LNC473 Regulating APAF1 IRES-Dependent Translation via Competitive Sponging miR574 and miR15b: Implications in Colorectal Cancer

Wu, Huizhe; Hu, Xiaoyun; Li, Yalun; Chen, Qiuchen; Qiao, Yun; Qin, Wenyan; Wu, Zhuona; Fu, Boshi; Zhao, Haishan; Zhang, Rui

doi:10.1016/j.omtn.2020.07.009

Cited by 5 publications

(8 citation statements)

References 45 publications

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“…In addition, we found in primary colorectal tumors that the hypermethylation of LINC00473 was associated with a decrease in the expression of this lncRNA. These results are in line with a previous work, which identified the downregulation of expression and tumor suppressor properties of LINC00473 in association with the initiation and pathogenesis of CRC [ 15 ]. Similarly, other authors have found epigenetic deregulation of important TSGs, such as p16/CDKN2A and hMLH1 , throughout the colorectal carcinogenesis process [ 20 , 21 ].…”

Section: Discussionsupporting

confidence: 93%

“…LINC00473 is a lncRNA with pro-apoptotic tumor suppressor properties in CRC whose expression is downregulated in this tumor type. This lncRNA is able to sponge endogenous miR574-5p or miR15b-5p, inhibit cell proliferation and colony formation capacity, and induce cell apoptosis by activating the APAF1-CASP9-CASP3 pathway [ 15 ]. In addition, a genome-wide analysis of the CRC cell line HCT-116 recently identified promoter hypermethylation of LINC00473 [ 14 ].…”

Section: Discussionmentioning

confidence: 99%

“…LINC00473 is a lncRNA downregulated in CRC that exerts tumor suppressor functions in this disease by promoting apoptotic protease-activating factor 1 (APAF1) IRES activity through competitively sponging miR574-5p and miR15b-5p in tumor initiation and pathogenesis [ 15 ]. Of note, Diaz-Lagares et al recently identified that the CpGI in the promoter of LINC00473 is hypermethylated in CRC [ 14 ].…”

Section: Introductionmentioning

confidence: 99%

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Noninvasive early detection of colorectal cancer by hypermethylation of the LINC00473 promoter in plasma cell-free DNA

et al. 2022

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Background Current noninvasive assays have limitations in the early detection of colorectal cancer. We evaluated the clinical utility of promoter methylation of the long noncoding RNA LINC00473 as a noninvasive biomarker to detect colorectal cancer and associated precancerous lesions. Methods We evaluated the epigenetic regulation of LINC00473 through promoter hypermethylation in colorectal cancer cell lines using bisulfite genomic sequencing and expression analyses. DNA methylation of LINC00473 was analyzed in primary colorectal tumors using 450K arrays and RNA-seq from The Cancer Genome Atlas (TCGA). Tissue-based findings were validated in several independent cohorts of colorectal cancer and advanced colorectal polyp patients by pyrosequencing. We explored the clinical utility of LINC00473 methylation for the early detection of colorectal cancer in plasma cell-free DNA by quantitative methylation-specific PCR and droplet digital PCR. Results LINC00473 showed transcriptionally silencing due to promoter hypermethylation in colorectal cancer cell lines and primary tumors. Methylation of the LINC00473 promoter accurately detected primary colorectal tumors in two independent clinical cohorts, with areas under the receiver operating characteristic curves (AUCs) of 0.94 and 0.89. This biomarker also identified advanced colorectal polyps from two other tissue-based clinical cohorts with high diagnostic accuracy (AUCs of 0.99 and 0.78). Finally, methylation analysis of the LINC00473 promoter in plasma cell-free DNA accurately identified patients with colorectal cancer and advanced colorectal polyps (AUCs of 0.88 and 0.84, respectively), which was confirmed in an independent cohort of patients. Conclusions Hypermethylation of the LINC00473 promoter is a new promising biomarker for noninvasive early detection of colorectal cancer and related precancerous lesions.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Noninvasive early detection of colorectal cancer by hypermethylation of the LINC00473 promoter in plasma cell-free DNA

et al. 2022

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“…Shang et al (115) found that the tumor-derived exosome, circPACRGL, acts as a sponge molecule of miR-142-3p/miR-506-3p, promoting the propagation, diversion, invasion, and adhesion of CC cells and N1 to N2 neutrophil differentiation. Wu et al (116) showed that the LNC473-MIR574/miR15B-APAF1 IRES signaling axis could manipulate the propagation and apoptosis of CRC cells to influence the initiation and progression of CRC. In this study, a ceRNA regulatory network was constructed with 1 lncRNA, 5 miRNAs, and 3 mRNAs, revealing the potential regulatory mechanism of lncRNA-miRNA-mRNA in CC, and indicating the direction for further exploration of the pathogenesis of CC.…”

Section: Discussionmentioning

confidence: 99%

Integrated analysis of necroptosis-related genes for evaluating immune infiltration and colon cancer prognosis

Yang

Lu²,

Peng³

et al. 2022

Front. Immunol.

