Mesenchymal Transformation Research Articles

The possible molecular mechanism underlying the involvement of the variable shear factor QKI in the epithelial-mesenchymal transformation of oesophageal cancer.

Based on the GEO, TCGA and GTEx databases, we reveal the possible molecular mechanism of the variable shear factor QKI in epithelial mesenchymal transformation (EMT) of oesophageal cancer. Based on the TCGA and GTEx databases, the differential expression of the variable shear factor QKI in oesophageal cancer samples was analysed, and functional enrichment analysis of QKI was performed based on the TCGA-ESCA dataset. The percent-spliced in (PSI) data of oesophageal cancer samples were downloaded from the TCGASpliceSeq database, and the genes and variable splicing types that were significantly related to the expression of the variable splicing factor QKI were screened out. We further identified the significantly upregulated circRNAs and their corresponding coding genes in oesophageal cancer, screened the EMT-related genes that were significantly positively correlated with QKI expression, predicted the circRNA-miRNA binding relationship through the circBank database, predicted the miRNA-mRNA binding relationship through the TargetScan database, and finally obtained the circRNA-miRNA-mRNA network through which QKI promoted the EMT process. Compared with normal control tissue, QKI expression was significantly upregulated in tumour tissue samples of oesophageal cancer patients. High expression of QKI may promote the EMT process in oesophageal cancer. QKI promotes hsa_circ_0006646 and hsa_circ_0061395 generation by regulating the variable shear of BACH1 and PTK2. In oesophageal cancer, QKI may promote the production of the above two circRNAs by regulating variable splicing, and these circRNAs further competitively bind miRNAs to relieve the targeted inhibition of IL-11, MFAP2, MMP10, and MMP1 and finally promote the EMT process. Variable shear factor QKI promotes hsa_circ_0006646 and hsa_circ_0061395 generation, and downstream related miRNAs can relieve the targeted inhibition of EMT-related genes (IL11, MFAP2, MMP10, MMP1) and promote the occurrence and development of oesophageal cancer, providing a new theoretical basis for screening prognostic markers of oesophageal cancer patients.

Cryptotanshinone alleviates radiation-induced lung fibrosis via modulation of gut microbiota and bile acid metabolism.

Cryptotanshinone (CPT), a major biological active ingredient extracted from root of Salvia miltiorrhiza (Danshen), has shown several pharmacological activities. However, the effect of CPT on radiation-induced lung fibrosis (RILF) is unknown. In this study, we explored the protective effects of CPT on RILF from gut-lung axis angle, specifically focusing on the bile acid (BA)-gut microbiota axis. We found that CPT could inhibit the process of epithelial mesenchymal transformation (EMT) and suppress inflammation to reduce the deposition of extracellular matrix in lung fibrosis in mice induced by radiation. In addition, 16S rDNA gene sequencing and BAs-targeted metabolomics analysis demonstrated that CPT could improve the dysbiosis of gut microbiota and BA metabolites in RILF mice. CPT significantly enriched the proportion of the beneficial genera Enterorhabdus and Akkermansia, and depleted that of Erysipelatoclostridium, which were correlated with increased intestinal levels of several farnesoid X receptor (FXR) natural agonists, such as deoxycholic acid and lithocholic acid, activating the FXR pathway. Taken together, these results suggested that CPT can regulate radiation-induced disruption of gut microbiota and BAs metabolism of mice, and reduce the radiation-induced lung inflammation and fibrosis. Thus, CPT may be a promising drug candidate for treating RILF.

Isorhamnetin and anti-PD-L1 antibody dual-functional mesoporous silica nanoparticles improve tumor immune microenvironment and inhibit YY1-mediated tumor progression

