Su Shuang, Wu Lili, Huang Chen, He Cuiying, Wang Lianjing, Li Weijing, Liu Wei, Liu Lihong
Department of Hematology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, 050011, China.
Hebei Provincial Key Laboratory of Tumor Microenvironment and Drug Resistance, The Fourth Hospital of Hebei Medical University, Shijiazhuang, 050011, China.
Discov Oncol. 2025 Apr 9;16(1):499. doi: 10.1007/s12672-025-02264-1.
This study analyzes the expression and functional role of activating transcription factor 6 (ATF6) in diffuse large B-cell lymphoma (DLBCL) and its effects on disease progression. ATF6, a core component of the unfolded protein response (UPR) pathway, participates in many cellular activities and notably contributes to tumorigenesis. Through a combination of techniques, including immunohistochemistry (IHC) staining to assess ATF6 and pS6K levels, siRNA-mediated ATF6 knockdown, cytotoxicity assays, flow cytometry, quantitative real-time PCR (qRT-PCR), as well as Western blotting, this study clarified the functioning mechanisms of ATF6 in DLBCL and its potential clinical relevance. Further exploration of ATF6's involvement in the mTORC1 pathway was achieved through RNA sequencing (RNA-seq) and gene set enrichment analysis (GSEA). Our findings demonstrate that ATF6 expression is upregulated in DLBCL and linked to poor prognosis, particularly in people aged over 60 with Ann Arbor stage III-IV disease, B symptoms, non-GCB subtype, an international prognostic index (IPI) score greater than 2, and extranodal involvement. Notably, the ATF6 inhibitor ceapinA7 was shown to suppress ATF6 and mTORC1 activation, leading to less cell proliferation and the induction of apoptosis in DLBCL cells. Additionally, ceapinA7 increased the sensitivity of DLBCL cells to adriamycin. The foregoing results underscore the critical role of ATF6 in DLBCL and lay a theoretical and experimental foundation for future targeted therapies and drug development aimed at improving treatment outcomes for DLBCL.
本研究分析了激活转录因子6（ATF6）在弥漫性大B细胞淋巴瘤（DLBCL）中的表达及功能作用，及其对疾病进展的影响。ATF6作为未折叠蛋白反应（UPR）途径的核心组成部分，参与多种细胞活动，尤其在肿瘤发生过程中发挥重要作用。通过免疫组织化学（IHC）染色评估ATF6和pS6K水平、小干扰RNA（siRNA）介导的ATF6敲低、细胞毒性测定、流式细胞术、定量实时聚合酶链反应（qRT-PCR）以及蛋白质免疫印迹等多种技术的结合，本研究阐明了ATF6在DLBCL中的作用机制及其潜在的临床相关性。通过RNA测序（RNA-seq）和基因集富集分析（GSEA）进一步探索了ATF6在哺乳动物雷帕霉素靶蛋白复合物1（mTORC1）途径中的参与情况。我们的研究结果表明，ATF6在DLBCL中的表达上调，且与预后不良相关，特别是在年龄超过60岁、Ann Arbor分期为III-IV期、有B症状、非生发中心B细胞（GCB）亚型、国际预后指数（IPI）评分大于2以及有结外受累的患者中。值得注意的是，ATF6抑制剂ceapinA7可抑制ATF6和mTORC1的激活，导致DLBCL细胞增殖减少并诱导其凋亡。此外，ceapinA7增加了DLBCL细胞对阿霉素的敏感性。上述结果强调了ATF6在DLBCL中的关键作用，为未来旨在改善DLBCL治疗效果的靶向治疗和药物开发奠定了理论和实验基础。