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BackgroundColon cancer (CC) is the second most common gastrointestinal malignancy. About one in five patients have already developed distant metastases at the time of initial diagnosis, and up to half of patients develop distant metastases from initial local disease, which leads to a poor prognosis for CC patients. Necroptosis plays a key role in promoting tumor growth in different tumors. The purpose of this study was to construct a prognostic model composed of necroptosis-related genes (NRGs) in CC.MethodsThe Cancer Genome Atlas was used to obtain information on clinical features and gene expression. Gene expression differential analysis, weighted gene co-expression network analysis, univariate Cox regression analysis and the least absolute shrinkage and selection operator regression algorithm were utilized to identify prognostic NRGs. Thereafter, a risk scoring model was established based on the NRGs. Biological processes and pathways were identified by gene ontology and gene set enrichment analysis (GSEA). Further, protein-protein interaction and ceRNA networks were constructed based on mRNA-miRNA-lncRNA. Finally, the effect of necroptosis related risk score on different degrees of immune cell infiltration was evaluated.ResultsCALB1, CHST13, and SLC4A4 were identified as NRGs of prognostic significance and were used to establish a risk scoring model. The time-dependent receiver operating characteristic curve analysis revealed that the model could well predict the 1-, 3-, and 5-year overall survival (OS). Further, GSEA suggested that the NRGs may participate in biological processes, such as the WNT pathway and JAK-Stat pathway. Eight key hub genes were identified, and a ceRNA regulatory network, which comprised 1 lncRNA, 5 miRNAs and 3 mRNAs, was constructed. Immune infiltration analysis revealed that the low-risk group had significantly higher immune-related scores than the high-risk group. A nomogram of the model was constructed based on the risk score, necroptosis, and the clinicopathological features (age and TNM stage). The calibration curves implied that the model was effective at predicting the 1-, 3-, and 5-year OS of CC.ConclusionOur NRG-based prognostic model can assist in the evaluation of CC prognosis and the identification of therapeutic targets for CC.

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“…Apoptotic peptidase activating factor 1 (APAF1) is a core pro-apoptotic factor in the cytochrome C-dependent apoptosis signaling pathway [ 41 ]. Its expression is significantly downregulated in many tumors, suggesting that it is a tumor suppressor gene [ 42 ]. Induction of apoptosis is an important goal in tumor therapy.…”

Section: Discussionmentioning

confidence: 99%

Exosomal microRNA⁃93⁃3p secreted by bone marrow mesenchymal stem cells downregulates apoptotic peptidase activating factor 1 to promote wound healing

et al. 2021

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Wounds are soft tissue injuries, which are difficult to heal and can easily lead to other skin diseases. Bone marrow mesenchymal stem cells (BMSCs) and the secreted exosomes play a key role in skin wound healing. This study aims to clarify the effects and mechanisms of exosomes derived from BMSCs in wound healing. Exosomes were extracted from the supernatant of the BMSCs. The expression of the micro-RNA miR-93-3p was determined by qRT-PCR analysis. HaCaT cells were exposed to hydrogen peroxide (H 2 O 2 ) to establish a skin lesion model. MTT, flow cytometry, and transwell assays were conducted to determine cellular functions. The binding relationship between miR-93-3p and apoptotic peptidase activating factor 1 (APAF1) was measured using a dual luciferase reporter gene assay. The results showed that BMSC-derived exosomes or BMSC-exos promoted proliferation and migration and suppressed apoptosis in HaCaT cells damaged by H 2 O 2 . However, the depletion of miR-93-3p in BMSC-exos antagonized the effects of BMSC-exos on HaCaT cells. In addition, APAF1 was identified as a target of miR-93-3p. Overexpression of APAF1 induced the dysfunction of HaCaT cells. Collectively, the results indicate that BMSC-derived exosomes promote skin wound healing via the miR-93-3p/APAF1 axis. This finding may help establish a new therapeutic strategy for skin wound healing.

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LNC473 Regulating APAF1 IRES-Dependent Translation via Competitive Sponging miR574 and miR15b: Implications in Colorectal Cancer

Cited by 5 publications

References 45 publications

Noninvasive early detection of colorectal cancer by hypermethylation of the LINC00473 promoter in plasma cell-free DNA

Noninvasive early detection of colorectal cancer by hypermethylation of the LINC00473 promoter in plasma cell-free DNA

Integrated analysis of necroptosis-related genes for evaluating immune infiltration and colon cancer prognosis

Exosomal microRNA⁃93⁃3p secreted by bone marrow mesenchymal stem cells downregulates apoptotic peptidase activating factor 1 to promote wound healing

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