BackgroundThe immune checkpoint inhibitor (ICI) anti-PD-L1 monoclonal antibody can inhibit the progress of hepatocellular carcinoma (HCC). Epithelial–mesenchymal transformation (EMT) can promote tumor migration and the formation of immune-suppression microenvironment, which affects the therapeutic effect of ICI. Yin-yang-1 (YY1) is an important transcription factor regulating proliferation, migration and EMT of tumor cells. This work proposed a drug-development strategy that combined the regulation of YY1-mediated tumor progression with ICIs for the treatment of HCC.MethodsWe first studied the proteins that regulated YY1 expression by using pull-down, co-immunoprecipitation, and duo-link assay. The active compound regulating YY1 content was screened by virtual screening and cell-function assay. Isorhamnetin (ISO) and anti-PD-L1 antibody dual-functional mesoporous silica nanoparticles (HMSN-ISO@ProA-PD-L1 Ab) were prepared as an antitumor drug to play a synergistic anti-tumor role.ResultsYY1 can specifically bind with the deubiquitination enzyme USP7. USP7 can prevent YY1 from ubiquitin-dependent degradation and stabilize YY1 expression, which can promote the proliferation, migration and EMT of HCC cells. Isorhamnetin (ISO) were screened out, which can target USP7 and promote YY1 ubiquitin-dependent degradation. The cell experiments revealed that the HMSN-ISO@ProA-PD-L1 Ab nanoparticles can specifically target tumor cells and play a role in the controlled release of ISO. HMSN-ISO@ProA-PD-L1 Ab nanoparticles inhibited the growth of Hepa1-6 transplanted tumors and the effect was better than that of PD-L1 Ab treatment group and ISO treatment group. HMSN-ISO@ProA-PD-L1 Ab nanoparticles also exerted a promising effect on reducing MDSC content in the tumor microenvironment and promoting T-cell infiltration in tumors.ConclusionsThe isorhamnetin and anti-PD-L1 antibody dual-functional nanoparticles can improve tumor immune microenvironment and inhibit YY1-mediated tumor progression. This study demonstrated the possibility of HCC treatment strategies based on inhibiting USP7-mediated YY1 deubiquitination combined with anti-PD-L1 monoclonal Ab.

Analysis of the characteristics of immune infiltration in endometrial carcinoma and its relationship with prognosis based on bioinformatics.

To explore immune-related molecules that affect the prognosis of endometrial carcinoma (EC) using bioinformatic data mining. The expression data related to EC were downloaded from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus databases. After differential expression analysis, the intersection with immune related genes in the ImmPort database was used to obtain immune related differentially expressed genes (IRDEGs). The correlation between clinicopathological information and the prognosis of IRDEGs was further analyzed to obtain prognosis related differentially expressed immune genes (PRDEIG). Gene correlation analysis and Gene Set Enrichment Analysis (GSEA) enrichment analysis showed that PRDEIG was enriched in cancer-related functional pathways. We then analyzed the relationship between PRDEIG and immune cell infiltration, and further analyzed the mRNA and protein expression of PRDEIG in EC using TCGA and the human protein expression atlas (THPA) databases. After the intersection of the differential expression analysis results and immune-related genes, 4 IRDEGs were obtained: osteoglycin (OGN), LTBP4, CXCL12, and SPP1. After analyzing the relationship between 4 IRDEGs and clinicopathological parameters and prognosis of patients with EC, revealed that only OGN was not only related to tumor immunity, but also affected the prognosis of patients with EC. Gene correlation and GSEA enrichment of OGN were analyzed. The results showed that OGN was significantly enriched in 6 functional pathways: epithelial mesenchymal transition, KRAS signaling up, myogenesis, UV response, allograft rejection and apical junction. In addition, it was also found that OGN was significantly correlated with a variety of immune cells. The results of TCGA and THPA database showed that the mRNA and protein expression levels of OGN decreased in EC. OGN may affect the epithelial mesenchymal transformation (EMT) of tumor by affecting the infiltration of tumor immune cells.

Macrophage Membrane‐Coated Nanoparticles Sensitize Glioblastoma to Radiation by Suppressing Proneural–Mesenchymal Transformation in Glioma Stem Cells

