Background Transmembrane 4 L six family member 1 (TM4SF1) is upregulated in several epithelial cancers and is closely associated with poor prognosis. However, the role of TM4SF1 and its potential mechanism in colorectal cancer (CRC) remain elusive. Methods We investigated the expression of TM4SF1 in the Oncomine, the Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases and confirmed the results by immunohistochemistry (IHC), qPCR and Western blotting (WB) of CRC tissues. The effect of TM4SF1 on the epithelial-to-mesenchymal transition (EMT) and cancer stemness of CRC cells was investigated by Transwell, wound healing and sphere formation assays. A series of in vitro and in vivo experiments were conducted to reveal the mechanisms by which TM4SF1 modulates EMT and cancer stemness in CRC. Results TM4SF1 expression was markedly higher in CRC tissues than in non-tumour tissues and was positively correlated with poor prognosis. Downregulation of TM4SF1 inhibited the migration, invasion and tumour sphere formation of SW480 and LoVo cells. Conversely, TM4SF1 overexpression significantly enhanced the migration, invasion and tumoursphere formation potential of CRC cells, Additionally, TM4SF1 silencing inhibited the EMT mediated by transforming growth factor-β1 (TGF-β1). Mechanistically, gene set enrichment analysis (GSEA) predicted that the Wnt signalling pathway was one of the most impaired pathways in TM4SF1-deficient CRC cells compared to controls. The results were further validated by WB, which revealed that TM4SF1 modulated SOX2 expression in a Wnt/β-catenin activation-dependent manner. Furthermore, we found that knockdown of TM4SF1 suppressed the expression of c-Myc, leading to decreased c-Myc binding to the SOX2 gene promoter. Finally, depletion of TM4SF1 inhibited metastasis and tumour growth in a xenograft mouse model. Conclusion Our study substantiates a novel mechanism by which TM4SF1 maintains cancer cell stemness and EMT via the Wnt/β-catenin/c-Myc/SOX2 axis during the recurrence and metastasis of CRC.
Ferroptosis is a novel form of cell death that is closely associated with the formation of many tumors. Our study focused on the mechanism by which long noncoding RNAs (lncRNAs) regulate ferroptosis in gastric cancer (GC) peritoneal metastasis (PM). We utilized lncRNA sequencing and protein profiling analysis to identify ferroptosis-associated lncRNAs and proteins. qRT-PCR was used to analyze the expression of BDNF-AS and FBXW7 in GC tissues and adjacent normal tissues. Chromatin isolation by RNA purification (ChIRP), RNA immunoprecipitation (RIP), chromatin immunoprecipitation (ChIP), and coimmunoprecipitation (co-IP) assays were performed to investigate the interaction between BDNF-AS and its downstream targets. Finally, the function of BDNF-AS was validated in vivo . We demonstrated that BDNF-AS was highly expressed in GC and PM tissues. High BDNF-AS expression was positively related to GC progression and poor prognosis. Functionally, BDNF-AS overexpression protected GC cells from ferroptosis and promoted the progression of GC and PM. Mechanistically, BDNF-AS could regulate FBXW7 expression by recruiting WDR5, thus affecting FBXW7 transcription, and FBXW7 regulated the protein expression of VDAC3 through ubiquitination. Conclusively, our research demonstrated that the BDNF-AS/WDR5/FBXW7 axis regulates ferroptosis in GC by affecting VDAC3 ubiquitination. BDNF-AS might be a biomarker for the evaluation of GC prognosis and the treatment of GC.
Renal ischemia–reperfusion injury (IRI) is less extensive in females than males in both animals and humans; however, this protection diminishes after menopause, suggesting that estrogen plays a pivotal role in IRI, but the underlying mechanism remains largely unknown. Our study found that 45 min of warm ischemia was sufficient to induce significant pathological changes without causing death in model animals. Compared with male rats, female rats exhibited less extensive apoptosis, kidney injury, and fibrosis; these effects were worsened in ovariectomized (OVX) rats and ameliorated upon estradiol (E2) supplementation. Furthermore, the levels of TGF-βRI, but not TGF-βRII or TGF-β1, were significantly increased in OVX rats, accompanied by phosphorylated SMAD2/3 activation. Interestingly, the alteration trend of the nuclear ERα level was opposite that of TGF-βRI. Furthermore, dual luciferase reporter and chromatin immunoprecipitation assays showed that ERα could bind to the promoter region of TGF-βRI and negatively regulate its mRNA expression. Moreover, an in vitro study using NRK-52E cells showed that ERα knockdown blocked E2-mediated protection, while TGF-βRI knockdown protected cells against hypoxic insult. The findings of this study suggest that renal IRI is closely related to the TGF-βRI-SMAD pathway in females and that E2 exert its protective effect via the ERα-mediated transcriptional inhibition of TGF-βRI expression.
Metastasis is the leading cause of colorectal cancer treatment failure and mortality. Communication between endothelium and tumor cells in the tumor microenvironment is required for cancer metastasis. Tumor-derived exosomes have been shown to increase vascular permeability by delivering microRNA (miRNA) to vascular endothelial cells, facilitating cancer metastasis. The mechanism by which Epithelial mesenchymal transition (EMT) tumor cell-derived exosomes influence vascular permeability remains unknown. MicroRNA-29a (miR-29a) expression is up-regulated in colorectal cancer (CRC)tissues, which is clinically significant in metastasis. Exosomal miR-29a secreted by EMT-CRC cells has been found to decrease the expression of Zonula occlusion 1 (ZO-1), Claudin-5, and Occludin via targeting Kruppel-like factor 4 (KLF4). In vitro co-culture investigations further revealed that EMT cancer cells release exosomal miR-29a, which alters vascular endothelial permeability. Furthermore, exosomal miR-29a promoted liver metastases in CRC mice. Our findings demonstrate that EMT-CRC cells may transport exosomal miR-29a to endothelial cells in the tumor microenvironment (TME). As a result, increased vascular permeability promotes the development and metastasis of CRC. Exosomal miR-29a has the potential to be a predictive marker for tumor metastasis as well as a viable therapeutic target for CRC.
