Department of Oncology, University of Turin, San Luigi Hospital, Orbassano, Italy.
Department of Oncology, University of Turin, "Città della Salute e della Scienza" Hospital, Turin, Italy.
Neuroendocrinology. 2021;111(1-2):115-122. doi: 10.1159/000506401. Epub 2020 Feb 11.
To validate the prognostic role of a panel of genes previously uncovered by our group to be specific targets of miRNAs differentially expressed in lung carcinoids with aggressive pathological features.
Four genes, namely, cyclic AMP response element binding protein-1 (CREBP1), activin A receptor type 2B (ACVR2B), LIM homeobox 2 (LHX2), and Krüppel-like factor 12 (KLF12), were identified in a previous study by our group using in silico analysis to be regulated by 3 miRNAs (miR-409-3p, miR-409-5p, and miR-431-5p) that were shown to be downregulated in aggressive lung carcinoids. These genes were analyzed using real-time PCR in a cohort of 102 lung carcinoids. Fifty high-grade lung carcinomas served as control group. Their expression was correlated with the expression of miR-409-3p, miR-409-5p, and miR-431-5p and with clinical pathological parameters and disease-free survival.
The expression of all but CREBP1 gene was significantly different between lung carcinoids and high-grade neuroendocrine carcinomas. ACVR2B and LHX2 were significantly inversely correlated with miR-409-3p and miR-409-5p. High levels of ACVR2B and LHX2 were significantly associated with atypical histotype, high tumor grade, and higher proliferation Ki-67 index (all p < 0.05). Low levels of KLF12 were significantly associated with the presence of necrosis and positive nodal status (all p < 0.05). Finally, low KLF12 expression was associated with shorter disease-free survival in lung carcinoids as a whole and in atypical carcinoids, only (all p < 0.001).
ACVR2B, LHX2, and KFL12 are novel potential biomarkers associated with aggressive features in lung carcinoids.
验证我们小组先前发现的一组基因的预后作用，这些基因是我们通过计算分析确定的，是差异表达的 miRNA 的特定靶点，这些 miRNA 在具有侵袭性病理特征的肺类癌中表达下调。
我们小组在之前的研究中使用实时 PCR 分析了 102 例肺类癌中的 4 个基因，即环磷酸腺苷反应元件结合蛋白-1（CREBP1）、激活素 A 受体型 2B（ACVR2B）、LIM 同源盒 2（LHX2）和 Krüppel 样因子 12（KLF12）。这 4 个基因被证明在侵袭性肺类癌中表达下调。50 例高级别肺神经内分泌癌作为对照组。分析它们的表达与 miR-409-3p、miR-409-5p 和 miR-431-5p 的表达以及临床病理参数和无病生存率的关系。
除 CREBP1 基因外，所有基因在肺类癌和高级别神经内分泌癌之间的表达均有显著差异。ACVR2B 和 LHX2 与 miR-409-3p 和 miR-409-5p 呈显著负相关。ACVR2B 和 LHX2 高表达与非典型组织学类型、高肿瘤分级和较高的增殖 Ki-67 指数显著相关（均 P < 0.05）。KLF12 低表达与坏死和阳性淋巴结状态显著相关（均 P < 0.05）。最后，KLF12 低表达与肺类癌和非典型类癌的无病生存率显著相关（均 P < 0.001）。
ACVR2B、LHX2 和 KFL12 是与肺类癌侵袭性特征相关的新的潜在生物标志物。
