DNA 损伤诱导转录物 4 (DDIT4) 的核过度表达与胰腺肿瘤患者的侵袭性肿瘤行为相关。
Nuclear overexpression of DNA damage-inducible transcript 4 (DDIT4) is associated with aggressive tumor behavior in patients with pancreatic tumors.
发表日期:2023 Nov 08
作者:
Fatemeh Tajik, Fahimeh Fattahi, Fereshteh Rezagholizadeh, Behnaz Bouzari, Pegah Babaheidarian, Masoud Baghai Wadji, Zahra Madjd
来源:
Protein & Cell
摘要:
DNA 损伤诱导转录物 4 (DDIT4) 在各种细胞应激条件下被诱导。多项研究表明,DDIT4 的失调与不同的恶性肿瘤有关,并具有矛盾的表达和作用。因此,本研究探讨了DDIT4在不同类型胰腺肿瘤(PT)中的临床意义、预后和诊断价值。使用实时定量 PCR (RT-qPCR) 在 27 个新鲜 PT 样本中检测 DDIT4 和长非编码 RNA (TPTEP1) mRNA 水平的表达。此外,收集200份福尔马林固定石蜡包埋的PT组织以及27份癌旁正常组织,通过组织微阵列(TMA)载玻片上的免疫组织化学(IHC)评估DDIT4表达的临床意义、预后和诊断价值。 RT-qPCR结果显示,肿瘤样本中DDIT4的表达高于正常样本,这与肿瘤分级高(P = 0.015)和淋巴管侵犯(P = 0.048)有关。与此类似,IHC 对细胞核、细胞质和膜定位的发现显示 PT 样本中的 DDIT4 蛋白表达高于附近的正常组织。在胰腺导管腺癌 (PDAC) 和胰腺神经内分泌肿瘤 (PNET) 中,DDIT4 蛋白的高水平核表达与淋巴管侵犯 (P = 0.025) 以及晚期 TNM 分期 (P = 0.034) 之间存在统计学显着相关性), 分别。相反,DDIT4蛋白的低水平膜表达与晚期组织学分级(P = 0.011)、边缘受累(P = 0.007)、神经周围侵犯(P = 0.023)以及淋巴血管侵犯(P = 0.005)在 PDAC 中。在这两种类型中,生存结果与 DDIT4 表达之间没有发现显着关联。结果发现DDIT4作为诊断标志物具有合理的准确性和高灵敏度。我们的结果揭示了 DDIT4 表达蛋白基于核和膜表达位点的矛盾作用。这项研究的结果表明,DDIT4 的核表达升高与 PT 患者的疾病进展和进展之间存在相关性。相反,DDIT4 的高膜表达与 PDAC 患者较低的侵袭性肿瘤行为相关。然而,未来的研究需要进一步研究 DDIT4 的预后价值和生物学功能。© 2023。作者。
DNA damage-inducible transcript 4 (DDIT4) is induced in various cellular stress conditions. Several studies showed that the dysregulation of DDIT4 is involved in different malignancies with paradoxical expressions and roles. Therefore, this study investigated the clinical significance, prognostic, and diagnostic value of DDIT4 in different types of pancreatic tumors (PT). The expression of DDIT4 and long non-coding RNA (TPTEP1) in mRNA level was examined in 27 fresh PT samples using Real-time quantitative PCR (RT-qPCR). Moreover, 200 formalin-fixed paraffin-embedded PT tissues, as well as 27 adjacent normal tissues, were collected to evaluate the clinical significance, prognostic, and diagnosis value of DDIT4 expression by immunohistochemistry (IHC) on tissue microarrays (TMA) slides. The results of RT-qPCR showed that the expression of DDIT4 in tumor samples was higher than in normal samples which was associated with high tumor grade (P = 0.015) and lymphovascular invasion (P = 0.048). Similar to this, IHC findings for nucleus, cytoplasm, and membrane localization showed higher expression of DDIT4 protein in PT samples rather than in nearby normal tissues. A statistically significant association was detected between a high level of nuclear expression of DDIT4 protein, and lymphovascular invasion (P = 0.025), as well as advanced TNM stage (P = 0.034) pancreatic ductal adenocarcinoma (PDAC) and in pancreatic neuroendocrine tumor (PNET), respectively. In contrast, a low level of membranous expression of DDIT4 protein showed a significant association with advanced histological grade (P = 0.011), margin involvement (P = 0.007), perineural invasion (P = 0.023), as well as lymphovascular invasion (P = 0.005) in PDAC. No significant association was found between survival outcomes and expression of DDIT4 in both types. It was found that DDIT4 has rational accuracy and high sensitivity as a diagnostic marker. Our results revealed a paradoxical role of DDIT4 expression protein based on the site of nuclear and membranous expression. The findings of this research indicated that there is a correlation between elevated nuclear expression of DDIT4 and the advancement and progression of disease in patients with PT. Conversely, high membranous expression of DDIT4 was associated with less aggressive tumor behavior in patients with PDAC. However, further studies into the prognostic value and biological function of DDIT4 are needed in future studies.© 2023. The Author(s).