Background Colorectal cancer (CRC) is one of the leading causes of cancer-related death worldwide. Single-cell transcriptome sequencing (scRNA-seq) can provide accurate gene expression data for individual cells. In this study, a new prognostic model was constructed by scRNA-seq and bulk transcriptome sequencing (bulk RNA-seq) data of CRC samples to develop a new understanding of CRC. Methods CRC scRNA-seq data were downloaded from the GSE161277 database, and CRC bulk RNA-seq data were downloaded from the TCGA and GSE17537 databases. The cells were clustered by the FindNeighbors and FindClusters functions in scRNA-seq data. CIBERSORTx was applied to detect the abundance of cell clusters in the bulk RNA-seq expression matrix. WGCNA was performed with the expression profiles to construct the gene coexpression networks of TCGA-CRC. Next, we used a tenfold cross test to construct the model and a nomogram to assess the independence of the model for clinical application. Finally, we examined the expression of the unreported model genes by qPCR and immunohistochemistry. A clone formation assay and orthotopic colorectal tumour model were applied to detect the regulatory roles of unreported model genes. Results A total of 43,851 cells were included after quality control, and 20 cell clusters were classified by the FindCluster () function. We found that the abundances of C1, C2, C4, C5, C15, C16 and C19 were high and the abundances of C7, C10, C11, C13, C14 and C17 were low in CRC tumour tissues. Meanwhile, the results of survival analysis showed that high abundances of C4, C11 and C13 and low abundances of C5 and C14 were associated with better survival. The WGCNA results showed that the red module was most related to the tumour and the C14 cluster, which contains 615 genes. Lasso Cox regression analysis revealed 8 genes (PBXIP1, MPMZ, SCARA3, INA, ILK, MPP2, L1CAM and FLNA), which were chosen to construct a risk model. In the model, the risk score features had the greatest impact on survival prediction, indicating that the 8-gene risk model can better predict prognosis. qPCR and immunohistochemistry analysis showed that the expression levels of MPZ, SCARA3, MPP2 and PBXIP1 were high in CRC tissues. The functional experiment results indicated that MPZ, SCARA3, MPP2 and PBXIP1 could promote the colony formation ability of CRC cells in vitro and tumorigenicity in vivo. Conclusions We constructed a risk model to predict the prognosis of CRC patients based on scRNA-seq and bulk RNA-seq data, which could be used for clinical application. We also identified 4 previously unreported model genes (MPZ, SCARA3, MPP2 and PBXIP1) as novel oncogenes in CRC. These results suggest that this model could potentially be used to evaluate the prognostic risk and provide potential therapeutic targets for CRC patients.
The 2019 Coronavirus Disease (COVID-19) has become an unprecedented public crisis. We retrospectively investigated the clinical data of 197 COVID-19 patients and identified 88 patients as disease aggravation cases. Compared with patients without disease aggravation, the aggravation cases had more comorbidities, including hypertension (25.9%) and diabetes (20.8%), and presented with dyspnoea (23.4%), neutrophilia (31.5%), and lymphocytopenia (46.7%). These patients were more prone to develop organ damage in liver, kidney, and heart (P < 0.05). A multivariable regression analysis showed that advanced age, comorbidities, dyspnea, lymphopenia, and elevated levels of Fbg, CTnI, IL-6, and serum ferritin were significant predictors of disease aggravation. Further, we performed a Kaplan–Meier analysis to evaluate the prognosis of COVID-19 patients, which suggested that 64.9% of the patients had not experienced ICU transfers and survival from the hospital.
Background The interaction between the tumor-microenvironment (TME) and the cancer cells has emerged as a key player in colorectal cancer (CRC) metastasis. A small proportion of CRC cells which undergo epithelial-mesenchymal transition (EMT) facilitate the reshaping of the TME by regulating various cellular ingredients. Methods Immunohistochemical analysis, RNA immunoprecipitation (RIP), RNA Antisense Purification (RAP), dual luciferase assays were conducted to investigate the biological function and regulation of LINC00543 in CRC. A series in vitro and in vivo experiments were used to clarify the role of LINC00543 in CRC metastasis. Results Here we found that the long non-coding RNA LINC00543, was overexpressed in colorectal cancer tissues, which correlated with advanced TNM stage and poorer prognosis of CRC patients. The overexpression of LINC00543 promoted tumorigenesis and metastasis of CRC cells by enhancing EMT and remodeling the TME. Mechanistically, LINC00543 blocked the transport of pre-miR-506-3p across the nuclear-cytoplasmic transporter XPO5, thereby reducing the production of mature miR-506-3p, resulting in the increase in the expression of FOXQ1 and induction of EMT. In addition, upregulation of FOXQ1 induced the expression of CCL2 that accelerated the recruitment of macrophages and their M2 polarization. Conclusions Our study showed that LINC00543 enhanced EMT of CRC cells through the pre-miR-506-3p/FOXQ1 axis. This resulted in the upregulation of CCL2, leading to macrophages recruitment and M2 polarization, and ultimately stimulating the progression of CRC.
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