Ibarrola-Villava Maider, Llorca-Cardeñosa Marta J, Tarazona Noelia, Mongort Cristina, Fleitas Tania, Perez-Fidalgo José Alejandro, Roselló Susana, Navarro Samuel, Ribas Gloria, Cervantes Andrés
Hematology and Medical Oncology Unit, Biomedical Research Institute INCLIVA, University of Valencia, 46010, Valencia, Spain.
Department of Pathology, Biomedical Research Institute INCLIVA, University of Valencia, 46010, Valencia, Spain.
Oncotarget. 2015 Sep 29;6(29):26935-45. doi: 10.18632/oncotarget.4775.
Genetic and epigenetic alterations play an important role in gastric cancer (GC) pathogenesis. Aberrations of the phosphatidylinositol-3-kinase signaling pathway are well described. However, emerging genes have been described such as, the chromatin remodeling gene ARID1A. Our aim was to determine the expression levels of four GC-related genes, ARID1A, CDH1, cMET and PIK3CA, and 14 target-related microRNAs (miRNAs). We compared mRNA and miRNA expression levels among 66 gastric tumor and normal adjacent mucosa samples using quantitative real-time reverse transcription PCR. Moreover, ARID1A, cMET and PIK3CA protein levels were assessed by immunohistochemistry (IHC). Finally, gene and miRNAs associations with clinical characteristics and outcome were also evaluated. An increased cMET and PIK3CA mRNA expression was found in 78.0% (P = 2.20 × 10-5) and 73.8% (P = 1.00 × 10-3) of the tumors, respectively. Moreover, IHC revealed that cMET and PIK3CA expression was positive in 63.6% and 87.8% of the tumors, respectively. Six miRNAs had significantly different expression between paired-samples, finding five up-regulated [miR-223-3p (P = 1.65 × 10-6), miR-19a-3p (P = 1.23 × 10-4), miR-128-3p (P = 3.49 × 10-4), miR-130b-3p (P = 1.00 × 10-3) and miR-34a-5p (P = 4.00 × 10-3)] and one down-regulated [miR-124-3p (P = 0.03)]. Our data suggest that cMET, PIK3CA and target-related miRNAs play an important role in GC and may serve as potential targets for therapy.
遗传和表观遗传改变在胃癌（GC）发病机制中起重要作用。磷脂酰肌醇-3-激酶信号通路的畸变已有详细描述。然而，也有一些新出现的基因被报道，如染色质重塑基因ARID1A。我们的目的是确定四个与GC相关的基因ARID1A、CDH1、cMET和PIK3CA以及14个与靶点相关的微小RNA（miRNA）的表达水平。我们使用定量实时逆转录PCR比较了66例胃肿瘤及其正常相邻黏膜样本中的mRNA和miRNA表达水平。此外，通过免疫组织化学（IHC）评估ARID1A、cMET和PIK3CA的蛋白水平。最后，还评估了基因和miRNA与临床特征及预后的相关性。分别在78.0%（P = 2.20×10⁻⁵）和73.8%（P = 1.00×10⁻³）的肿瘤中发现cMET和PIK3CA mRNA表达增加。此外，免疫组织化学显示，cMET和PIK3CA表达在63.6%和87.8%的肿瘤中呈阳性。六个miRNA在配对样本间有显著不同的表达，发现五个上调[miR-223-3p（P = 1.65×10⁻⁶）、miR-19a-3p（P = 1.23×10⁻⁴）、miR-128-3p（P = 3.49×10⁻⁴）、miR-130b-3p（P = 1.00×10⁻³）和miR-34a-5p（P = 4.00×10⁻³）]，一个下调[miR-124-3p（P = 0.03）]。我们的数据表明，cMET、PIK3CA和与靶点相关的miRNA在胃癌中起重要作用，可能作为潜在的治疗靶点。
