Upregulation of METTL14 mediates the elevation of PERP mRNA N6 adenosine methylation promoting the growth and metastasis of pancreatic cancer

Wang, Min; Li, Jun; Zhao, Yan; He, Ruizhi; Xu, Xiaodong; Guo, Xiaomao; Xu, Li; Xu, Simiao; Miao, Ji; Guo, Jianpin; Zhang, Hang; Gong, Jun; Zhu, Feng; Tian, Rui; Shi, Changcheng; Peng, Feng; Feng, Yechen; Yu, Shuo; Xie, Yu; Jiang, Jianxin; Li, Min; Wei, Wenyi; He, Chuan; Qin, Renyi

doi:10.1186/s12943-020-01249-8

Cited by 155 publications

(145 citation statements)

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“…The role of METTL14 and IGF2BP3 in human cancers was studied before. The promotion function by METTL14 in pancreatic cancer was uncovered ( 75 ) and IGF2BP3 was found to be a potential prognosis marker and therapeutic target of colon cancer ( 76 ). Yet the miRNA-mediated mechanisms of METTL14 and IGF2BP3 , if any, remain unclear.…”

Section: Discussionmentioning

confidence: 99%

Comprehensive Analysis of Expression Regulation for RNA m6A Regulators With Clinical Significance in Human Cancers

et al. 2021

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BackgroundN6-methyladenosine (m6A), the most abundant chemical modification on eukaryotic messenger RNA (mRNA), is modulated by three class of regulators namely “writers,” “erasers,” and “readers.” Increasing studies have shown that aberrant expression of m6A regulators plays broad roles in tumorigenesis and progression. However, it is largely unknown regarding the expression regulation for RNA m6A regulators in human cancers.ResultsHere we characterized the expression profiles of RNA m6A regulators in 13 cancer types with The Cancer Genome Atlas (TCGA) data. We showed that METTL14, FTO, and ALKBH5 were down-regulated in most cancers, whereas YTHDF1 and IGF2BP3 were up-regulated in 12 cancer types except for thyroid carcinoma (THCA). Survival analysis further revealed that low expression of several m6A regulators displayed longer overall survival times. Then, we analyzed microRNA (miRNA)-regulated and DNA methylation-regulated expression changes of m6A regulators in pan-cancer. In total, we identified 158 miRNAs and 58 DNA methylation probes (DMPs) involved in expression regulation for RNA m6A regulators. Furthermore, we assessed the survival significance of those regulatory pairs. Among them, 10 miRNAs and 7 DMPs may promote cancer initiation and progression; conversely, 3 miRNA/mRNA pairs in kidney renal clear cell carcinoma (KIRC) may exert tumor-suppressor function. These findings are indicative of their potential prognostic values. Finally, we validated two of those miRNA/mRNA pairs (hsa-miR-1307-3p/METTL14 and hsa-miR-204-5p/IGF2BP3) that could serve a critical role for potential clinical application in KIRC patients.ConclusionsOur findings highlighted the importance of upstream regulation (miRNA and DNA methylation) governing m6A regulators’ expression in pan-cancer. As a result, we identified several informative regulatory pairs for prognostic stratification. Thus, our study provides new insights into molecular mechanisms of m6A modification in human cancers.

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Section: Discussionmentioning

confidence: 99%

Comprehensive Analysis of Expression Regulation for RNA m6A Regulators With Clinical Significance in Human Cancers

et al. 2021

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“…The role of CRABP2 and NUSAP1 in pancreatic cancer is currently unclear, but CRABP2 and NUSAP1 favors proliferation and invasion of several types of tumor, such as prostate, lung, gastric and colorectal cancer ( Gordon et al, 2017 ; Han G. et al, 2018 ; Wu et al, 2019 ; Ge et al, 2020 ; Xu et al, 2020 ). Interestingly, a recent study showed that knocking down the expression of PERP in pancreatic cancer cells promotes proliferation and invasion of the cells, suggesting a tumor-suppressive function of PERP in pancreatic cancer ( Wang et al, 2020 ). Indeed, PERP has a well-known pro-apoptotic function by dependently or independently of p53 signal pathways, and loss of the gene is linked to tumorigenesis ( Attardi et al, 2000 ; Beaudry et al, 2010 ; McDonnell et al, 2019 ; Awais et al, 2016 ).…”

Section: Discussionmentioning

confidence: 99%

Multi-Omics Analysis of Anlotinib in Pancreatic Cancer and Development of an Anlotinib-Related Prognostic Signature

Zhang

Liu

Zhang

et al. 2021

Front. Cell Dev. Biol.

