ATXN2-mediated translation of TNFR1 promotes esophageal squamous cell carcinoma via m6A-dependent manner

Li, Rui; Zeng, Lingxing; Zhao, Hongzhe; Deng, Junge; Pan, Ling; Zhang, Shaoping; Wu, Guandi; Ye, Ying; Zhang, Jialiang; Su, Jiachun; Zheng, Yanfen; Deng, Shuang; Bai, Ruihong; Zhuang, Lisha; Li, Mei; Zuo, Zhixiang; Lin, Dong; Zheng, Jian; Huang, Xudong

doi:10.1016/j.ymthe.2022.01.006

Cited by 21 publications

(19 citation statements)

References 53 publications

(123 reference statements)

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“…The expression of in ammatory cytokines is tightly linked with the activation of NF-κB and MAPK signaling pathways [35,36]. Furthermore, accumulating evidence has indicated that m 6 A mRNA modi cation contributes to different functions via MAPK and NF-κB signaling pathways [23,[39][40][41][42]. We found that Fto knockdown upregulated Il-6, Mcp1, and Mmp9 in TNF-α-induced OCCM-30 cells.…”

Section: Discussionmentioning

confidence: 70%

m6A demethylase Fto regulates TNF-α-induced inflammatory response in cementoblasts

Sun

et al. 2022

Preprint

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Apical periodontitis is among the most frequently occurring pathological lesions around the root apex, which can cause alveolar bone defect and tooth loss, even leading to rheumatoid arthritis, cardiovascular diseases, and diabetes. The exactly underlying molecular mechanisms are still evolving. Fat mass and obesity-associated protein (Fto) is the first identified RNA m6A demethylase/eraser that plays key regulatory roles in multiple biological processes. However, it remains unclear whether Fto is involved in the inflammatory response in cementoblasts. In the current study, we investigated the effect of tumor necrosis factor-alpha (TNF-α)-induced Fto expression in mouse cementoblast cell line (OCCM-30 cells). Following apical periodontitis induction, mice showed downregulation in the expression of Fto, associated with a significant increase in the inflammatory cell infiltration around the root apex. Moreover, OCCM-30 cells exposed to TNF-α showed similar changes, which presented an upregulation in inflammatory-related genes, whereas a decrease of Fto. Furthermore, qRT-PCR and ELISA analysis showed knockdown of Fto promoted in the expression of Il-6, Mcp1, and Mmp9 in TNF-α-treated OCCM-30 cells as compared to NC cells, whereas did not affect the mRNA stability. Interestingly, Fto knockdown activated the p65, p38, and ERK1/2 but not JNK signaling pathways after TNF-α administration in OCCM-30 cells. Taken together, these data suggest that TNF-α decreasing expression of Fto might play a critical role in the inflammatory response, and modulation of Fto might change the inflammatory response.

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Section: Discussionmentioning

confidence: 70%

m6A demethylase Fto regulates TNF-α-induced inflammatory response in cementoblasts

Sun

et al. 2022

Preprint

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“…As chemotherapy remains the primary treatment choice for progressive GC, chemoresistance has a more prominent impact on GC treatment compared with other cancers and is the most problematic issue in our clinical work, which greatly affects patient survival [ 3 ]. The Ataxin-2 protein encoded by ATXN2 is a protein involved in RNA metabolism and metabolic homeostasis [ 30 ]. In our study, we revealed that ATXN2 has proliferative and antiapoptotic effects and that a high ATXN2 level was related to an adverse prognosis.…”

Section: Discussionmentioning

confidence: 99%

ATXN2-Mediated PI3K/AKT Activation Confers Gastric Cancer Chemoresistance and Attenuates CD8+ T Cell Cytotoxicity

