Department of Surgery, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119228, Singapore.
School of Engineering, Biomedical Engineering, Temasek Polytechnic, Singapore 529757, Singapore.
Int J Mol Sci. 2024 Aug 16;25(16):8947. doi: 10.3390/ijms25168947.
Glutathione-S-transferases (GST) enzymes detoxify xenobiotics and are implicated in response to anticancer therapy. This study evaluated the association of GST theta 1 (GSTT1), GSTT2, and GSTT2B with Mycobacterium bovis Bacillus Calmette-Guérin (BCG) response in non-muscle-invasive bladder cancer treatment. In vitro assessments of GSTT2 knockout (KO) effects were performed using cell lines and dendritic cells (DCs) from GSTT2KO mice. Deletion of GSTT2B, GSTT1, and single-nucleotide polymorphisms in the promoter region of GSTT2 was analysed in patients ( = 205) and healthy controls ( = 150). Silencing GSTT2 expression in MGH cells (GSTT2B) resulted in increased BCG survival ( < 0.05) and decreased cellular reactive oxygen species. In our population, there are 24.2% with GSTT2B and 24.5% with GSTT2B. With ≤ 8 instillations of BCG therapy ( = 51), 12.5% of GSTT2B and 53.8% of GSTT2B patients had a recurrence ( = 0.041). With ≥9 instillations ( = 153), the disease recurred in 45.5% of GSTT2B and 50% of GSTT2B. GSTT2 patients had an increased likelihood of recurrence post-BCG therapy (HR 5.5 [1.87-16.69] < 0.002). DCs from GSTT2KO mice produced three-fold more IL6 than wild-type DCs, indicating a robust inflammatory response. To summarise, GSTT2B patients respond better to less BCG therapy and could be candidates for a reduced surveillance regimen.
谷胱甘肽 S-转移酶（GST）酶可以解毒异源物质，并与抗癌治疗的反应有关。本研究评估了 GST theta 1（GSTT1）、GSTT2 和 GSTT2B 与牛分枝杆菌卡介苗（BCG）在非肌肉浸润性膀胱癌治疗中的反应之间的关联。使用 GSTT2KO 小鼠的细胞系和树突状细胞（DC）进行 GSTT2 敲除（KO）效应的体外评估。在患者（=205）和健康对照组（=150）中分析 GSTT2B、GSTT1 和 GSTT2 启动子区域的单核苷酸多态性缺失。在 MGH 细胞（GSTT2B）中沉默 GSTT2 表达导致 BCG 存活增加（<0.05）和细胞内活性氧减少。在我们的人群中，有 24.2%的人携带 GSTT2B，24.5%的人携带 GSTT2B。在接受 ≤ 8 次 BCG 治疗（=51）的患者中，GSTT2B 的 12.5%和 GSTT2B 的 53.8%患者出现复发（=0.041）。接受 ≥9 次治疗（=153）的患者中，GSTT2B 的 45.5%和 GSTT2B 的 50%患者疾病复发。GSTT2 患者在接受 BCG 治疗后复发的可能性增加（HR 5.5 [1.87-16.69] <0.002）。来自 GSTT2KO 小鼠的 DC 比野生型 DC 产生三倍的 IL6，表明存在强烈的炎症反应。总之，GSTT2B 患者对较少的 BCG 治疗反应更好，可能是减少监测方案的候选者。
