Department of E.N.T, Qingdao Jiaozhou Center Hospital, Qingdao, Shandong Province 266300, China.
Department of Otolaryngology, Zibo Central Hospital, Zibo, Shandong Province 255000, China.
Arch Oral Biol. 2024 Aug;164:105977. doi: 10.1016/j.archoralbio.2024.105977. Epub 2024 Apr 21.
The potentiation of glycolysis is a leading driver of squamous cell carcinoma. Targeted modulation of the glycolytic process might be a pivotal tool for treating squamous cell carcinoma. Tribble homolog 3 (TRIB3) expression is elevated in some squamous cell carcinomas and correlates with poor prognosis. We investigated whether increased TRIB3 expression contributes to the progression of oral squamous cell carcinoma (OSCC) by modulating glycolysis.
We analyzed the expression of TRIB3 in the TCGA database for clinical tissue samples, in vitro, and in vivo. Cell proliferation, migration, invasion, and apoptosis were observed by overexpressing or knocking down TRIB3. Crucially, the impact of TRIB3 on aerobic glycolysis in OSCC was also probed in our study, including glucose uptake, lactate content, ATP production, extracellular acidification rate, and oxygen consumption rate. Importantly, we examined the relationship between TRIB3 and the JNK/JUN pathway and whether it regulates glycolytic processes in OSCC cells through the JNK/JUN pathway. Finally, tumor growth in vivo was tested using Xenograft models to observe the effect of knockdown TRIB3.
Our study identified TRIB3 as the most variable and prognostic in OSCC. A significant high expression of TRIB3 in OSCC cells was determined in vitro and promoted cell proliferation, migration, invasion, apoptosis, and aerobic glycolysis. Knockdown of TRIB3 produced opposite effects. In addition, these effects are regulated by the JNK/JUN pathway. The use of JNK inhibitor inhibited the pro-growth and glycolytic effects of TRIB3 on OSCC cells. Finally, we further determined that TRIB3 knockdown would effectively suppress tumor growth in vivo.
This study reveals that TRIB3 promotes OSCC growth by regulating JNK/JUN pathway-mediated aerobic glycolysis, and TRIB3 may be a potential target for treating OSCC.
糖酵解的增强是鳞状细胞癌的主要驱动因素。靶向调节糖酵解过程可能是治疗鳞状细胞癌的关键工具。TRIB3 在一些鳞状细胞癌中的表达升高，与预后不良相关。我们研究了TRIB3 表达的增加是否通过调节糖酵解促进口腔鳞状细胞癌（OSCC）的进展。
我们分析了 TCGA 数据库中临床组织样本、体外和体内 TRIB3 的表达。通过过表达或敲低 TRIB3 观察细胞增殖、迁移、侵袭和凋亡。至关重要的是，我们还研究了 TRIB3 对 OSCC 中有氧糖酵解的影响，包括葡萄糖摄取、乳酸含量、ATP 生成、细胞外酸化率和耗氧量。重要的是，我们检查了 TRIB3 与 JNK/JUN 通路之间的关系，以及它是否通过 JNK/JUN 通路调节 OSCC 细胞中的糖酵解过程。最后，使用异种移植模型测试体内肿瘤生长，观察敲低 TRIB3 的效果。
我们的研究确定 TRIB3 是 OSCC 中最具变异性和预后性的。体外实验确定 OSCC 细胞中 TRIB3 表达显著升高，并促进细胞增殖、迁移、侵袭、凋亡和有氧糖酵解。敲低 TRIB3 则产生相反的效果。此外，这些作用受 JNK/JUN 通路调节。使用 JNK 抑制剂抑制了 TRIB3 对 OSCC 细胞的促生长和糖酵解作用。最后，我们进一步确定，TRIB3 敲低可有效抑制体内肿瘤生长。
本研究表明，TRIB3 通过调节 JNK/JUN 通路介导的有氧糖酵解促进 OSCC 生长，TRIB3 可能是治疗 OSCC 的潜在靶点。