AbstractRadiotherapy is identified as a crucial treatment for patients with glioblastoma, but recurrence is inevitable. The efficacy of radiotherapy is severely hampered partially due to the tumor evolution. Growing evidence suggests that proneural glioma stem cells can acquire mesenchymal features coupled with increased radioresistance. Thus, a better understanding of mechanisms underlying tumor subclonal evolution may develop new strategies. Herein, data highlighting a positive correlation between the accumulation of macrophage in the glioblastoma microenvironment after irradiation and mesenchymal transdifferentiation in glioblastoma are presented. Mechanistically, elevated production of inflammatory cytokines released by macrophages promotes mesenchymal transition in an NF‐κB‐dependent manner. Hence, rationally designed macrophage membrane‐coated porous mesoporous silica nanoparticles (MMNs) in which therapeutic anti‐NF‐κB peptides are loaded for enhancing radiotherapy of glioblastoma are constructed. The combination of MMNs and fractionated irradiation results in the blockage of tumor evolution and therapy resistance in glioblastoma‐bearing mice. Intriguingly, the macrophage invasion across the blood‐brain barrier is inhibited competitively by MMNs, suggesting that these nanoparticles can fundamentally halt the evolution of radioresistant clones. Taken together, the biomimetic MMNs represent a promising strategy that prevents mesenchymal transition and improves therapeutic response to irradiation as well as overall survival in patients with glioblastoma.

Circ-MALAT1 accelerates cell proliferation and epithelial mesenchymal transformation of colorectal cancer through regulating miR-506-3p/KAT6B axis.

Colorectal cancer (CRC) is a prevalent malignant tumor of the digestive tract. Circular RNAs may play important roles in the progression of CRC. In this study, we investigated the roles and mechanisms of action of circ-MALAT1 in CRC. Gene expression and protein abundance were determined using qRT-PCR and western blot, respectively. Cell proliferation and migration were assessed by MTT, clone formation, and wound-healing assays. The interactions among the long non-coding RNA metastasis-associated lung adenocarcinoma transcript 1 (circ-MALAT1), miR-506-3p, and lysine acetyltransferase 6B (KAT6B) were predicted using the StarBase software and confirmed by the luciferase activity assay. Circ-MALAT1 and KAT6B were upregulated, while miR-506-3p was downregulated in CRC cells. We validated that knocking down of circ-MALAT1 suppressed proliferation, migration, and epithelial-mesenchymal transition (EMT) of CRC cells, and these effects were abolished by miR-506-3p downregulation or KAT6B sufficiency. Our study suggests that circ-MALAT1 could sponge miR-506-3p to regulate the expression of KAT6B. Moreover, KAT6B sufficiency could neutralize miR-506-3p-dependent growth arrest, migration, and EMT. Circ-MALAT1 promotes cell proliferation, migration, and EMT of CRC cells via the miR-506-3p/KAT6B axis, thereby acting as a novel potential therapeutic target for the treatment of colorectal cancer.

High SNRPA1 expression leads to poor prognosis in patients with lung adenocarcinoma.

SNRPA1, a subunit of spliceosome complex, has been implicated in diverse cancers, while its biological effect in LUAD remains elusive. Therefore, we sought to decipher the relationship between SNRPA1 expression and the prognosis of patients with LUAD and reveal the underlying molecular mechanism. Based on the clinical data from TCGA databases, the multivariate Cox model was constructed to screen the prognostic value of SNRPA1. qRT-PCR and immunohistochemical staining were used to examine SNRPA1 mRNA and protein expression in LUAD. The effect of SNRPA1 on LUAD cell proliferation, migration, and epithelial mesenchymal transformation were examined using colony formation assays, wound healing, and western blot assays, respectively. Finally, the influence of SNRPA1 on LUAD immune microenvironment were validated from the Tumor Immune Estimation Resource database. SNRPA1 was significantly upregulated in both LUAD tissues and cell lines, and highly expressed SNRPA1 contributed to poor prognosis of LUAD patients. In vitro, SNRPA1 knockdown inhibited the proliferation and migration, as well as delayed the EMT differentiation of LUAD cells. Lastly, SNRPA1 was found to be positively associated with immune infiltration and some immune-check-point markers. Our findings indicate that SNRPA1 may be a new biomarker for prognostic prediction and a potential therapeutic target in the treatment of LUAD.

The Emerging, Multifaceted Role of WTAP in Cancer and Cancer Therapeutics.

