogeneous genetic disorder, characterized by congenital growth abnormalities, bone marrow failure, and predisposition to cancer. On the other hand, the breast cancer susceptibility genes, BRCA1 and BRCA2, also known as FANCS and FANCD1, respectively, are involved in the FA pathway; hence, researchers have studied the association between the FA pathway and cancer predisposition. Here, we mainly focused on and systematically reviewed the clinical and mechanistic implications of the predisposition of individuals with abnormalities in the FA pathway to cancer, especially breast cancer.

Oncogenic functions of the EMT-related transcription factor ZEB1 in breast cancer.

Zinc finger E-box binding homeobox 1 (ZEB1, also termed TCF8 and δEF1) is a crucial member of the zinc finger-homeodomain transcription factor family, originally identified as a binding protein of the lens-specific δ1-crystalline enhancer and is a pivotal transcription factor in the epithelial-mesenchymal transition (EMT) process. ZEB1 also plays a vital role in embryonic development and cancer progression, including breast cancer progression. Increasing evidence suggests that ZEB1 stimulates tumor cells with mesenchymal traits and promotes multidrug resistance, proliferation, and metastasis, indicating the importance of ZEB1-induced EMT in cancer development. ZEB1 expression is regulated by multiple signaling pathways and components, including TGF-ß, ß-catenin, miRNA and other factors. Here, we summarize the recent discoveries of the functions and mechanisms of ZEB1 to understand the role of ZEB1 in EMT regulation in breast cancer.

Analysis of the Differentially Expressed Genes Induced by Cisplatin Resistance in Oral Squamous Cell Carcinomas and Their Interaction.

BACKGROUND: Oral squamous cell carcinoma (OSCC) is a solid tumor, which originates from squamous epithelium, with about 400,000 new-cases/year worldwidely. Presently, chemoradiotherapy is the most important adjuvant treatment for OSCC, mostly in advanced tumors. However, clinical resistance to chemotherapy still leads to poor prognosis of OSCC patients. Via high-throughput analysis of gene expression database of OSCC, we investigated the molecular mechanisms underlying cisplatin resistance in OSCC, analyzing the differentially expressed genes (DEGs) and their regulatory relationship, to clarify the molecular basis of OSCC chemotherapy resistance and provide a theoretical foundation for the treatment of patients with OSCC and individualized therapeutic targets accurately. METHODS: Datasets related to "OSCC" and "cisplatin resistance" (GSE111585 and GSE115119) were downloaded from the GEO database and analyzed by GEO2R. Venn diagram was used to obtain drug-resistance-related DEGs. Functional enrichment analysis and Kyoto encyclopedia of genes and genomes (KEGG) pathway analysis were performed on DEGs using The Database for Annotation, Visualization and Integrated Discovery (DAVID) software. Protein-protein interaction (PPI) network was constructed by STRING (search tool for recurring instances of neighbouring genes) database. Potential target genes of miRNA were predicted via miRDB, and cBioportal was used to analyze the function and survival of the potential functional genes. RESULTS: Forty-eight upregulated DEGs and 49 downregulated DEGs were obtained from the datasets, with cutoff as p < 0.01 and |log FC| > 1. The DEGs in OSCC mainly enriched in cell proliferation regulation, and chemokine activity. In PPI network with hub score > 300, the hub genes were identified as NOTCH1, JUN, CTNNB1, CEBPA, and ETS1. Among miRNA-mRNA targeting regulatory network, hsa-mir-200c-3p, hsa-mir-200b-3p, hsa-mir-429, and hsa-mir-139-5p were found to simultaneously regulate multiple hub genes. Survival analysis showed that patients with high CTNNB1 or low CEBPA expression had poor outcome. CONCLUSIONS: In the OSCC cisplatin-resistant cell lines, NOTCH1, JUN, CTNNB1, CEBPA, and ETS1 were found as the hub genes involved in regulating the cisplatin resistance of OSCC. Members of the miR-200 family may reverse drug resistance of OSCC cells by regulating the hub genes, which can act as potential targets for the treatment of OSCC patients with cisplatin resistance.

Dysregulation of p53-RBM25-mediated circAMOTL1L biogenesis contributes to prostate cancer progression through the circAMOTL1L-miR-193a-5p-Pcdha pathway.

p53, circRNAs and miRNAs are important components of the regulatory network that activates the EMT program in cancer metastasis. In prostate cancer (PCa), however, it has not been investigated whether and how p53 regulates EMT by circRNAs and miRNAs. Here we show that a Amotl1-derived circRNA, termed circAMOTL1L, is downregulated in human PCa, and that decreased circAMOTL1L facilitates PCa cell migration and invasion through downregulating E-cadherin and upregulating vimentin, thus leading to EMT and PCa progression. Mechanistically, we demonstrate that circAMOTL1L serves as a sponge for binding miR-193a-5p in PCa cells, relieving miR-193a-5p repression of Pcdha gene cluster (a subset of the cadherin superfamily members). Accordingly, dysregulation of the circAMOTL1L-miR-193a-5p-Pcdha8 regulatory pathway mediated by circAMOTL1L downregulation contributes to PCa growth in vivo. Further, we show that RBM25 binds directly to circAMOTL1L and induces its biogenesis, whereas p53 regulates EMT via direct activation of RBM25 gene. These findings have linked p53/RBM25-mediated circAMOTL1L-miR-193a-5p-Pcdha regulatory axis to EMT in metastatic progression of PCa. Targeting this newly identified regulatory axis provides a potential therapeutic strategy for aggressive PCa.