Department of Cardiothoracic Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang, China.
Cancer Sci. 2023 Mar;114(3):855-869. doi: 10.1111/cas.15668. Epub 2022 Dec 7.
The role of TELO2-interacting protein 1 (TTI1) in the progression of several types of cancer has been reported recently. The aim of this study was to estimate the expression and potential value of TTI1 in non-small-cell lung cancer (NSCLC) patients. The expression of TTI1 and its prognostic value in NSCLC from The Cancer Genome Atlas (TCGA) database and Gene Expression Omnibus (GEO) database were analyzed. To verify the bioinformatics findings, a tissue microarray containing 160 NSCLC and paired peritumoral tissues from NSCLC patients was analyzed by immunohistochemistry for TTI1. Subsequently, the roles of TTI1 in NSCLC cells were investigated in vivo by establishing xenograft models in nude mice and in vitro by transwell, CCK-8, wound healing, and colony formation assays. In addition, quantitative real-time polymerase chain reaction and western blot were applied to explore the underlying mechanism by which TTI1 promotes tumor progression. Finally, the relationship between TTI1 and Ki67 expression level in NSCLC was probed, and Kaplan-Meier and Cox analyses were performed to assess the prognostic merit of TTI1 and Ki67 in NSCLC patients. We found that the expression of TTI1 was significantly upregulated in NSCLC tissues compared to paired peritumoral tissues, which coincides with the bioinformatics findings from the TCGA and GEO databases. TTI1 was highly expressed in NSCLC patients with large tumors, advanced tumor stage, and lymphatic metastasis. In addition, the prognostic analysis identified TTI1 as an independent indication for poor prognosis of NSCLC patients. In vitro, upregulation of TTI1 in NSCLC cells could facilitate cell invasion, metastasis, viability, and proliferation. Mechanistically, our study verified that TTI1 could regulate mTOR activity, which has a pivotal role in human cancer. Consistently, the expressions of TTI1 and Ki67 had a positive relationship in NSCLC cells and tissues. Notably, patients with overexpression of TTI1 or Ki67 had a shorter overall survival rate and a higher disease-free survival rate compared to patients with low expression of TTI1 or Ki67, and the combination of TTI1 and Ki67 was an independent parameter predicting the prognosis and recurrence of NSCLC patients. We conclude that TTI1 promotes NSCLC cell proliferation, metastasis, and invasion by regulating mTOR activity, and the combination of TTI1 and Ki67 is a valuable molecular biomarker for the survival and recurrence of NSCLC patients.
TELO2 相互作用蛋白 1（TTI1）在多种癌症的进展中发挥了作用，最近已有报道。本研究旨在评估 TTI1 在非小细胞肺癌（NSCLC）患者中的表达及其潜在价值。分析了来自癌症基因组图谱（TCGA）数据库和基因表达综合数据库（GEO）的 TTI1 在 NSCLC 中的表达及其预后价值。为了验证生物信息学发现，通过免疫组织化学法对包含 160 例 NSCLC 患者的组织微阵列中的 TTI1 进行了分析。随后，通过建立裸鼠异种移植模型和体外 transwell、CCK-8、划痕愈合和集落形成实验，研究了 TTI1 在 NSCLC 细胞中的作用。此外，应用实时定量聚合酶链反应和蛋白质印迹法探讨了 TTI1 促进肿瘤进展的潜在机制。最后，探讨了 TTI1 与 NSCLC 中 Ki67 表达水平的关系，并进行 Kaplan-Meier 和 Cox 分析，以评估 TTI1 和 Ki67 在 NSCLC 患者中的预后价值。结果发现，与配对的癌旁组织相比，TTI1 在 NSCLC 组织中的表达明显上调，这与 TCGA 和 GEO 数据库的生物信息学结果一致。TTI1 在肿瘤较大、肿瘤分期较晚和有淋巴转移的 NSCLC 患者中高表达。此外，预后分析将 TTI1 鉴定为 NSCLC 患者预后不良的独立指标。在体外，上调 NSCLC 细胞中的 TTI1 可促进细胞侵袭、转移、活力和增殖。在机制上，本研究验证了 TTI1 可调节 mTOR 活性，而 mTOR 活性在人类癌症中具有关键作用。一致地，在 NSCLC 细胞和组织中，TTI1 和 Ki67 的表达呈正相关。值得注意的是，与 TTI1 或 Ki67 低表达的患者相比，高表达 TTI1 或 Ki67 的患者的总生存率和无病生存率均较短，而 TTI1 和 Ki67 的联合是预测 NSCLC 患者预后和复发的独立参数。我们得出结论，TTI1 通过调节 mTOR 活性促进 NSCLC 细胞的增殖、转移和侵袭，TTI1 和 Ki67 的联合是 NSCLC 患者生存和复发的有价值的分子生物标志物。
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