Cancer is a grave and persistent illness, with the rates of both its occurrence and death toll increasing at an alarming pace. N6-methyladenosine (m6A), the most prevalent mRNA modification in eukaryotic organisms, is catalyzed by methyltransferases and has a significant impact on various aspects of cancer progression. WT1-associated protein (WTAP) is a crucial component of the m6A methyltransferase complex, catalyzing m6A methylation on RNA. It has been demonstrated to participate in numerous cellular pathophysiological processes, including X chromosome inactivation, cell proliferation, cell cycle regulation, and alternative splicing. A better understanding of the role of WTAP in cancer may render it a reliable factor for early diagnosis and prognosis, as well as a key therapeutic target for cancer treatment. It has been found that WTAP is closely related to tumor cell cycle regulation, metabolic regulation, autophagy, tumor immunity, ferroptosis, epithelial mesenchymal transformation (EMT), and drug resistance. In this review, we will focus on the latest advances in the biological functions of WTAP in cancer, and explore the prospects of its application in clinical diagnosis and therapy.

Predicting the immunotherapy response based on molecular subtypes of pan-immune signatures in gastrointestinal stromal tumor.

e23512 Background: Gastrointestinal stromal tumor (GIST) is the most common sarcoma, often originate in the stomach or the small intestine. Although the application of imatinib has brought a breakthrough in the clinical treatment of GIST, not all GIST patients are effective, and most GIST patients who receive imatinib sensitivity will develop drug resistance and eventually malignant progression. The tumor microenvironment (TME) is a key mediator of cancer progression and treatment outcome, and plays an important role in predicting cancer prognosis and treatment response. This study aims to investigate the role of TME in the treatment of GIST and the response to immunotherapy. Methods: Raw microarray data of 199 GIST patients were downloaded from GEO, including 159 KIT-mutant, 21 PDGFRA-mutant and 19 WT. All affymetrix datasets were re-normalized using the gcRMA package with default parameters. We integrated 275 TME and malignant signaling pathways related signatures from different database and previous researches, including CIBERSORT, MCP-counter, TIMER, and others. Fisher exact test's was used to identify signatures that differential between KIT-mutant, PDGFRA-mutant, and WT (p < 0.05), and 85 signatures were finally obtained. To classify the molecular profiles, the expression patterns were assessed in all 199 GIST patients using unsupervised clustering based on their ssGSEA scores, and can be clustered into three distinct microenvironments. Results: Using GSEA with all TME signatures genes ranked by the log2(fold change) between the threee clustes, we found that gene sets were considered immune favorable in cluster A, including gene sets related to activated CD8+ T cells (p = 0.0003)and activated CD4 T cell signaling pathway (p = 0.009). Cluster B enriched to the epithelial mesenchymal transformation pathway (p = 0.04) and TGFb signaling pathway (p = 0.003), cluster C enriched into DNA-repair pathway (p = 0.02). In an independent skin cutaneous melanoma cohorts (n = 86) treated with anti-PD-1 therapy, patients were classified into three molecular clusters, which significantly corrleated with response to ipilimumab (p = 0.007). The percentage of responders to anti-PD-1 therapy in cluster A was 75% in contrast to only 10% in cluster B. The three molecular clusters discern a potential responder versus non-responder (AUC = 0.87; p = 0.0015), with essentially a 80% chance of correctly predicting the response, which supporting the utilization of the classification method. Conclusions: In this study, the immuno-infiltrating landscape was characterized based on pan-immune signatures using transcriptomic profile in GIST. The molecular subtypes derived from pan-immune signatures have the potential to predict the efficacy of immunotherapy.

Circular RNA circ0001955 promotes cervical cancer tumorigenesis and metastasis via the miR-188-3p/NCAPG2 axis

