Centre for Mechanochemical Cell Biology, Warwick Medical School, University of Warwick, Gibbet Hill Road, Coventry, CV4 7AL, UK.
Centre for Mechanochemical Cell Biology, Warwick Medical School, University of Warwick, Gibbet Hill Road, Coventry, CV4 7AL, UK
Open Biol. 2017 Aug;7(8). doi: 10.1098/rsob.170080.
Fibroblast growth factor receptor 3-transforming acidic coiled-coil containing protein 3 (FGFR3-TACC3; FT3) is a gene fusion resulting from rearrangement of chromosome 4 that has been identified in many cancers including those of the urinary bladder. Altered FGFR3 signalling in FT3-positive cells is thought to contribute to cancer progression. However, potential changes in TACC3 function in these cells have not been explored. TACC3 is a mitotic spindle protein required for accurate chromosome segregation. Errors in segregation lead to aneuploidy, which can contribute to cancer progression. Here we show that FT3-positive bladder cancer cells have lower levels of endogenous TACC3 on the mitotic spindle, and that this is sufficient to cause mitotic defects. FT3 is not localized to the mitotic spindle, and by virtue of its TACC domain, recruits endogenous TACC3 away from the spindle. Knockdown of the fusion gene or low-level overexpression of TACC3 partially rescues the chromosome segregation defects in FT3-positive bladder cancer cells. This function of FT3 is specific to TACC3 as inhibition of FGFR3 signalling does not rescue the TACC3 level on the spindle in these cancer cells. Models of FT3-mediated carcinogenesis should, therefore, include altered mitotic functions of TACC3 as well as altered FGFR3 signalling.
成纤维细胞生长因子受体 3 转化酸性卷曲螺旋蛋白 3（FGFR3-TACC3；FT3）是一种基因融合，源于染色体 4 的重排，已在包括膀胱癌在内的许多癌症中被发现。FT3 阳性细胞中 FGFR3 信号的改变被认为有助于癌症的进展。然而，这些细胞中 TACC3 功能的潜在变化尚未被探索。TACC3 是一种有丝分裂纺锤体蛋白，对于准确的染色体分离是必需的。分离错误会导致非整倍体，这可能会促进癌症的进展。在这里，我们发现 FT3 阳性膀胱癌细胞在有丝分裂纺锤体上的内源性 TACC3 水平较低，这足以导致有丝分裂缺陷。FT3 不在有丝分裂纺锤体上定位，并且通过其 TACC 结构域，将内源性 TACC3 从纺锤体上招募下来。融合基因的敲低或 TACC3 的低水平过表达部分挽救了 FT3 阳性膀胱癌细胞的染色体分离缺陷。FT3 的这种功能是特异性针对 TACC3 的，因为抑制 FGFR3 信号不会挽救这些癌细胞中纺锤体上的 TACC3 水平。因此，FT3 介导的致癌作用模型应该包括 TACC3 的有丝分裂功能改变以及 FGFR3 信号的改变。
