Gene expression profiling using targeted RNA-sequencing to elucidate the progression from histologically normal lung tissues to non-invasive lesions in invasive lung adenocarcinoma
Gene expression profiling using targeted RNA-sequencing to elucidate the progression from histologically normal lung tissues to non-invasive lesions in invasive lung adenocarcinoma
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DOI：
10.1007/s00428-021-03250-y
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发表时间：
2022-01-24
期刊：
影响因子：
3.5
通讯作者：
Umekita, Yoshihisa
中科院分区：
文献类型：
--
作者：
Kadonaga, Taichi;Sakabe, Tomohiko;Umekita, Yoshihisa
肺腺癌（LUAD）的形态学特征不均一，从原位腺癌到微创腺癌再到浸润性LUAD呈阶梯性进展。虽然多种遗传改变与进展有关，但尚未研究侵袭性LUAD中非侵袭性病变（非IL）和相邻组织学正常肺（aNL）组织的基因表达谱之间的差异。在此，我们分析了LUAD早期癌变特异性差异表达基因（DEG）。从7名病理学I期LUAD患者中获得含有非IL和aNL组织的侵袭性LUAD组织样本，并对每种成分进行显微切割。使用靶向RNA测序确定每个组分的基因表达谱。总共有2536个DEG，包括863个上调和1673个下调的基因，在非IL中被鉴定。在非IL中，SLC 44 A5（胆碱转运体样蛋白编码基因）的表达显著上调，TMEM 100（跨膜蛋白编码基因）的表达显著下调。据报道，SLC 44 A5在肝细胞癌的发生和发展中起重要作用，而TMEM 100在非小细胞肺癌中起肿瘤抑制剂的作用。基因集富集分析表明，非IL中的DEG在细胞死亡和免疫应答中呈负富集。免疫组化分析显示，IL中SLC 44 A5表达增加，TMEM 100表达减少。蛋白质-蛋白质相互作用（PPI）网络分析鉴定了在非IL中高度上调和下调的枢纽基因。总之，几个新的DEG和关键的PPI网络枢纽基因在非IL中被确定，有助于了解LUAD的早期致癌作用。
Lung adenocarcinoma (LUAD) shows heterogeneous morphological features and the stepwise progression from adenocarcinoma in situ to minimally invasive adenocarcinoma to invasive LUAD. Although multiple genetic alterations have been linked to the progression, the differences between the gene expression profiles of non-invasive lesions (non-ILs) and adjacent histologically normal lung (aNL) tissues within invasive LUAD have not been investigated. Herein, we analyzed differentially expressed genes (DEGs) specific to early-stage carcinogenesis in LUAD. Invasive LUAD tissue samples containing both non-ILs and aNL tissues were obtained from seven patients with pathological stage I LUAD, and each component was subjected to microdissection. Gene expression profiles of each component were determined using targeted RNA-sequencing. In total, 2536 DEGs, including 863 upregulated and 1673 downregulated genes, were identified in non-ILs. In non-ILs, the expression of SLC44A5, a choline transporter-like protein-coding gene, was significantly upregulated, and that of TMEM100, a gene encoding a transmembrane protein, was significantly downregulated. Reportedly, SLC44A5 plays an important role in the development and progression of hepatocellular carcinoma, whereas TMEM100 functions as a tumor suppressor in non-small cell lung cancer. Gene set enrichment analysis showed that DEGs in non-ILs were negatively enriched in cell death and immune response. Immunohistochemical analysis revealed that increased SLC44A5 expression and decreased TMEM100 expression were maintained in ILs. A protein-protein interaction (PPI) network analysis identified several upregulated and downregulated hub genes with high degrees in non-ILs. In conclusion, several new DEGs and key PPI network hub genes were identified in non-ILs, contributing to understanding of early-stage carcinogenesis in LUAD.