BackgroundCircular RNAs (circRNAs) are known to play a crucial role in a variety of malignancies. However, the precise role of circRNAs in cervical squamous cell carcinoma (CSCC) remains largely unknown.MethodsThe expression of circ0001955 was determined by real-time quantitative PCR and fluorescence in situ hybridization. To examine the effects of circ0001955 on CSCC metastasis and growth, functional experiments were conducted in vitro and in vivo. Mechanistically, nucleocytoplasmic separation, dual luciferase reporter assay, RNA antisense purification experiments, and rescue experiments were performed to confirm the interaction between circ0001955, miR-188-3p, and NCAPG2 in CSCC.ResultsHere, we demonstrated that a circRNA derived from the CSNK1G1 gene (circ0001955) is significantly upregulated in CSCC. The overexpression of circ0001955 promotes tumor proliferation and metastasis, whereas the knockdown of circ0001955 exerts the opposite effects. Mechanistically, circ0001955 competitively binds miR-188-3p and prevents miR-188-3p from reducing the levels of NCAPG2, activating the AKT/mTOR signaling pathway to induce epithelial mesenchymal transformation. Notably, the application of an inhibitor of mTOR significantly antagonized circ0001955-mediated CSCC tumorigenesis.Conclusioncirc0001955 promotes CSCC tumorigenesis and metastasis via the miR-188-3p/NCAPG2 axis which would provide an opportunity to search new therapeutic targets for CSCC.Graphical

Towards a Unified Approach in Autoimmune Fibrotic Signalling Pathways.

Autoimmunity is a chronic process resulting in inflammation, tissue damage, and subsequent tissue remodelling and organ fibrosis. In contrast to acute inflammatory reactions, pathogenic fibrosis typically results from the chronic inflammatory reactions characterizing autoimmune diseases. Despite having obvious aetiological and clinical outcome distinctions, most chronic autoimmune fibrotic disorders have in common a persistent and sustained production of growth factors, proteolytic enzymes, angiogenic factors, and fibrogenic cytokines, which together stimulate the deposition of connective tissue elements or epithelial to mesenchymal transformation (EMT) that progressively remodels and destroys normal tissue architecture leading to organ failure. Despite its enormous impact on human health, there are currently no approved treatments that directly target the molecular mechanisms of fibrosis. The primary goal of this review is to discuss the most recent identified mechanisms of chronic autoimmune diseases characterized by a fibrotic evolution with the aim to identify possible common and unique mechanisms of fibrogenesis that might be exploited in the development of effective antifibrotic therapies.

Olmesartan alleviates SARS-CoV-2 envelope protein induced renal fibrosis by regulating HMGB1 release and autophagic degradation of TGF-β1.

Background and aims: Renal damage in severe coronavirus disease 2019 (COVID-19) is highly associated with mortality. Finding relevant therapeutic candidates that can alleviate it is crucial. Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin-receptor blockers (ARBs) have been shown to be harmless to COVID-19 patients, but it remains elusive whether ACEIs/ARBs have protective benefits to them. We wished to determine if ACEIs/ARBs had a protective effect on the renal damage associated with COVID-19, and to investigate the mechanism. Methods: We used the envelope (E) protein of severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) to induce COVID-19-like multiple organ damage and observed renal fibrosis. We induced the epithelial-mesenchymal transformation of HK-2 cells with E protein, and found that olmesartan could alleviate it significantly. The protective effects of olmesartan on E protein-induced renal fibrosis were evaluated by renal-function assessment, pathologic alterations, inflammation, and the TGF-β1/Smad2/3 signaling pathway. The distribution of high-mobility group box (HMGB)1 was examined after stimulation with E protein and olmesartan administration. Results: E protein stimulated HMGB1 release, which triggered the immune response and promoted activation of TGF-β1/Smad2/3 signaling: both could lead to renal fibrosis. Olmesartan regulated the distribution of HMGB1 under E protein stimulation. Olmesartan inhibited the release of HMGB1, and reduced the inflammatory response and activation of TGF-β1/Smad2/3 signaling. Olmesartan increased the cytoplasmic level of HMGB1 to promote the autophagic degradation of TGF-β1, thereby alleviating fibrosis further. Conclusion: Olmesartan alleviates E protein-induced renal fibrosis by regulating the release of HMGB1 and its mediated autophagic degradation of TGF-β1.

