背景与目的m6A RNA甲基化修饰在肺癌的发生与进展中起着重要作用,可以调节肿瘤免疫进而影响疾病预后。目前很多集中在某些特定的m6A效应器的差异表达及对肿瘤免疫细胞浸润的影响,但单个效应器表达的变化远远不足以反映m6A修饰特征的全貌...背景与目的m6A RNA甲基化修饰在肺癌的发生与进展中起着重要作用,可以调节肿瘤免疫进而影响疾病预后。目前很多集中在某些特定的m6A效应器的差异表达及对肿瘤免疫细胞浸润的影响,但单个效应器表达的变化远远不足以反映m6A修饰特征的全貌,且关于m6A修饰对肺腺癌免疫微环境影响的研究仍较少。本研究拟探讨不同m6A修饰模式对肺腺癌中免疫微环境的影响。方法从癌症基因组图谱数据库(e Cancer Genome Atlas,TCGA)、加州大学圣克鲁兹分校泛癌全基因数据分析工具数据库(University of California Santa Cruz Xena,UCSC Xena)、基因表达综合数据库(Gene Expression Omnibus,GEO)获取肺腺癌相关数据信息。使用Maftools R分析肺腺癌队列中24个m6A效应器的基因突变,比较肺腺癌组织和正常组织中m6A效应器的表达差异,并通过Cox回归分析进行生存分析。通过Consensus Cluster Plus R非监督聚类的方法构建m6A修饰模式,进行m6A聚类生存分析、GSVA通路富集分析、免疫评分及免疫细胞浸润分析。在68例肺腺癌组织中,通过免疫组化分析LRPPRC蛋白表达水平与CD8、CD68的表达水平,验证LRPPRC与CD8;细胞毒性T细胞及巨噬细胞浸润的关系。结果在567例肺腺癌样本中有150例发生了m6A效应器突变,频率为26.46%。与正常组织相比,肺腺癌组织中共有6个读取器和3个写入器的表达明显上调。IGF2BP1和HNRNPC是影响肺腺癌患者预后的独立危险因素,且各效应器之间也存在大量的相互作用。构建了3种具有不同免疫细胞浸润特征和临床预后的m6A修饰模式。发现LRPPRC的表达与包括杀伤性T细胞和巨噬细胞在内的多种免疫细胞的浸润呈负相关,并在68例肺腺癌组织中得到验证。结论m6A修饰对肺腺癌免疫微环境的调节起着重要作用,LRPPRC有可能作为预测抗PD1免疫治疗效果的潜在生物标记物。展开更多
Phosphatase and tensin homolog(PTEN)is a multifunctional gene involved in a variety of physiological and pathological processes.Circular RNAs(circRNAs)are generated from back-splicing events during mRNA processing and...Phosphatase and tensin homolog(PTEN)is a multifunctional gene involved in a variety of physiological and pathological processes.Circular RNAs(circRNAs)are generated from back-splicing events during mRNA processing and participate in cell biological processes through binding to RNAs or proteins.However,PTEN-related circRNAs are largely unknown.Here,we report that circPTEN-mitochondria(MT)(hsa_circ_0002934)is a circular RNA encoded by exons 3,4,and 5 of PTEN and is a critical regulator of mitochondrial energy metabolism.CircPTEN-MT is localized to mitochondria and physically associated with leucine-rich pentatricopeptide repeat-containing protein(LRPPRC),which regulates posttranscriptional gene expression in mitochondria.Knocking down circPTEN-MT reduces the interaction of LRPPRC and steroid receptor RNA activator(SRA)stem-loop interacting RNA binding protein(SLIRP)and inhibits the polyadenylation of mitochondrial mRNA,which decreases the mRNA level of the mitochondrial complex I subunit and reduces mitochondrial membrane potential and adenosine triphosphate production.Our data demonstrate that circPTEN-MT is an important regulator of cellular energy metabolism.This study expands our understanding of the role of PTEN,which produces both linear and circular RNAs with different and independent functions.展开更多
文摘背景与目的m6A RNA甲基化修饰在肺癌的发生与进展中起着重要作用,可以调节肿瘤免疫进而影响疾病预后。目前很多集中在某些特定的m6A效应器的差异表达及对肿瘤免疫细胞浸润的影响,但单个效应器表达的变化远远不足以反映m6A修饰特征的全貌,且关于m6A修饰对肺腺癌免疫微环境影响的研究仍较少。本研究拟探讨不同m6A修饰模式对肺腺癌中免疫微环境的影响。方法从癌症基因组图谱数据库(e Cancer Genome Atlas,TCGA)、加州大学圣克鲁兹分校泛癌全基因数据分析工具数据库(University of California Santa Cruz Xena,UCSC Xena)、基因表达综合数据库(Gene Expression Omnibus,GEO)获取肺腺癌相关数据信息。使用Maftools R分析肺腺癌队列中24个m6A效应器的基因突变,比较肺腺癌组织和正常组织中m6A效应器的表达差异,并通过Cox回归分析进行生存分析。通过Consensus Cluster Plus R非监督聚类的方法构建m6A修饰模式,进行m6A聚类生存分析、GSVA通路富集分析、免疫评分及免疫细胞浸润分析。在68例肺腺癌组织中,通过免疫组化分析LRPPRC蛋白表达水平与CD8、CD68的表达水平,验证LRPPRC与CD8;细胞毒性T细胞及巨噬细胞浸润的关系。结果在567例肺腺癌样本中有150例发生了m6A效应器突变,频率为26.46%。与正常组织相比,肺腺癌组织中共有6个读取器和3个写入器的表达明显上调。IGF2BP1和HNRNPC是影响肺腺癌患者预后的独立危险因素,且各效应器之间也存在大量的相互作用。构建了3种具有不同免疫细胞浸润特征和临床预后的m6A修饰模式。发现LRPPRC的表达与包括杀伤性T细胞和巨噬细胞在内的多种免疫细胞的浸润呈负相关,并在68例肺腺癌组织中得到验证。结论m6A修饰对肺腺癌免疫微环境的调节起着重要作用,LRPPRC有可能作为预测抗PD1免疫治疗效果的潜在生物标记物。
基金Y.Yin including the National Natural Science Foundation of China(82030081 and 81874235)the National Key Research and Development Program of China(2021YFA1300601)the Shenzhen High-level Hospital Construction Fund and Shenzhen Basic Research Key Project(JCYJ20220818102811024).
文摘Phosphatase and tensin homolog(PTEN)is a multifunctional gene involved in a variety of physiological and pathological processes.Circular RNAs(circRNAs)are generated from back-splicing events during mRNA processing and participate in cell biological processes through binding to RNAs or proteins.However,PTEN-related circRNAs are largely unknown.Here,we report that circPTEN-mitochondria(MT)(hsa_circ_0002934)is a circular RNA encoded by exons 3,4,and 5 of PTEN and is a critical regulator of mitochondrial energy metabolism.CircPTEN-MT is localized to mitochondria and physically associated with leucine-rich pentatricopeptide repeat-containing protein(LRPPRC),which regulates posttranscriptional gene expression in mitochondria.Knocking down circPTEN-MT reduces the interaction of LRPPRC and steroid receptor RNA activator(SRA)stem-loop interacting RNA binding protein(SLIRP)and inhibits the polyadenylation of mitochondrial mRNA,which decreases the mRNA level of the mitochondrial complex I subunit and reduces mitochondrial membrane potential and adenosine triphosphate production.Our data demonstrate that circPTEN-MT is an important regulator of cellular energy metabolism.This study expands our understanding of the role of PTEN,which produces both linear and circular RNAs with different and independent functions.
