Department of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, No.58 Zhongshan II Road, Yuexiu District, Guangzhou, 510080, China.
Department of Gastroenterology, Peking Union Medical College Hospital, Beijing, China.
BMC Cancer. 2018 Jun 26;18(1):691. doi: 10.1186/s12885-018-4449-8.
The neuronal intermediate filament alpha-internexin (α-internexin) is a cytoskeleton protein which is involved in the tumor initiation and progression. In this study, we examined the expression and prognosis value of α-internexin in gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs).
α-internexin was detected with immunohistochemical staining in 286 tumor specimens from patients with GEP-NENs. Methylation status of α-internexin was evaluated by bisulfite genomic sequencing. We assessed the prognostic value of α-internexin and its correlation with relevant clinicalpathological characteristics.
The reduced/loss of expression rate of α-internexin in GEP-NEN was 73.4% (210/286), while the positive expression rate was 26.6% (76/286). The difference of α-internexin deficiency was not statistically significant between gastrointestinal NENs (GI-NENs) and pancreatic NENs (pNENs). However, we found significant difference of reduced/loss of α-internexin expression among different sites of GI-NENs (χ = 43.470, P < 0.001). The reduced/loss of expression of α-internexin was significantly associated with poorly differentiation (P < 0.001) and advanced tumor stage (P < 0.001). Univariate analyses showed that reduced/loss of expression of α-internexin predicted worse overall survival (OS) in GEP-NEN patients (P < 0.001), especially in subtype of GI-NENs (P < 0.001). However, in multivariable regression analysis, α-internexin expression was not an independent prognostic factor. The hypermethylation of α-internexin gene was significantly correlated with protein deficiency in GI-NENs, but not in pNENs. Hypermethylation of several CpG sites was significantly associated with poorly differentiated and advanced stage (P values range from 0.018 to 0.044). However, the methylation status of α-internexin was not associated with patient OS.
The expression of α-internexin was highly heterougeneous in different sites of GEP-NENs. The reduced/loss of expression of α-internexin was closely related to tumors with aggressiveness and patient's adverse prognosis. The hypermethylation of the regulatory region examined may be an important epigenetic regulation mechanism of α-internexin deficiency in subtype of GI-NENs.
神经元中间丝α-连接蛋白（α-internexin）是一种细胞骨架蛋白，参与肿瘤的发生和发展。本研究检测了α-internexin在胃肠胰神经内分泌肿瘤（GEP-NENs）中的表达和预后价值。
采用免疫组织化学染色法检测 286 例 GEP-NEN 患者肿瘤标本中α-internexin的表达。采用亚硫酸氢盐基因组测序评估α-internexin的甲基化状态。我们评估了α-internexin的预后价值及其与相关临床病理特征的相关性。
α-internexin在 GEP-NEN 中的表达缺失率为 73.4%（210/286），阳性表达率为 26.6%（76/286）。胃肠道神经内分泌肿瘤（GI-NENs）和胰腺神经内分泌肿瘤（pNENs）之间α-internexin缺乏的差异无统计学意义（p=0.213）。然而，我们发现不同部位 GI-NENs 之间α-internexin表达缺失率有显著差异（χ²=43.470，P<0.001）。α-internexin表达缺失与分化差（P<0.001）和肿瘤分期较高（P<0.001）显著相关。单因素分析显示，α-internexin表达缺失预测 GEP-NEN 患者总体生存（OS）不良（P<0.001），尤其是在 GI-NENs 亚组中（P<0.001）。然而，在多变量回归分析中，α-internexin表达不是独立的预后因素。α-internexin 基因的高甲基化与 GI-NENs 中蛋白缺失显著相关，但与 pNENs 无关。几个 CpG 位点的高甲基化与分化差和分期较高显著相关（P 值范围为 0.018 至 0.044）。然而，α-internexin 的甲基化状态与患者 OS 无关。
α-internexin在不同部位的 GEP-NENs 中表达高度异质性。α-internexin 表达缺失与侵袭性肿瘤和患者不良预后密切相关。所检测的调控区高甲基化可能是 GI-NENs 亚型中α-internexin 缺失的重要表观遗传调控机制。
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