Construction of a lipid metabolism-related and immune-associated prognostic score for gastric cancer

BackgroundThe interaction between tumor cells and immune or non-immune stromal cells creates a unique tumor microenvironment, which plays an important role in the growth, invasion and metastasis of gastric cancer (GC).MethodsThe candidate genes were selected to construct risk-score by univariate and multivariate Cox regression analysis. Nomograms were constructed by combining clinical pathological factors, and the model performance was evaluated by receiver operating characteristic curve, decision curve analysis, net reclassification improvement and integrated discrimination improvement. The functional enrichment between high-risk group (HRisk) and low-risk group (LRisk) was explored through GO, KEGG, GSVA and ssGSEA. CIBERSORT, quanTIseq and xCell were used to explore the immune cell infiltration between HRisk and LRisk. The relevant EMT scores, macrophage infiltration scores and various metabolic scores were calculated through the “IOBR” package and analyzed visually.ResultsThrough univariate and multivariate Cox regression analysis, we obtained the risk-score of fittings six lipid metabolism related genes (LMAGs). Through survival analysis, we found that risk-score has significant prognostic significance and can accurately reflect the metabolic level of patients. The AUCs of the nomogram model incorporating risk-score 1, 3 and 5 years were 0.725, 0.729 and 0.749 respectively. In addition, it was found that the inclusion of risk-score could significantly improve the prediction performance of the model. It was found that the arachidonic acid metabolism and prostaglandin synthesis were up-regulated in HRisk, and more tumor metastasis related markers and immune related pathways were also enriched. Further study found that HRisk had higher immune score and M2 macrophage infiltration. More importantly, the immune checkpoints of tumor associated macrophages involved in tumor antigen recognition disorders increased significantly. We also found that ST6GALNAC3 can promote arachidonic acid metabolism and up-regulate prostaglandin synthesis, increase M2 macrophage infiltration, induce epithelial mesenchymal transformation, and affect the prognosis of patients.ConclusionsOur research found a novel and powerful LMAGs signature. Six-LMAGs features can effectively evaluate the prognosis of GC patients and reflect the metabolic and immune status. ST6GALNAC3 may be a potential prognostic marker to improve the survival rate and prognostic accuracy of GC patients, and may even be a potential biomarker of GC patients, indicating the response to immunotherapy.

Profiling of idiopathic macular hole vitreous proteome identifies the role of extracellular matrix remodelling, epithelial–mesenchymal transformation and unfolded protein-response pathways

Purpose: To analyze and describe the proteome of the vitreous humour in eyes with idiopathic macular holes. Methods: We performed mass spectrometry (MS)-based label-free quantitative analysis of the vitreous proteome of idiopathic macular hole (IMH) and control donor vitreous. Comparative quantification was performed using SCAFFOLD software which calculated fold changes of differential expression. Bioinformatics analysis was performed using DAVID and STRING software. Results: A total of 448 proteins were identified by LC-MS/MS in IMH and cadaveric eye vitreous samples, of which 199 proteins were common. IMH samples had 189 proteins that were unique and 60 proteins were present only in the control cadaveric vitreous. We found upregulation of several extracellular matrix (ECM) and cytoskeletal proteins, namely collagen alpha-1 (XVIII) chain, N-cadherin, EFEMP1/fibulin-3, basement membrane-specific heparan sulfate proteoglycan core protein, and target of Nesh-3. Several cytoskeleton proteins, namely tubulin, actin, and fibronectin levels, were significantly lower in IMH vitreous, probably reflecting increased ECM degradation. IMH vitreous also had a downregulation of unfolded protein response-mediated-mediated apoptosis proteins, possibly related to a state of increased cell survival and proliferation, along with a remodelling and aberrant production of ECM contents. Conclusion: The pathogenesis of macular holes may involve ECM remodelling, epithelial–mesenchymal transformation, downregulation of apoptosis, protein folding defects, and complement pathway. The vitreo-retinal milieu in macular holes contain molecules related to both ECM degradation and inhibition of the same, thereby maintaining a homeostasis.

