膀胱癌（BC）患者中存在肺转移，但是这代表着疾病的最高严重性和不良结局。BC肺转移的分子机制尚不完全清楚。成纤维细胞生长因子受体2（FGFR2）信号在BC细胞生长和侵袭中起重要作用。在本研究中，我们评估了表皮剪接调节蛋白（ESRP）对BC肺转移中FGFR2的可变剪接调控。通过比较BC与相邻的非肿瘤膀胱组织的基因谱，从GEO公共数据库中获取数据以分析不同的基因和通路水平。此外，我们也在我们自己的临床样本中分析了ESRP1或ESRP2与BC肺转移之间的关系。通过对BC细胞系T24和RT4的ESRP1或ESRP2表达变化对FGFR2 IIIb和IIIc可变剪接进行分析。FGFR2 IIIb和IIIc代表了上皮和间充质样剪切。通过采用荧光素和荧光标记标记的ESRP1/2改造的BC细胞移植到裸鼠体内进行活体检测，评估ESRP1或ESRP2对BC肺转移的影响。我们在BC样本数据库中检测到ESRP1和ESRP2的显著降低。此外，我们的样本分析也显示了ESRP1或ESRP2在BC中的强烈下调，后者在具有肺转移的病例中更为明显。体外实验表明，ESRP1或ESRP2表达量的变化会导致FGFR2 IIIb和IIIc的剪接转换，从而改变肿瘤细胞的生长和转移潜力。在体内实验中，重新表达ESRP1或ESRP2不仅抑制了裸鼠中异种移植瘤的生长，而且还通过改变肿瘤相关巨噬细胞的极性降低了肺转移的发生。因此，我们的数据表明，ESRP1或ESRP2的减少通过改变FGFR2剪接和巨噬细胞极化促进了BC的肺转移。版权所有©2023 Zhao, Li, Wu, Miao and Liu。

Lung metastasis occurs in parts of the bladder carcinoma (BC) patients but represents the highest severity and a poor outcome of the disease. The molecular mechanism underlying lung metastasis of BC is not fully understood. Fibroblast growth factor receptor 2 (FGFR2) signaling plays a substantial role in the BC cell growth and invasion. In this study, we assessed the regulation of the alternative splicing of FGFR2 by epithelial splicing regulatory proteins (ESRPs) in lung metastasis of BC.Gene profile of BC in comparison with adjacent non-tumor bladder tissue was obtained from GEO public database to analyze the levels of differentiated genes and pathways. Moreover, the association of ESRP1 or ESRP2 with lung metastasis of BC was analyzed on our own clinic samples. The effects of altered expression of ESRP1 or ESRP2 on alternative splicing of FGFR2 IIIb and IIIc, which represents epithelial and mesenchymal-like splicing, were analyzed on BC cell lines T24 and RT4. The in vivo effects of ESRP1 or ESRP2 on lung metastasis of BC were assessed in mice subcutaneously grafted with ESRP1/2-modified BC labeled with fluorescent and luciferase reporters.We detected significant reduction of ESRP1 and ESRP2 in BC in public database of BC specimens. Moreover, analysis on our own specimens also showed strong downregulation of ESRP1 or ESRP2 in BC, and the latter was more pronounced in cases with lung metastasis. In vitro, altered levels of ESRP1 or ESRP2 caused a switch of FGFR2 splicing between FGFR2-IIIb and FGFR2-IIIc, resulting in changes in tumor cell growth and metastatic potential. In vivo, re-expression of ESRP1 or ESRP2 in BC cells not only inhibited the growth of the xenografted tumor formation in nude mice, but also reduced the occurrence of lung metastasis, partially through altering polarization of tumor-associated macrophages.Our data thus suggest that reduction in ESRP1 or ESRP2 promotes lung metastasis of BC through altering FGFR2 splicing and macrophage polarization.Copyright © 2023 Zhao, Li, Wu, Miao and Liu.