Khan Saif F, Burmeister Carly A, Scott David J, Sinkala Musalula, Ramburan Amsha, Wu Hue-Tsi, Schäfer Georgia, Katz Arieh A, Prince Sharon
Department of Human Biology, Faculty of Health Sciences, University of Cape Town, Observatory, Cape Town, South Africa.
Department of Integrative Biomedical Sciences, Faculty of Health Sciences, University of Cape Town, Observatory, Cape Town, South Africa.
Mol Cancer Res. 2023 Apr 1;21(4):345-358. doi: 10.1158/1541-7786.MCR-22-0598.
Cervical cancer is a leading cause of cancer-related deaths in women globally and 99% of cases are caused by persistent infection with high-risk strains of the human papillomavirus (HPV). The HPV oncoproteins E6 and E7 establish the cancer phenotype by cooperating with host proteins and identifying them may have important therapeutic benefits. T-box transcription factor 3 (TBX3) is a critical developmental regulator, and when it is overexpressed postnatally, it contributes to several cancers, but little is known about its expression and role in cervical cancer. The current study shows that TBX3 is upregulated in cervical cancer cell lines as well as precancerous and cervical cancer patient tissue and is associated with larger and more invasive tumors. Knockdown and overexpression cell culture models show that TBX3 promotes HPV-positive cell proliferation, migration, and spheroid growth; however, TBX3 inhibits these processes in HPV-negative cells. Importantly, we show that the tumor promoting activity of TBX3 in cervical cancer is dependent on E6/E7.
In summary, our study highlights the importance of TBX3 as a cooperating partner of E6/E7 in HPV-positive cervical cancer and identifies TBX3 as a potential therapeutic target to treat this neoplasm.
宫颈癌是全球女性癌症相关死亡的主要原因，99%的病例是由高危型人乳头瘤病毒（HPV）持续感染引起的。HPV癌蛋白E6和E7通过与宿主蛋白协同作用建立癌症表型，识别它们可能具有重要的治疗益处。T盒转录因子3（TBX3）是一种关键的发育调节因子，出生后过度表达时，它会导致多种癌症，但对其在宫颈癌中的表达和作用知之甚少。当前研究表明，TBX3在宫颈癌细胞系以及癌前和宫颈癌患者组织中上调，并且与更大、更具侵袭性的肿瘤相关。敲低和过表达细胞培养模型表明，TBX3促进HPV阳性细胞的增殖、迁移和球体生长；然而，TBX3在HPV阴性细胞中抑制这些过程。重要的是，我们表明TBX3在宫颈癌中的促肿瘤活性依赖于E6/E7。
总之，我们的研究强调了TBX3作为HPV阳性宫颈癌中E6/E7协同伙伴的重要性，并将TBX3确定为治疗这种肿瘤的潜在治疗靶点。
