鳞状或表皮样癌出现在复层上皮中，但也常见于肺的非表皮样上皮，其机制尚不清楚。一个研究不足的有丝分裂检查点驱动带有不可修复的遗传损伤的上皮细胞分化为表皮样细胞。我们进行了 RNA 测序基因搜索，以针对该反应的未知调节因子，并选择了 SUMO 调节蛋白 SENP2。 SENP2 表达的改变与某些类型的癌症有关。我们发现该蛋白质强烈定位于新鲜分离的人表皮细胞的有丝分裂纺锤体。用特定的 shRNA 沉默 SENP2 后，原代细胞迅速分化。同步上皮细胞中产生的 SENP2 缺失会导致有丝分裂进入和退出延迟以及染色体排列缺陷。这些结果有力地证明了 SENP2 在有丝分裂纺锤体中以及因此在控制分化中的重要作用。此外，在侵袭性肺癌的试点收集中，SENP2 的表达与免疫检查点生物标志物 PD-L1 呈负相关。一致地，对有丝分裂分化检查点没有反应的转移性头颈癌细胞对 SENP2 的消耗具有抵抗力。我们的结果确定 SENP2 是上皮细胞有丝分裂分化检查点的新型调节剂和上皮癌的潜在生物标志物。© 2024。作者。

Squamous or epidermoid cancer arises in stratified epithelia but also is frequent in the non-epidermoid epithelium of the lung by unclear mechanisms. A poorly studied mitotic checkpoint drives epithelial cells bearing irreparable genetic damage into epidermoid differentiation. We performed an RNA-sequencing gene search to target unknown regulators of this response and selected the SUMO regulatory protein SENP2. Alterations of SENP2 expression have been associated with some types of cancer. We found the protein to be strongly localised to mitotic spindles of freshly isolated human epidermal cells. Primary cells rapidly differentiated after silencing SENP2 with specific shRNAs. Loss of SENP2 produced in synchronised epithelial cells delays in mitotic entry and exit and defects in chromosomal alignment. The results altogether strongly argue for an essential role of SENP2 in the mitotic spindle and hence in controlling differentiation. In addition, the expression of SENP2 displayed an inverse correlation with the immuno-checkpoint biomarker PD-L1 in a pilot collection of aggressive lung carcinomas. Consistently, metastatic head and neck cancer cells that do not respond to the mitosis-differentiation checkpoint were resistant to depletion of SENP2. Our results identify SENP2 as a novel regulator of the epithelial mitosis-differentiation checkpoint and a potential biomarker in epithelial cancer.© 2024. The Author(s).