Horimasu Yasushi, Ishikawa Nobuhisa, Taniwaki Masaya, Yamaguchi Kakuhiro, Hamai Kosuke, Iwamoto Hiroshi, Ohshimo Shinichiro, Hamada Hironobu, Hattori Noboru, Okada Morihito, Arihiro Koji, Ohtsuki Yuji, Kohno Nobuoki
Department of Molecular and Internal Medicine, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan.
Department of Respiratory Medicine, Hiroshima Prefectural Hospital, 1-5-54 Ujina-Kanda, Minami-ku, Hiroshima, 734-8530, Japan.
BMC Med Genet. 2017 Aug 18;18(1):88. doi: 10.1186/s12881-017-0449-9.
Chronic fibrosing idiopathic interstitial pneumonia (IIP) is characterized by alveolar epithelial damage, activation of fibroblast proliferation, and loss of normal pulmonary architecture and function. This study aims to investigate the genetic backgrounds of IIP through gene expression profiling and pathway analysis, and to identify potential biomarkers that can aid in diagnosis and serve as novel therapeutic targets.
RNA extracted from lung specimens of 12 patients with chronic fibrosing IIP was profiled using Illumina Human WG-6 v3 BeadChips, and Ingenuity Pathway Analysis was performed to identify altered functional and canonical signaling pathways. For validating the results from gene expression analysis, immunohistochemical staining of 10 patients with chronic fibrosing IIP was performed.
Ninety-eight genes were upregulated in IIP patients relative to control subjects. Some of the upregulated genes, namely desmoglein 3 (DSG3), protocadherin gamma-A9 (PCDHGA9) and discoidin domain-containing receptor 1 (DDR1) are implicated in cell-cell interaction and/or adhesion; some, namely collagen type VII, alpha 1 (COL7A1), contactin-associated protein-like 3B (CNTNAP3B) and mucin-1 (MUC1) are encoding the extracellular matrix molecule or the molecules involved in cell-matrix interactions; and the others, namely CDC25C and growth factor independent protein 1B (GFI1B) are known to affect cell proliferation by affecting the progression of cell cycle or regulating transcription. According to pathway analysis, alternated pathways in IIP were related to cell death and survival and cellular growth and proliferation, which are more similar to cancer than to inflammatory response and immunological diseases. Using immunohistochemistry, we further validate that DSG3, the most highly upregulated gene, shows higher expression in chronic fibrosing IIP lung as compared to control lung.
We identified several genes upregulated in chronic fibrosing IIP patients as compared to control, and found genes and pathways implicated in cancer, rather than in inflammatory or immunological disease to play important roles in the pathogenesis of IIPs. Moreover, DSG3 is a novel potential biomarker for chronic fibrosing IIP with its significantly high expression in IIP lung.
慢性纤维化性特发性间质性肺炎（IIP）的特征是肺泡上皮损伤、成纤维细胞增殖激活以及正常肺结构和功能丧失。本研究旨在通过基因表达谱分析和通路分析来探究IIP的遗传背景，并识别有助于诊断且可作为新型治疗靶点的潜在生物标志物。
使用Illumina Human WG-6 v3 BeadChips对12例慢性纤维化性IIP患者肺标本中提取的RNA进行分析，并采用Ingenuity通路分析来识别功能和经典信号通路的改变。为验证基因表达分析结果，对10例慢性纤维化性IIP患者进行了免疫组化染色。
与对照受试者相比，IIP患者中有98个基因上调。一些上调基因，即桥粒芯糖蛋白3（DSG3）、原钙黏蛋白γ-A9（PCDHGA9）和盘状结构域受体1（DDR1）与细胞间相互作用和/或黏附有关；一些，即Ⅶ型胶原α1链（COL7A1）、接触蛋白相关蛋白样3B（CNTNAP3B）和黏蛋白1（MUC1）编码细胞外基质分子或参与细胞与基质相互作用的分子；其他的，即细胞周期蛋白磷酸酶25C（CDC25C）和生长因子独立蛋白1B（GFI1B）已知通过影响细胞周期进程或调节转录来影响细胞增殖。根据通路分析，IIP中改变的通路与细胞死亡和存活以及细胞生长和增殖有关，这与癌症更为相似，而非炎症反应和免疫性疾病。通过免疫组化，我们进一步验证了上调程度最高的基因DSG3在慢性纤维化性IIP肺组织中的表达高于对照肺组织。
我们鉴定出与对照相比在慢性纤维化性IIP患者中上调的几个基因，并发现与癌症相关而非炎症或免疫性疾病相关的基因和通路在IIP的发病机制中起重要作用。此外，DSG3因其在IIP肺组织中显著高表达，是慢性纤维化性IIP的一种新型潜在生物标志物。
