Bellis Claire, Mlaza Mihlali V, Ali Abid, Abrahams Amaal, Prince Sharon
Division of Cell Biology, Department of Human Biology, Faculty of Health Sciences, University of Cape Town, Observatory, 7925, Cape Town, South Africa.
Biochem Soc Trans. 2025 Feb 6;53(1):BST20241069. doi: 10.1042/BST20241069.
During embryonic development, the T-box transcription factor TBX2 regulates key processes such as cell fate decisions, migration and tissue morphogenesis, and mutations that lead to reduced TBX2 levels result in developmental abnormalities including congenital heart and skeletal defects. TBX2, on the other hand, is overexpressed in a plethora of cancers where it functions as a powerful oncogene contributing to processes ranging from the bypass of senescence and cell death pathways to the promotion of cell proliferation, and epithelial-to-mesenchymal transition to drive invasion and metastasis. Additionally, TBX2 has been implicated in conferring resistance to anti-cancer drugs resulting in poor therapeutic outcomes. To exert its oncogenic functions, TBX2 transcriptionally represses key tumour suppressor genes involved in controlling cell proliferation and epithelial-to-mesenchymal transition such as p21Cip1, p14/p19ARF PTEN, NDRG1, CST6 and E-cadherin. This repression has been shown to involve complex mechanisms by which TBX2 co-opts transcription factors and recruits co-repression complexes to the promoters of these tumour suppressor genes. While limited information is available on how TBX2 is regulated in cancers, there is evidence that the levels and oncogenic functions of TBX2 are induced by developmental signalling pathways that are hijacked by cancer cells such as the Wnt/β-catenin and PI3K/AKT pathways. Understanding the complex molecular networks that TBX2 is involved in to exert its oncogenic functions is important because it may reveal potential therapeutic strategies for targeting TBX2 in TBX2-dependent cancers. This minireview discusses TBX2's involvement in cancer signalling, its regulatory partners, and its impact on cancer progression and resistance to therapy.
在胚胎发育过程中，T 盒转录因子 TBX2 调控细胞命运决定、迁移和组织形态发生等关键过程，导致 TBX2 水平降低的突变会引发包括先天性心脏和骨骼缺陷在内的发育异常。另一方面，TBX2 在多种癌症中过度表达，它作为一种强大的致癌基因发挥作用，参与从衰老和细胞死亡途径的绕过到细胞增殖促进、上皮-间质转化以驱动侵袭和转移等过程。此外，TBX2 与抗癌药物耐药性相关，导致治疗效果不佳。为发挥其致癌功能，TBX2 通过转录抑制参与控制细胞增殖和上皮-间质转化的关键肿瘤抑制基因，如 p21Cip1、p14/p19ARF、PTEN、NDRG1、CST6 和 E-钙黏蛋白。这种抑制已被证明涉及复杂机制，通过该机制 TBX2 协同转录因子并招募共抑制复合物到这些肿瘤抑制基因的启动子区域。虽然关于癌症中 TBX2 如何被调控的信息有限，但有证据表明 TBX2 的水平和致癌功能是由癌细胞劫持的发育信号通路诱导的，如 Wnt/β-连环蛋白和 PI3K/AKT 通路。了解 TBX2 参与发挥其致癌功能的复杂分子网络很重要，因为这可能揭示在依赖 TBX2 的癌症中靶向 TBX2 的潜在治疗策略。本综述讨论了 TBX2 在癌症信号传导中的作用、其调控伙伴以及它对癌症进展和治疗耐药性的影响。
