Shi Qinlan, Huang Zhongting, Kuang Yeye, Wang Chan, Fang Xiao, Hu Xiaotong
Biomedical Research Center and Key Laboratory of Biotherapy of Zhejiang Province, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, 310016, China.
Department of Anesthesiology, Sir Run Shaw Hospital,, Zhejiang University, Hangzhou, China.
Cancer Cell Int. 2024 May 11;24(1):169. doi: 10.1186/s12935-024-03352-y.
Forkhead box E1 (FOXE1), also known as thyroid transcription factor 2 (TTF-2), belongs to a large family of forkhead transcription factors. It plays important roles in embryogenesis, cell growth, and differentiation. Cancer-specific FOXE1 hypermethylation events have been identified in several cancers. However, the expression and function of FOXE1 in the tumorigenesis of colorectal cancer remain still unknown. In this study, we examined FOXE1 expression and methylation in normal colon mucosa, colorectal cancer (CRC) cell lines, and primary tumors by immunohistochemistry, semi-quantitative RT-PCR, methylation-specific PCR, and bisulfite genomic sequencing. We found that FOXE1 was frequently methylated and silenced in CRC cell lines and was downregulated in CRC tissues compared with paired adjacent non-tumor tissues. Meanwhile, low FOXE1 expression was significantly correlated with lymph node metastasis and advanced TNM stages, indicating its potential as a tumor marker. Subsequently, we established colon cancer cell lines with stable FOXE1 expression to observe the biological effect on colorectal cancer, including cell growth, migration, actin cytoskeleton, and growth of human colorectal xenografts in nude mice. Ectopic expression of FOXE1 could suppress tumor cell growth and migration and affect the organization of the actin cytoskeleton together with suppressing tumorigenicity in vivo. FOXE1 methylation was frequently seen in association with a complete absence of or downregulated gene expression, and FOXE1 plays a suppressive role in the development and progression of colorectal cancer.
叉头框E1（FOXE1），也被称为甲状腺转录因子2（TTF-2），属于叉头转录因子的一个大家族。它在胚胎发生、细胞生长和分化中发挥着重要作用。在几种癌症中已发现了癌症特异性的FOXE1高甲基化事件。然而，FOXE1在结直肠癌发生中的表达和功能仍然未知。在本研究中，我们通过免疫组织化学、半定量逆转录-聚合酶链反应（RT-PCR）、甲基化特异性PCR和亚硫酸氢盐基因组测序，检测了正常结肠黏膜、结直肠癌细胞系和原发性肿瘤中FOXE1的表达和甲基化情况。我们发现，与配对的相邻非肿瘤组织相比，FOXE1在结直肠癌细胞系中频繁发生甲基化并沉默，在结直肠癌组织中表达下调。同时，低FOXE1表达与淋巴结转移和晚期TNM分期显著相关，表明其作为肿瘤标志物的潜力。随后，我们建立了稳定表达FOXE1的结肠癌细胞系，以观察其对结直肠癌的生物学效应，包括细胞生长、迁移、肌动蛋白细胞骨架以及裸鼠体内人结直肠癌异种移植瘤的生长。FOXE1的异位表达可抑制肿瘤细胞生长和迁移，影响肌动蛋白细胞骨架的组织，并在体内抑制肿瘤发生。FOXE1甲基化经常与基因表达完全缺失或下调相关，并且FOXE1在结直肠癌的发生和发展中起抑制作用。
