PP2A B55α 由 PPP2R2A 编码，充当丝氨酸/苏氨酸磷酸酶 PP2A 的调节亚基。尽管在非小细胞肺癌 (NSCLC) 病例中 PPP2R2A 杂合性经常丢失，但对 PP2A B55α 功能的研究仍然有限且存在争议。为了研究 PP2A B55α 的生物学作用，我们进行了批量 RNA 测序，以评估在 NSCLC 细胞系中使用两种 shRNA 敲低 PPP2R2A 的影响。 RNA 测序数据的基因集富集分析 (GSEA) 揭示了上皮间质转化 (EMT) 途径的显着富集，其中 SNAI2（编码 Slug 的基因）成为最重要的候选者之一。我们的研究结果表明，PP2A B55α 抑制 EMT，因为 PPP2R2A 缺陷通过敲低或纯合或半合子缺失促进 NSCLC 细胞的 EMT 和转移行为，EMT 生物标志物、侵袭和迁移能力以及尾静脉测定中的转移的变化证明了这一点。从机制上讲，PP2A B55α 通过 GSK3β-β-连环蛋白途径下调 SNAI2 表达来抑制 EMT。重要的是，PPP2R2A 缺陷还会通过破坏 DNA 复制来减缓细胞增殖，特别是在 PPP2R2A-/- 细胞中。此外，PPP2R2A 缺陷，尤其是 PPP2R2A-/- 细胞，会导致癌症干细胞群增加，这与化疗耐药性增强相关。总体而言，由于半合子/纯合子缺失导致 PP2A B55α 水平降低，尽管其增殖不利，但仍增强了 NSCLC 细胞的 EMT 和转移或干性/耐药性潜力。我们的研究强调了 PP2A B55α 在 EMT 和转移中的重要性，并表明针对 EMT/干性可能是治疗 PPP2R2A 缺陷的 NSCLC 的潜在治疗策略。版权所有 © 2024。由 Elsevier B.V. 出版。

PP2A B55α, encoded by PPP2R2A, acts as a regulatory subunit of the serine/threonine phosphatase PP2A. Despite a frequent loss of heterozygosity of PPP2R2A in cases of non-small cell lung cancer (NSCLC), research on PP2A B55α's functions remains limited and controversial. To investigate the biological roles of PP2A B55α, we conducted bulk RNA-sequencing to assess the impact of PPP2R2A knockdown using two shRNAs in a NSCLC cell line. Gene set enrichment analysis (GSEA) of the RNA-sequencing data revealed significant enrichment of the epithelial-mesenchymal transition (EMT) pathway, with SNAI2 (the gene encoding Slug) emerging as one of the top candidates. Our findings demonstrate that PP2A B55α suppresses EMT, as PPP2R2A deficiency through knockdown or homozygous or hemizygous depletion promotes EMT and metastatic behavior in NSCLC cells, as evidenced by changes in EMT biomarkers, invasion and migration abilities, as well as metastasis in a tail vein assay. Mechanistically, PP2A B55α inhibits EMT by downregulating SNAI2 expression via the GSK3β-β-catenin pathway. Importantly, PPP2R2A deficiency also slows cell proliferation by disrupting DNA replication, particularly in PPP2R2A-/- cells. Furthermore, PPP2R2A deficiency, especially PPP2R2A-/- cells, leads to an increase in the cancer stem cell population, which correlates with enhanced resistance to chemotherapy. Overall, the decrease in PP2A B55α levels due to hemizygous/homozygous depletion heightens EMT and the metastatic or stemness/drug resistance potential of NSCLC cells despite their proliferation disadvantage. Our study highlights the significance of PP2A B55α in EMT and metastasis and suggests that targeting EMT/stemness could be a potential therapeutic strategy for treating PPP2R2A-deficient NSCLC.Copyright © 2024. Published by Elsevier B.V.