背景:胰腺癌(PC)的特征是预后不良和治疗选择有限。Ferroptosis在癌症中起着重要作用,含有SET和MYND结构域的蛋白2(SMYD2)在各种癌症中广泛表达。然而,SMYD2在调节PC铁凋亡中的作用仍未被探索。本研究旨在探讨SMYD2在介导铁凋亡中的作用及其在PC进展中的机制意义。
方法:SMYD2,c-Myc,和NCOA4在PC组织中进行评估,和肿瘤周围组织。在人PC细胞系中进一步分析SMYD2表达。在BxPC3细胞,c-Myc的表达,NCOA4,自噬相关蛋白,和线粒体形态,在用si-SMYD2转染并用自噬抑制剂和铁凋亡抑制剂处理后进行评估。使用流式细胞术和ELISA测定定量铁凋亡水平。进行RNA免疫沉淀以阐明c-Myc和NCOA4mRNA之间的相互作用。构建异种移植小鼠模型以验证SMYD2敲低对PC生长的影响。
结果:发现SMYD2和c-Myc在PC组织中高表达,而NCOA4显示表达降低。在研究的PC细胞系中,BxPC3细胞表现出最高的SMYD2表达。SMYD2敲除导致c-Myc水平降低,NCOA4表达增加,自噬相关蛋白表达减少,线粒体收缩,铁中毒水平升高。此外,确定了c-Myc和NCOA4之间的相互作用。在体内,SMYD2敲低抑制肿瘤生长。
结论:靶向SMYD2通过c-Myc/NCOA4轴促进铁蛋白吞噬依赖性铁凋亡抑制PC进展。这些发现为PC的潜在诊断和治疗策略提供了见解。
BACKGROUND: Pancreatic cancer (PC) is characterized by a poor prognosis and limited treatment options. Ferroptosis plays an important role in cancer, SET and MYND domain-containing protein 2 (SMYD2) is widely expressed in various cancers. However, the role of
SMYD2 in regulating ferroptosis in PC remains unexplored. This study aimed to investigate the role of SMYD2 in mediating ferroptosis and its mechanistic implications in PC progression.
METHODS: The levels of SMYD2, c-Myc, and NCOA4 were assessed in PC tissues, and peritumoral tissues.
SMYD2 expression was further analyzed in human PC cell lines. In BxPC3 cells, the expression of c-Myc, NCOA4, autophagy-related proteins, and mitochondrial morphology, was evaluated following transfection with si-SMYD2 and treatment with autophagy inhibitors and ferroptosis inhibitors. Ferroptosis levels were quantified using flow cytometry and ELISA assays. RNA immunoprecipitation was conducted to elucidate the interaction between c-Myc and NCOA4 mRNA. A xenograft mouse model was constructed to validate the impact of
SMYD2 knockdown on PC growth.
RESULTS: SMYD2 and c-Myc were found to be highly expressed in PC tissues, while NCOA4 showed reduced expression. Among the PC cell lines studied, BxPC3 cells exhibited the highest
SMYD2 expression. SMYD2 knockdown led to decreased c-Myc levels, increased NCOA4 expression, reduced autophagy-related protein expression, mitochondrial shrinkage, and heightened ferroptosis levels. Additionally, an interaction between c-Myc and NCOA4 was identified. In vivo,
SMYD2 knockdown inhibited tumor growth.
CONCLUSIONS: Targeting SMYD2 inhibits PC progression by promoting ferritinophagy-dependent ferroptosis through the c-Myc/NCOA4 axis. These findings provide insights into potential diagnostic and therapeutic strategies for PC.