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Aberrant regulation of angiogenesis involves in the growth and metastasis of tumors, but angiogenesis inhibitors fail to improve overall survival of pancreatic cancer patients in previous phase III clinical trials. A comprehensive knowledge of the mechanism of angiogenesis inhibitors against pancreatic cancer is helpful for clinical purpose and for the selection of patients who might benefit from the inhibitors. In this work, multi-omics analyses (transcriptomics, proteomics, and phosphoproteomics profiling) were carried out to delineate the mechanism of anlotinib, a novel angiogenesis inhibitor, against pancreatic cancer cells. The results showed that anlotinib exerted noteworthy cytotoxicity on pancreatic cancer cells. Multi-omics analyses revealed that anlotinib had a profound inhibitory effect on ribosome, and regulated cell cycle, RNA metabolism and lysosome. Based on the multi-omics results and available data deposited in public databases, an anlotinib-related gene signature was further constructed to identify a subgroup of pancreatic cancer patients who had a dismal prognosis and might be responsive to anlotinib.

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“…After boiling at 100 • C for 5 min, the equal amounts of protein extract were electrophoresed in a 10% sodium dodecyl sulfatepolyacrylamide gel electrophoresis (SDS-PAGE) at 80 V for 20 min and then 120 V for 1 h. Subsequently, the protein extract was transferred to PVDF membranes (Biosharp, Shanghai, China) at 220 mA for 60 min. After repeated washing using tris-buffered saline containing Tween 20 (TBST), the PVDF membranes were blocked with 5% bull serum albumin (BSA) blocking buffer for 2 h at 37 • C, and then incubated with primary antibody collagen I, 1:1,000; collagen III, 1:1,000; α-smooth muscle actin (α-SMA), 1:1,000; Epac1, 1:1,500; p-Akt, 1:1000; t-Akt, 1:1,000; p-PI3K, 1:1000; t-PI3K, 1:1,000; GAPDH, 1:2,500 overnight at 4 • C. Afterward, the PVDF membranes were incubated with a secondary antibody (anti-rabbit IgG, HRPlinked antibody, 1:5,000; anti-mouse IgG, HRP-linked antibody, 1:5,000) for 1 h at 37 • C (Wang et al, 2020b). Finally, signals were visualized using the enhanced chemiluminescence (ECL) detection kit (Yeasen, Shanghai, China), and the relative protein abundance was measured by ImageJ image analysis software (version 1.44p, National Institutes of Health, United States).…”

Section: Western Blot Analysismentioning

confidence: 99%

Circular RNA CircCOL5A1 Sponges the MiR-7-5p/Epac1 Axis to Promote the Progression of Keloids Through Regulating PI3K/Akt Signaling Pathway

Liu

Zhang

et al. 2021

Front. Cell Dev. Biol.

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Keloids, as a result of abnormal wound healing in susceptible individuals, are characterized by the hyper-proliferation of fibroblasts and exaggerated deposition of extracellular matrix. Current surgical and therapeutic modalities provide limited satisfactory results. Growing evidence has highlighted the roles of circRNAs in acting as miRNA sponges. However, up to date, the regulatory mechanism of circRNAs in the pathological process of keloids has rarely been reported. In this study, cell proliferation, cell migration, flow cytometry, western blotting, fluorescence in situ hybridization, dual-luciferase activity, and immunohistochemistry assays were applied to explore the roles and mechanisms of the circCOL5A1/miR-7-5p/Epac1 axis in the keloid. The therapeutic potential of circCOL5A1 was investigated by establishing keloid implantation models. The RT-qPCR result revealed that circCOL5A1 expression was obviously higher in keloid tissues and keloid fibroblasts. Subsequent cellular experiments demonstrated that circCOL5A1 knockdown repressed the proliferation, migration, extracellular matrix (ECM) deposition, whereas promoted cell apoptosis, through the PI3K/Akt signaling pathway. Furthermore, RNA-fluorescence in situ hybridization (RNA-FISH) illustrated that both circCOL5A1 and miR-7-5p were located in the cytoplasm. The luciferase reporter gene assay confirmed that exact binding sites were present between circCOL5A1 and miR-7-5p, as well as between miR-7-5p and Epac1. Collectively, the present study revealed that circCOL5A1 functioned as competing endogenous RNA (ceRNA) by adsorbing miR-7-5p to release Epac1, which contributed to pathological hyperplasia of keloids through activating the PI3K/Akt signaling pathway. Our data indicated that circCOL5A1 might serve as a novel promising therapeutic target and represent a new avenue to understand underlying pathogenesis for keloids.

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Upregulation of METTL14 mediates the elevation of PERP mRNA N6 adenosine methylation promoting the growth and metastasis of pancreatic cancer

Cited by 155 publications

References 50 publications

Comprehensive Analysis of Expression Regulation for RNA m6A Regulators With Clinical Significance in Human Cancers

Comprehensive Analysis of Expression Regulation for RNA m6A Regulators With Clinical Significance in Human Cancers

Multi-Omics Analysis of Anlotinib in Pancreatic Cancer and Development of an Anlotinib-Related Prognostic Signature

Circular RNA CircCOL5A1 Sponges the MiR-7-5p/Epac1 Axis to Promote the Progression of Keloids Through Regulating PI3K/Akt Signaling Pathway

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