TTI1 promotes non-small-cell lung cancer progression by regulating the mTOR signaling pathway.
TTI1 promotes non-small-cell lung cancer progression by regulating the mTOR signaling pathway.
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TTI1通过调节mTOR信号通路促进非小细胞肺癌进展
DOI：
10.1111/cas.15668
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发表时间：
2023-03
期刊：
影响因子：
5.7
通讯作者：
Zhu, Shu-Qiang
中科院分区：
文献类型：
--
作者：
Zhang, Ling-Xian;Yang, Xin;Wu, Zhi-Bo;Liao, Zhong-Min;Wang, Ding-Guo;Chen, Shi-Wei;Lu, Feng;Wu, Yong-Bing;Zhu, Shu-Qiang
TELO 2相互作用蛋白1（TTI 1）在几种类型的癌症进展中的作用最近已有报道。本研究的目的是评估TTI 1在非小细胞肺癌（NSCLC）患者中的表达和潜在价值。分析TCGA数据库和GEO数据库中TTI 1在NSCLC中的表达及其预后价值。为了验证生物信息学的发现，通过免疫组织化学分析了包含160个NSCLC和配对的NSCLC患者瘤周组织的组织微阵列的TTI 1。随后，通过在裸鼠中建立异种移植模型在体内和通过transwell、CCK-8、伤口愈合和集落形成测定在体外研究了TTI 1在NSCLC细胞中的作用。此外，定量真实的时间聚合酶链反应和蛋白质印迹被应用于探索TTI 1促进肿瘤进展的潜在机制。最后，探讨TTI 1和Ki 67在NSCLC中表达水平的关系，并进行Kaplan-Meier和考克斯分析以评估TTI 1和Ki 67在NSCLC患者中的预后价值。我们发现TTI 1的表达在NSCLC组织中显著上调，与配对的瘤周组织相比，这与TCGA和GEO数据库的生物信息学结果一致。TTI 1在具有大肿瘤、晚期肿瘤和淋巴结转移的NSCLC患者中高表达。此外，预后分析将TTI 1确定为NSCLC患者预后不良的独立指征。在体外，NSCLC细胞中TTI 1的上调可促进细胞侵袭、转移、存活和增殖。从机制上讲，我们的研究证实TTI 1可以调节mTOR活性，这在人类癌症中具有关键作用。TTI 1和Ki 67在NSCLC细胞和组织中的表达呈正相关。值得注意的是，与TTI 1或Ki 67低表达的患者相比，TTI 1或Ki 67过表达的患者的总生存率较短，无病生存率较高，TTI 1和Ki 67的组合是预测NSCLC患者预后和复发的独立参数。结论：TTI 1通过调节mTOR活性促进NSCLC细胞增殖、转移和侵袭，TTI 1和Ki 67的联合表达是NSCLC患者生存和复发的一个有价值的分子生物标志物。我们的研究首次证明TTI 1在体外可以促进NSCLC细胞的增殖、侵袭和转移，在体内可以促进NSCLC细胞的进展。该研究还证明了TTI 1在NSCLC中的独立预后作用。TTI 1可能通过调节mTOR信号通路发挥作用。TTI 1和KI 67在NSCLC中的表达呈正相关，联合检测TTI 1和KI 67可作为预测NSCLC患者生存和复发的一个有价值的生物标志物。
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. Our study demonstrated for the first time that TTI1 could promote NSCLC cell proliferation, invasion and metastasis in vitro, and boost NSCLC cell progression in vivo. The study also demonstrated an independent prognostic role of TTI1 in NSCLC. In terms of mechanism, TTI1 could regulate the mTOR signaling pathway. The expression of TTI1 and KI67 had a positive correlation in NSCLC and combination of TTI1 and KI67 is a valuable biomarker for predicting the survival and recurrence of patients with NSCLC.
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