信号转导子和转录激活子 3 (STAT3) 是一种转录因子，主要由酪氨酸 705 (Y705) 或丝氨酸 727 (S727) 残基的磷酸化激活，调节细胞分化、凋亡抑制或细胞存活等重要过程。 STAT3 的异常激活与近 50% 的人类癌症的发生有关，包括透明细胞肾细胞癌 (ccRCC)。事实上，phosho-S727 (pS727) 水平与 ccRCC 患者的总生存期相关。为了阐明 STAT3 磷酸化在 ccRCC 发育和进展中的作用，我们生成了携带 STAT3 Y705 和 S727 磷酸突变体的人源 ccRCC 细胞系。我们的数据表明，磷酸模拟取代 Ser727Asp 以不依赖 Y705 磷酸化的方式在体外促进促肿瘤表型。此外，我们描述了 STAT3 磷酸化状态决定了与不同生物过程相关的不同靶基因子集的表达，其中 pS727 依赖性基因与癌症的细胞特征最相关。总之，本研究首次分析了 STAT3 磷酸化状态在 ccRCC 中的作用，并证明 pS727 促进特定靶基因子集的表达，这些基因可能作为 ccRCC 的新型生物标志物和潜在治疗靶点具有临床相关性。© 2023。作者。

The signal transducer and activator of transcription 3 (STAT3) is a transcription factor mainly activated by phosphorylation in either tyrosine 705 (Y705) or serine 727 (S727) residues that regulates essential processes such as cell differentiation, apoptosis inhibition, or cell survival. Aberrant activation of STAT3 has been related to development of nearly 50% of human cancers including clear cell renal cell carcinoma (ccRCC). In fact, phosho-S727 (pS727) levels correlate with overall survival of ccRCC patients. With the aim to elucidate the contribution of STAT3 phosphorylation in ccRCC development and progression, we have generated human-derived ccRCC cell lines carrying STAT3 Y705 and S727 phosphomutants. Our data show that the phosphomimetic substitution Ser727Asp facilitates a pro-tumoral phenotype in vitro, in a Y705-phosphorylation-independent manner. Moreover, we describe that STAT3 phosphorylation state determines the expression of different subsets of target genes associated with distinct biological processes, being pS727-dependent genes the most related to cellular hallmarks of cancer. In summary, the present study constitutes the first analysis on the role of overall STAT3 phosphorylation state in ccRCC and demonstrates that pS727 promotes the expression of a specific subset of target genes that might be clinically relevant as novel biomarkers and potential therapeutic targets for ccRCC.© 2023. The Author(s).