Gan Guifang, Zhou Xinxia, Zheng Qiaoping, Gao Xianfu, Chen Xu, Zhang Han, Liu Jinghao, Shi Zhaopeng, Chen Fuxiang
Shanghai Ninth People's Hospital, Department of Clinical Laboratory medicine, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, PR China; College of Health Science and Technology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, PR China.
Shanghai Ninth People's Hospital, Department of Clinical Laboratory medicine, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, PR China.
Transl Oncol. 2025 Feb;52:102278. doi: 10.1016/j.tranon.2025.102278. Epub 2025 Jan 11.
The specific role of 3-hydroxyanthranilic acid(3-HAA) in oral squamous cell carcinoma (OSCC) remains unclear. This study investigated the roles of 3-HAA in OSCC and the underlying mechanism.
The effects of 3-HAA on OSCC were examined using CCK-8, colony formation, EdU incorporation assays and xenograft mouse model. The underlying mechanisms were investigated with RNA-seq, apoptosis array and cell cycle array. Short hairpin RNAs (shRNAs) were used to knockdown the expression of growth arrest and DNA damage inducible alpha (GADD45A) in OSCC cells. CCK-8 and xenograft mouse model were employed to elucidate the role of GADD45A. The binding sites between GADD45A and Yin Yang 1(YY1) were determined using luciferase reporter assay.
3-HAA was selectively down-regulated in OSCC patients and the decreasing level intensified with pathological progression. Higher expression of kynurenine 3-monooxygenase (KMO) and kynureninase (KYNU), which can increase the content of 3-HAA, was associated with poorer prognosis of OSCC patients. Exogenous 3-HAA hampered growth of OSCC cells both in vitro and in vivo. 3-HAA induced growth arrest, G2/M-phase arrest, and apoptosis of OSCC cells. RNA-seq indicated that 3-HAA significantly increased GADD45A expression. 3-HAA promoted transcription of GADD45A by transcription factor YY1. Knockdown of GADD45A significantly reversed 3-HAA-induced growth inhibition of OSCC cells in vivo and in vitro.
3-HAA induced apoptosis and cell cycle arrest of OSCC cells via GADD45A, indicating that 3-HAA and GADD45A are potential therapeutic targets for OSCC.
3-羟基邻氨基苯甲酸（3-HAA）在口腔鳞状细胞癌（OSCC）中的具体作用尚不清楚。本研究调查了3-HAA在OSCC中的作用及其潜在机制。
使用CCK-8、集落形成、EdU掺入试验和异种移植小鼠模型检测3-HAA对OSCC的影响。通过RNA测序、凋亡阵列和细胞周期阵列研究潜在机制。使用短发夹RNA（shRNA）敲低OSCC细胞中生长停滞和DNA损伤诱导α（GADD45A）的表达。采用CCK-8和异种移植小鼠模型阐明GADD45A的作用。使用荧光素酶报告基因试验确定GADD45A与阴阳1（YY1）之间的结合位点。
OSCC患者中3-HAA选择性下调，且随着病理进展水平降低加剧。犬尿氨酸3-单加氧酶（KMO）和犬尿氨酸酶（KYNU）的高表达可增加3-HAA的含量，这与OSCC患者较差的预后相关。外源性3-HAA在体外和体内均阻碍OSCC细胞的生长。3-HAA诱导OSCC细胞生长停滞、G2/M期停滞和凋亡。RNA测序表明3-HAA显著增加GADD45A的表达。3-HAA通过转录因子YY1促进GADD45A的转录。敲低GADD45A可显著逆转3-HAA在体内和体外诱导的OSCC细胞生长抑制。
3-HAA通过GADD45A诱导OSCC细胞凋亡和细胞周期停滞，表明3-HAA和GADD45A是OSCC潜在的治疗靶点。
