CLEC3A, MMP7, and LCN2 as novel markers for predicting recurrence in resected G1 and G2 pancreatic neuroendocrine tumors
CLEC3A, MMP7, and LCN2 as novel markers for predicting recurrence in resected G1 and G2 pancreatic neuroendocrine tumors
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DOI：
10.1002/cam4.2232
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发表时间：
2019-07-01
期刊：
影响因子：
4
通讯作者：
Ogawa, Yoshihiro
中科院分区：
文献类型：
--
作者：
Miki, Masami;Oono, Takamasa;Ogawa, Yoshihiro
尽管据报道胰腺神经内分泌肿瘤（PNS）的术后复发率为13.5%-30%，但缺乏有价值的生物标志物来预测复发，这给早期发现复发带来了问题。因此，本研究旨在确定新的生物标志物来预测PNNI的复发。我们对从1998年至2015年在我们机构中治愈切除的所有局部G1/G2 PNIPs中取样的冷冻原发性肿瘤中分离的RNA进行RNA测序（RNA-Seq）。我们计算了倾向匹配队列中肿瘤复发和未复发（>= 3年）的差异表达基因（DEG）。还对鉴定的DEG进行基因本体分析。此外，我们通过免疫染色评估了作为复发预测因子的候选基因的表达水平。比较有和没有复发的肿瘤中的转录水平，确定了166个DEG。在这些肿瘤中具有高度显著性的上调和下调基因主要分别与细胞外组织和细胞粘附有关。我们观察了前三个上调的基因，C型凝集素结构域家族3成员A（CLEC 3A），基质金属蛋白酶-7（MMP 7）和脂质运载蛋白2（LCN 2），并比较了它们在复发和非复发肿瘤中的水平。CLEC 3A（P = 0.028）、MMP 7（P = 0.003）和LCN 2（P = 0.040）阳性表达者复发率明显高于阴性表达者。我们确定CLEC 3A、MMP 7和LCN 2已知与磷脂酰肌醇-3-激酶/Akt通路相关，作为潜在的新标志物来预测术后复发的PNAs。
Although the postoperative recurrence rate for pancreatic neuroendocrine tumors (PNETs) is reported to be 13.5%-30%, the paucity of valuable biomarkers to predict recurrence poses a problem for the early detection of relapse. Hence, this study aimed to identify new biomarkers to predict the recurrence of PNETs. We performed RNA sequencing (RNA-Seq) on RNA isolated from frozen primary tumors sampled from all localized G1/G2 PNETs resected curatively from 1998 to 2015 in our institution. We calculated differentially expressed genes (DEGs) in tumor with and without recurrence (>= 3 years) for the propensity-matched cohort. Gene ontology analysis for the identified DEGs was also performed. Furthermore, we evaluated the expression levels of candidate genes as recurrence predictors via immunostaining. Comparison of transcriptional levels in tumors with and without recurrence identified 166 DEGs. Up- and downregulated genes with high significance in these tumors were mainly related to extracellular organization and cell adhesion, respectively. We observed the top three upregulated genes, C-type lectin domain family 3 member A (CLEC3A), matrix metalloproteinase-7 (MMP7), and lipocalin2 (LCN2) immunohistochemically and compared their levels in recurrent and nonrecurrent tumors. Significantly higher recurrence rate was shown in patients with positive expression of CLEC3A (P = 0.028), MMP7 (P = 0.003), and LCN2 (P = 0.040) than that with negative expression. We identified CLEC3A, MMP7, and LCN2 known to be associated with the phosphatidylinositol-3-kinase/Akt pathway, as potential novel markers to predict the postoperative recurrence of PNETs.