Yang Xiaowen, Shen Xinzhuang, Liu Zongjun, Li Yifei, Liu Hangchu, Zhan Yiting, Liu Yipeng, Liang Chengjin, Zhao Luping, Zhang Xiaoyuan, Huang Yongming, Shen Wenzhi
Cheeloo College of Medicine, Shandong University, Jinan, 250012, China.
Shandong Provincial Precision Medicine Laboratory for Chronic Non-communicable Diseases, Institute of Precision Medicine, Jining Medical University, Jining, 272067, China.
Int J Biol Sci. 2025 Jan 1;21(1):328-345. doi: 10.7150/ijbs.97920. eCollection 2025.
T-box transcription factor 21 (TBX21) plays a vital role in regulating immune responses, systemic diseases, and tumor progression. However, the role of TBX21 in colorectal cancer (CRC) metastasis remains unclear. In this study, we observed that TBX21 expression was marked decreased in CRC tissues compared to normal tissues and was negatively correlated with TNM stages. Interestingly, CRC and normal cell lines lacked TBX21 expression. Ectopic expression of TBX21 inhibited CRC cell migration and metastasis . Furthermore, a human phospho-kinase array analysis indicated that TBX21 expression reduced phosphorylation of glycogen synthase kinase 3 beta (GSK3β). RNA sequencing identified Rho GTPase activating protein 29 (ARHGAP29) and MYC target 1 (MYCT1) as potential TBX21-related target genes. TBX21 directly binds to the ARHGAP29 promoter to upregulate ARHGAP29, which, in turn, inhibits GSK3β phosphorylation. Concurrently, TBX21 promotes MYCT1 expression, leading to interaction with ZO-1 to regulate the cytoskeleton. Together, the ARHGAP29/GSK3β and MYCT1/ZO-1 pathways suppress CRC cell metastasis. Conversely, knockdown of TBX21, ARHGAP29, or MYCT1, or LiCl application, which enhances GSK3β phosphorylation, counteracted TBX21-mediated inhibition of CRC cell migration and . These findings suggest TBX21 suppresses CRC metastasis, identifying it as a potential target for metastatic cancer treatment.
T盒转录因子21（TBX21）在调节免疫反应、全身性疾病和肿瘤进展中起着至关重要的作用。然而，TBX21在结直肠癌（CRC）转移中的作用仍不清楚。在本研究中，我们观察到与正常组织相比，CRC组织中TBX21表达明显降低，且与TNM分期呈负相关。有趣的是，CRC和正常细胞系均缺乏TBX21表达。TBX21的异位表达抑制了CRC细胞的迁移和转移。此外，一项人类磷酸激酶阵列分析表明，TBX21表达降低了糖原合酶激酶3β（GSK3β）的磷酸化水平。RNA测序确定Rho GTP酶激活蛋白29（ARHGAP29）和MYC靶点1（MYCT1）为潜在的TBX21相关靶基因。TBX21直接与ARHGAP29启动子结合以上调ARHGAP29，进而抑制GSK3β磷酸化。同时，TBX21促进MYCT1表达，导致其与紧密连接蛋白1（ZO-1）相互作用以调节细胞骨架。总之，ARHGAP29/GSK3β和MYCT1/ZO-1途径抑制CRC细胞转移。相反，敲低TBX21、ARHGAP29或MYCT1，或应用增强GSK3β磷酸化的氯化锂，可抵消TBX21介导的对CRC细胞迁移的抑制作用。这些发现表明TBX21可抑制CRC转移，将其确定为转移性癌症治疗的潜在靶点。