Aristolocholic acid I promotes renal tubular epithelial fibrosis by upregulating matrix metalloproteinase-9 expression via activating the C3a/C3aR axis of macrophages

Aristolochic acid I (AAI) can cause nephrotoxicity and is characterized by interstitial fibrosis. The C3a/C3aR axis of macrophages and matrix metalloproteinase-9 (MMP-9) play important roles in fibrosis, but whether they are involved in AAI-induced renal interstitial fibrosis and are related remains to be elucidated. In this study, we investigated whether C3a/C3aR axis of macrophages promotes renal interstitial fibrosis by regulating MMP-9 in aristolochic acid nephropathy (AAN). Intraperitoneal injection of AAI for 28 days successfully induced AAN in C57bl/6 mice. The content of C3a in the kidney of AAN mice was increased, and there was a significant distribution of macrophages in the renal tubules. The same results were observed in the in vitro experiment. We also explored the role and mechanism of macrophages after AAI administration in the epithelial–mesenchymal transformation (EMT) of renal tubular epithelial cells (RTECs) and found that AAI could activate the C3a/C3aR axis of macrophages to upregulate p65 expression in macrophages. p65 upregulated MMP-9 expression in macrophages not only directly but also by promoting the secretion if interleukin-6 by macrophages and then activating STAT3 in RTECs. The upregulation of MMP-9 expression could promote the EMT of RTECs. Taken together, our study demonstrated that the AAI-activated the C3a/C3aR axis of macrophages, which induced MMP-9 production, was one of the causes of renal interstitial fibrosis. Therefore, targeting the C3a/C3aR axis of macrophages is an effective therapeutic strategy for the prevention and treatment of renal interstitial fibrosis in AAN.

Hypoxia-Related lncRNA Prognostic Model of Ovarian Cancer Based on Big Data Analysis.

Hypoxia is regarded as a key factor in promoting the occurrence and development of ovarian cancer. In ovarian cancer, hypoxia promotes cell proliferation, epithelial to mesenchymal transformation, invasion, and metastasis. Long non-coding RNAs (lncRNAs) are extensively involved in the regulation of many cellular mechanisms, i.e., gene expression, cell growth, and cell cycle. In our study, a hypoxia-related lncRNA prediction model was established by applying LASSO-penalized Cox regression analysis in public databases. Patients with ovarian cancer were divided into two groups based on the median risk score. The survival rate was analyzed in the Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) datasets, and the mechanisms were investigated. Through the prognostic analysis of DElncRNAs (differentially expressed long non-coding RNAs), a total of 5 lncRNAs were found to be closely associated with OS (overall survival) in ovarian cancer patients. It was evaluated through Kaplan-Meier analysis that low-risk patients can live longer than high-risk patients (TCGA: p = 1.302e - 04; ICGC: 1.501e - 03). The distribution of risk scores and OS status revealed that higher risk score will lead to lower OS. It was evaluated that low-risk group had higher immune score (p = 0.0064) and lower stromal score (p = 0.00023). It was concluded that a hypoxia-related lncRNA model can be used to predict the prognosis of ovarian cancer. Our designed model is more accurate in terms of age, grade, and stage when predicting the overall survival of the patients of ovarian cancer.

Abstract 1411: Different treatment response in several head and neck squamous cell carcinoma(HNSCC) cell lines reflecting underlying genomic & molecular signatures

Abstract 1411: Different treatment response in several head and neck squamous cell carcinoma(HNSCC) cell lines reflecting underlying genomic & molecular signatures

Protective effects of Qing-Re-Huo-Xue formula on bleomycin-induced pulmonary fibrosis through the p53/IGFBP3 pathway

BackgroundIdiopathic pulmonary fibrosis (IPF) is a chronic, progressive fibrosing lung disease with high mortality. Inflammation and epithelial mesenchymal transformation (EMT) may play an important role in the occurrence and development of IPF. Qing-Re-Huo-Xue formula (QRHXF) has been used clinically by our team for half a century and has obvious therapeutic effects on lung disease. Nevertheless, the role and mechanism of QRHXF in the treatment of IPF have never been studied.MethodsA mouse pulmonary fibrosis model was established by intratracheal injection of BLM. The effects of QRHXF on the treatment of pulmonary fibrosis were studied by pulmonary function testing, imaging examination, pathological staining, transmission electron microscopy (TEM) observation and mRNA expression. Tandem mass tag (TMT)-based quantitative proteomics was carried out to analyse the lung protein expression profiles between the control (CTL), bleomycin (BLM) and QRHXF (BLM + QRHXF) groups. Immunohistochemistry and qRT-PCR were used to verify the possible existence of drug target proteins and signalling pathways.ResultsThe results of pulmonary function, lung pathology and imaging examinations showed that QRHXF could significantly alleviate BLM-induced pulmonary fibrosis in vivo. Additionally, inflammatory cell infiltration and EMT were markedly reduced in BLM-induced PF mice administered QRHXF. Proteomics detected a total of 35 proteins, of which 17 were upregulated and 18 were downregulated. A total of 19 differentially expressed proteins (DEPs) overlapped between the BLM versus CTL groups and the BLM + QRHXF versus BLM groups. The expression of p53 and IGFBP3 was reversed in the QRHXF intervention group, which was verified by immunohistochemistry and qRT-PCR.ConclusionsQRHXF attenuated BLM-induced pulmonary fibrosis, and regulation of the p53/IGFBP3 pathway might be associated with its efficacy, which holds promise as a novel treatment strategy for pulmonary fibrosis patients.Graphical

