Xiangyi Meng , Zhu Tan , Bihua Qiu , Jie Zhang , Ruobing Wang , Wensi Ni , Jialing Fan
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Using NB cell models with overexpressed PHOX2B, combined with lncRNA microarray analysis, we discovered that lncARSR is significantly upregulated in response to PHOX2B overexpression. Subsequent biological assays demonstrated that lncARSR promotes both the proliferation and metastasis of NB cells. Further molecular investigations revealed that lncARSR plays a crucial role in stabilizing PHOX2B expression within NB cells. Moreover, we identified that the expression of lncARSR is regulated by methylation through methyltransferase-like 3 (METTL3), which itself is positively correlated with PHOX2B expression. Rescue experiments underscored the functional importance of METTL3, lncARSR, and PHOX2B in NB cells. In summary, our findings provide new insights into the molecular functions of PHOX2B in the progression of neuroblastoma and propose a novel therapeutic target for this aggressive malignancy.</div></div>","PeriodicalId":19916,"journal":{"name":"Pathology, research and practice","volume":null,"pages":null},"PeriodicalIF":2.9000,"publicationDate":"2024-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"METTL3-induced lncARSR aggravates neuroblastoma tumorigenic properties through stabilizing PHOX2B\",\"authors\":\"Xiangyi Meng , Zhu Tan , Bihua Qiu , Jie Zhang , Ruobing Wang , Wensi Ni , Jialing Fan\",\"doi\":\"10.1016/j.prp.2024.155670\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><div>Neuroblastoma (NB), the most common extracranial solid tumor in pediatric patients, manifests with considerable variability across multiple primary sites. Despite this, the extent of genetic heterogeneity within these tumor foci and the identification of consistent oncogenic drivers remains largely unexplored. Of particular interest, genetic mutations in PHOX2B have been linked to familial cases of NB, yet the underlying molecular mechanisms are not fully delineated. In our research, we focus on unraveling the role of a novel functional long non-coding RNA (lncRNA) associated with PHOX2B in the context of NB. Using NB cell models with overexpressed PHOX2B, combined with lncRNA microarray analysis, we discovered that lncARSR is significantly upregulated in response to PHOX2B overexpression. Subsequent biological assays demonstrated that lncARSR promotes both the proliferation and metastasis of NB cells. Further molecular investigations revealed that lncARSR plays a crucial role in stabilizing PHOX2B expression within NB cells. Moreover, we identified that the expression of lncARSR is regulated by methylation through methyltransferase-like 3 (METTL3), which itself is positively correlated with PHOX2B expression. Rescue experiments underscored the functional importance of METTL3, lncARSR, and PHOX2B in NB cells. In summary, our findings provide new insights into the molecular functions of PHOX2B in the progression of neuroblastoma and propose a novel therapeutic target for this aggressive malignancy.</div></div>\",\"PeriodicalId\":19916,\"journal\":{\"name\":\"Pathology, research and practice\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":2.9000,\"publicationDate\":\"2024-10-21\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Pathology, research and practice\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://www.sciencedirect.com/science/article/pii/S0344033824005818\",\"RegionNum\":4,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q2\",\"JCRName\":\"PATHOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Pathology, research and practice","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0344033824005818","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"PATHOLOGY","Score":null,"Total":0}
引用次数: 0
摘要
神经母细胞瘤(NB)是儿科患者中最常见的颅外实体瘤,在多个原发部位表现出相当大的差异性。尽管如此,这些肿瘤病灶内的遗传异质性程度以及一致的致癌驱动因素在很大程度上仍未得到探索。尤其令人感兴趣的是,PHOX2B 基因突变与 NB 家族病例有关,但其潜在的分子机制尚未完全阐明。在我们的研究中,我们侧重于揭示与 PHOX2B 相关的新型功能性长非编码 RNA(lncRNA)在 NB 中的作用。利用过表达 PHOX2B 的 NB 细胞模型,结合 lncRNA 微阵列分析,我们发现 lncARSR 在 PHOX2B 过表达时显著上调。随后的生物学实验证明,lncARSR能促进NB细胞的增殖和转移。进一步的分子研究发现,lncARSR 在稳定 NB 细胞中 PHOX2B 的表达方面起着至关重要的作用。此外,我们还发现,lncARSR的表达通过类似甲基转移酶3(METTL3)受甲基化调控,而甲基化本身与PHOX2B的表达呈正相关。拯救实验强调了 METTL3、lncARSR 和 PHOX2B 在 NB 细胞中的功能重要性。总之,我们的研究结果为PHOX2B在神经母细胞瘤进展过程中的分子功能提供了新的见解,并为这种侵袭性恶性肿瘤提出了一个新的治疗靶点。
METTL3-induced lncARSR aggravates neuroblastoma tumorigenic properties through stabilizing PHOX2B
Neuroblastoma (NB), the most common extracranial solid tumor in pediatric patients, manifests with considerable variability across multiple primary sites. Despite this, the extent of genetic heterogeneity within these tumor foci and the identification of consistent oncogenic drivers remains largely unexplored. Of particular interest, genetic mutations in PHOX2B have been linked to familial cases of NB, yet the underlying molecular mechanisms are not fully delineated. In our research, we focus on unraveling the role of a novel functional long non-coding RNA (lncRNA) associated with PHOX2B in the context of NB. Using NB cell models with overexpressed PHOX2B, combined with lncRNA microarray analysis, we discovered that lncARSR is significantly upregulated in response to PHOX2B overexpression. Subsequent biological assays demonstrated that lncARSR promotes both the proliferation and metastasis of NB cells. Further molecular investigations revealed that lncARSR plays a crucial role in stabilizing PHOX2B expression within NB cells. Moreover, we identified that the expression of lncARSR is regulated by methylation through methyltransferase-like 3 (METTL3), which itself is positively correlated with PHOX2B expression. Rescue experiments underscored the functional importance of METTL3, lncARSR, and PHOX2B in NB cells. In summary, our findings provide new insights into the molecular functions of PHOX2B in the progression of neuroblastoma and propose a novel therapeutic target for this aggressive malignancy.
期刊介绍:
Pathology, Research and Practice provides accessible coverage of the most recent developments across the entire field of pathology: Reviews focus on recent progress in pathology, while Comments look at interesting current problems and at hypotheses for future developments in pathology. Original Papers present novel findings on all aspects of general, anatomic and molecular pathology. Rapid Communications inform readers on preliminary findings that may be relevant for further studies and need to be communicated quickly. Teaching Cases look at new aspects or special diagnostic problems of diseases and at case reports relevant for the pathologist''s practice.