Department of Respiratory and Critical Care Medicine, The Second Affiliated Hospital of Shandong First Medical University, Taian, Shandong, 271000, China.
Department of Internal Medicine, Shandong Provincial Taishan Hospital, Taian, Shandong, 271000, China.
Cell Death Dis. 2024 Sep 30;15(9):698. doi: 10.1038/s41419-024-07075-w.
The incidence of lung cancer has become the highest among all cancer types globally, also standing as a leading cause of cancer-related deaths. Lung cancer is broadly divided into small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC), with the latter accounting for 85% of total cases. SRY-box transcription factor 4 (SOX4), a crucial transcription factor, has been found to play a key role in the development of various cancers. However, the association between SOX4 and NSCLC is still unclear. This study investigated the clinical relevance of SOX4 and its potential mechanisms in the progression of NSCLC. Analysis of our NSCLC patient cohort revealed a significant increase in SOX4 levels in cancerous tissues, indicating its role as an independent prognostic indicator for NSCLC. In vitro experiments demonstrated that elevated SOX4 expression facilitated NSCLC cell migration, invasion, and EMT. Functionally, SOX4 drives NSCLC progression by enhancing the transcription and expression of B-cell-specific moloney leukemia virus insertion site 1 (BMI1). The oncogenic impact of SOX4-induced BMI1 expression on NSCLC advancement was validated through both in vivo and in vitro studies. In addition, our findings showed that BMI1 promoted the ubiquitination of histone H2A (H2Aub), leading to decreased zinc finger protein 24 (ZNF24) expression, which subsequently triggered vascular endothelial growth factor A (VEGF-A) secretion in NSCLC cells, thereby promoting NSCLC angiogenesis. Moreover, we evaluated the therapeutic potential of a BMI1 inhibitor in combination with Bevacizumab for NSCLC treatment using orthotopic models. The data presented in our study reveal a previously unrecognized role of the SOX4-BMI1 axis in promoting NSCLC progression and angiogenesis. This research significantly contributes to our knowledge of the interplay between SOX4 and BMI1 in NSCLC, potentially paving the way for the development of targeted therapies for this disease.
肺癌的发病率已成为全球所有癌症类型中最高的，也是癌症相关死亡的主要原因。肺癌广泛分为小细胞肺癌（SCLC）和非小细胞肺癌（NSCLC），后者占总病例的 85%。性别决定区 Y 框转录因子 4（SOX4）是一种关键的转录因子，已被发现在各种癌症的发展中发挥关键作用。然而，SOX4 与 NSCLC 之间的关联尚不清楚。本研究探讨了 SOX4 的临床相关性及其在 NSCLC 进展中的潜在机制。对我们的 NSCLC 患者队列的分析表明，癌组织中 SOX4 水平显著升高，表明其作为 NSCLC 的独立预后指标。体外实验表明，升高的 SOX4 表达促进了 NSCLC 细胞的迁移、侵袭和 EMT。功能上，SOX4 通过增强 B 细胞特异性莫洛尼白血病病毒插入位点 1（BMI1）的转录和表达来驱动 NSCLC 进展。通过体内和体外研究验证了 SOX4 诱导的 BMI1 表达对 NSCLC 进展的致癌作用。此外，我们的研究结果表明，BMI1 促进组蛋白 H2A 的泛素化（H2Aub），导致锌指蛋白 24（ZNF24）表达减少，从而触发 NSCLC 细胞中血管内皮生长因子 A（VEGF-A）的分泌，进而促进 NSCLC 血管生成。此外，我们还评估了 BMI1 抑制剂联合贝伐单抗治疗 NSCLC 的疗效，使用原位模型进行了研究。我们的研究结果揭示了 SOX4-BMI1 轴在促进 NSCLC 进展和血管生成中的以前未被认识的作用。这项研究极大地丰富了我们对 SOX4 和 BMI1 在 NSCLC 中的相互作用的认识，为针对这种疾病的靶向治疗的发展提供了可能。