Multiomics analysis revealed the mechanisms related to the enhancement of proliferation, metastasis and EGFR-TKI resistance in EGFR-mutant LUAD with ARID1A deficiency

IntroductionDysregulated ARID1A expression is frequently detected in lung adenocarcinoma (LUAD) and mediates significant changes in cancer behaviors and a poor prognosis. ARID1A deficiency in LUAD enhances proliferation and metastasis, which could be induced by activation of the Akt signaling pathway. However, no further exploration of the mechanisms has been performed.MethodsLentivirus was used for the establishment of the ARID1A knockdown (ARID1A-KD) cell line. MTS and migration/invasion assays were used to examine changes in cell behaviors. RNA-seq and proteomics methods were applied. ARID1A expression in tissue samples was determined by IHC. R software was used to construct a nomogram.ResultsARID1A KD significantly promoted the cell cycle and accelerated cell division. In addition, ARID1A KD increased the phosphorylation level of a series of oncogenic proteins, such as EGFR, ErbB2 and RAF1, activated the corresponding pathways and resulted in disease progression. In addition, the bypass activation of the ErbB pathway, the activation of the VEGF pathway and the expression level changes in epithelial–mesenchymal transformation biomarkers induced by ARID1A KD contributed to the insensitivity to EGFR-TKIs. The relationship between ARID1A and the sensitivity to EGFR-TKIs was also determined using tissue samples from LUAD patients.ConclusionLoss of ARID1A expression influences the cell cycle, accelerates cell division, and promotes metastasis. EGFR-mutant LUAD patients with low ARID1A expression had poor overall survival. In addition, low ARID1A expression was associated with a poor prognosis in EGFR-mutant LUAD patients who received first-generation EGFR-TKI treatment.7Ri7oJWPiw-vggUB99u973Video abstract

LncRNA MBNL1-AS1 Suppresses Cell Proliferation and Metastasis of Pancreatic Adenocarcinoma through Targeting Carcinogenic miR-301b-3p.

Pancreatic adenocarcinoma (PAAD) has been a huge challenge to public health due to its increasing incidence, frequent early metastasis, and poor outcome. The molecular basis of tumorigenesis and metastasis in PAAD is largely unclear. Here, we identified a novel tumor-suppressor long noncoding RNA (lncRNA) MBNL1-AS1, in PAAD and revealed its downstream mechanism. Quantitative real-time PCR (qRT-PCR) data showed that MBNL1-AS1 expression was significantly downregulated in PAAD tissues and cells, which was closely associated with metastasis and poor prognosis. Cell counting kit-8 (CCK-8) assay, transwell assay, and western blot verified that overexpression of MBNL1-AS1 suppressed cell proliferation, migration, and epithelial mesenchymal transformation (EMT) behavior in PAAD cells. By using a dual luciferase reporter gene system, we confirmed that miR-301b-3p was a direct target of MBNL1-AS1. Further mechanismic study revealed that upregulation of miR-301b-3p abolished the inhibitory effect of MBNL1-AS1 overexpression on cell proliferation, tumorigenesis, migration and EMT. Our results demonstrate that MBNL1-AS1 plays a tumor-suppressive role in PAAD mainly by downregulating miR-301b-3p, providing a novel therapeutic target for PAAD.