Department of Radiation Oncology, Huaian Hospital of Huaian City, Huaian, 223299, Jiangsu, China.
Department of Radiation Oncology, Huaian Cancer Hospital, Huaian, 223299, Jiangsu, China.
Mol Med. 2024 Oct 28;30(1):192. doi: 10.1186/s10020-024-00962-0.
Esophageal Squamous Cell Carcinoma (ESCC) remains a predominant health concern in the world, characterized by high prevalence and mortality rates. Advances in single-cell transcriptomics have revolutionized cancer research by enabling a precise dissection of cellular and molecular diversity within tumors.
This study aims to elucidate the cellular dynamics and molecular mechanisms in ESCC, focusing on the transcriptional influence of STAT3 (Signal Transducer and Activator of Transcription 3) and its interaction with LHPP, thereby uncovering potential therapeutic targets.
Single-cell RNA sequencing was employed to analyze 44,206 cells from tumor and adjacent normal tissues of ESCC patients, identifying distinct cell types and their transcriptional shifts. We conducted differential gene expression analysis to assess changes within the tumor microenvironment (TME). Validation of key regulatory interactions was performed using qPCR in a cohort of 21 ESCC patients and further substantiated through experimental assays in ESCC cell lines.
The study revealed critical alterations in cell composition and gene expression across identified cell populations, with a notable shift towards pro-tumorigenic states. A significant regulatory influence of STAT3 on LHPP was discovered, establishing a novel aspect of ESCC pathogenesis. Elevated levels of STAT3 and suppressed LHPP expression were validated in clinical samples. Functional assays confirmed that STAT3 directly represses LHPP at the promoter level, and disruption of this interaction by promoter mutations diminished STAT3's repressive effect.
This investigation underscores the central role of STAT3 as a regulator in ESCC, directly impacting LHPP expression and suggesting a regulatory loop crucial for tumor behavior. The insights gained from our comprehensive cellular and molecular analysis offer a deeper understanding of the dynamics within the ESCC microenvironment. These findings pave the way for targeted therapeutic interventions focusing on the STAT3-LHPP axis, providing a strategic approach to improve ESCC management and prognosis.
食管鳞状细胞癌（ESCC）仍然是全球主要的健康关注点，其具有高患病率和死亡率的特点。单细胞转录组学的进步通过精确解析肿瘤内细胞和分子多样性，彻底改变了癌症研究。
本研究旨在阐明 ESCC 中的细胞动态和分子机制，重点关注 STAT3（信号转导和转录激活因子 3）的转录影响及其与 LHPP 的相互作用，从而揭示潜在的治疗靶点。
采用单细胞 RNA 测序分析 44206 例 ESCC 患者肿瘤和相邻正常组织中的细胞，鉴定不同的细胞类型及其转录变化。我们进行了差异基因表达分析，以评估肿瘤微环境（TME）内的变化。在 21 例 ESCC 患者的队列中通过 qPCR 验证关键调节相互作用，并通过 ESCC 细胞系中的实验进一步证实。
研究揭示了在鉴定的细胞群体中细胞组成和基因表达的关键变化，向促肿瘤状态的显著转变。发现 STAT3 对 LHPP 具有显著的调节影响，确立了 ESCC 发病机制的新方面。在临床样本中验证了 STAT3 和 LHPP 表达的升高。功能测定证实 STAT3 直接在启动子水平上抑制 LHPP，并且启动子突变破坏这种相互作用会减弱 STAT3 的抑制作用。
本研究强调了 STAT3 作为 ESCC 调节因子的核心作用，直接影响 LHPP 的表达，并提示肿瘤行为的关键调节环。我们全面的细胞和分子分析提供了对 ESCC 微环境动态的更深入理解。这些发现为针对 STAT3-LHPP 轴的靶向治疗干预铺平了道路，为改善 ESCC 管理和预后提供了一种策略方法。