Wang

Cao²,

Zhang

et al. 2022

Journal of Immunology Research

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As one of the primary therapeutic choices, chemotherapy is widely adopted for progressive gastric cancer (GC), but the development of chemoresistance has limited chemotherapy efficacy and partly contributes to poor prognosis. Immunotherapy is increasingly being applied in the clinical treatment of GC and is also benefitting patients. To ascertain whether ATXN2 affects chemotherapy efficacy in GC cells and its role in GC immune escape, we performed high-throughput sequencing to clarify genes differentially expressed between 5-FU-resistant and 5-FU-sensitive GC cells and then conducted qRT–PCR to assess ATXN2 expression in GC tissues. Furthermore, the influence of ATXN2 on resistance was studied in vitro and in vivo, ATXN2 and other protein expression levels were detected using Western blotting and immunohistochemistry (IHC), and the direct association of SP1 and ATXN2 was confirmed through luciferase reporter gene analysis. We found elevated ATXN2 in GC tumors and a negative correlation between ATXN2 levels and the prognosis of GC. Furthermore, by activating the PI3K/AKT pathway, ATXN2 was found to promote chemoresistance in GC, facilitating BCL2L1 expression. In GC cells, ATXN2 further stimulated PD-L1 expression and provided better immunotherapy efficacy. Finally, we demonstrated that SP1 transcriptionally regulated the expression of ATXN2 and prompted GC chemoresistance and immune escape. In conclusion, our study reveals the important roles of the SP1/ATXN2/PI3K-AKT/BCL2L1 signalling pathway in GC chemoresistance and of the SP1/ATXN2/PI3K-AKT/PD-L1 signalling pathway in GC immunotherapy. Our findings provide new theories and experimental references for overcoming chemotherapy resistance in GC and enhancing the efficacy of immunotherapy for GC.

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“…Thus, the A allele of rs5746136 in SOD2 was associated with a reduced risk of bladder cancer [ 57 ]. m 6 A could deposit on various type of RNA, such as coding RNA and non-coding RNA, participate in all steps of RNA metabolism and post-transcriptionally regulate the expression of the gene ( Table 1 ) [ 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 , 71 , 72 , 73 , 74 , 75 , 76 , 77 , 78 , 79 , 80 , 81 , 82 , 83 ].…”

Section: M 6 a Modification And Its Effect On Vari...mentioning

confidence: 99%

“…The expression, clinical significance and biological function of m 6 A regulators in ESCA are shown in Supplementary Table S1 [ 59 , 60 , 61 , 66 , 69 , 72 , 73 , 74 , 75 , 76 , 79 , 80 , 83 , 84 , 85 , 86 , 122 , 123 , 124 , 125 , 126 , 127 , 128 , 129 , 130 , 131 , 132 , 133 , 134 , 135 , 136 , 137 , 138 , 139 ].…”

Section: The Role Of M 6 a Regulators In Developme...mentioning

confidence: 99%

“…The m 6 A regulators affected the biological behavior of ESCC cells through the same or a different gene/signaling pathway, which is shown in Figure 1 , Figure 2 , Figure 3 , Figure 4 , Figure 5 , Figure 6 and Figure 7 [ 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 68 , 69 , 70 , 71 , 72 , 73 , 74 , 75 , 76 , 78 , 79 , 80 , 81 , 82 , 83 , 84 , 85 , 86 , 124 , 126 , 127 , 131 , 132 , 133 , 134 , 135 , 136 , 137 , 138 , 139 , 141 ].…”

Section: The Role Of M 6 a Regulators In Developme...mentioning

confidence: 99%

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The Role of m6A Modification and m6A Regulators in Esophageal Cancer

Niu

Wang

et al. 2022

Cancers

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N6-methyladenosine (m6A) modification, the most prevalent RNA modification, is involved in all aspects of RNA metabolism, including RNA processing, nuclear export, stability, translation and degradation. Therefore, m6A modification can participate in various physiological functions, such as tissue development, heat shock response, DNA damage response, circadian clock control and even in carcinogenesis through regulating the expression or structure of the gene. The deposition, removal and recognition of m6A are carried out by methyltransferases, demethylases and m6A RNA binding proteins, respectively. Aberrant m6A modification and the dysregulation of m6A regulators play critical roles in the occurrence and development of various cancers. The pathogenesis of esophageal cancer (ESCA) remains unclear and the five-year survival rate of advanced ESCA patients is still dismal. Here, we systematically reviewed the recent studies of m6A modification and m6A regulators in ESCA and comprehensively analyzed the role and possible mechanism of m6A modification and m6A regulators in the occurrence, progression, remedy and prognosis of ESCA. Defining the effect of m6A modification and m6A regulators in ESCA might be helpful for determining the pathogenesis of ESCA and providing some ideas for an early diagnosis, individualized treatment and improved prognosis of ESCA patients.

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ATXN2-mediated translation of TNFR1 promotes esophageal squamous cell carcinoma via m6A-dependent manner

Cited by 21 publications

References 53 publications

m6A demethylase Fto regulates TNF-α-induced inflammatory response in cementoblasts

m6A demethylase Fto regulates TNF-α-induced inflammatory response in cementoblasts

ATXN2-Mediated PI3K/AKT Activation Confers Gastric Cancer Chemoresistance and Attenuates CD8+ T Cell Cytotoxicity

The Role of m6A Modification and m6A Regulators in Esophageal Cancer

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