Department of Hepatobiliary Pancreatic Vascular Surgery, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, No 55 Zhenhai Road, Xiamen, 361003, Fujian, China.
Funct Integr Genomics. 2024 Sep 18;24(5):163. doi: 10.1007/s10142-024-01429-5.
Cellular proto-oncogene C-Fos forms the AP-1 transcription factor by dimerizing with proto-oncogene c-Jun; this factor upregulates the transcription of genes associated with different malignancies. However, its functions in pancreatic adenocarcinoma (PAAD) remain poorly understood. In this study, the c-Fos was increased in PAAD cells and tissues through bioinformatic analysis, RT-PCR, and WB. In two PAAD cell lines, PANC-1 and BxPC-3, we performed c-Fos knockdown studies using short hairpin RNA (shRNA). Functional analysis indicated that c-Fos depletion in PAAD cells inhibits cell proliferation and promotes ferroptosis. Chromatin Immunoprecipitation (ChIP) and Dual-luciferase experiments showed that c-Fos coupled to the promoter region of SLC7A11 stimulated its transcription, providing mechanistic insight into the process. Moreover, SLC7A11 blocked the decline of proliferation and ferroptosis by c-Fos knockdown in PAAD cells. Furthermore, a xenograft nude mouse model was established to study the impact of c-Fos on tumorigenesis in vivo. Depletion of c-Fos could suppress PC tumor growth and the expressions of SLC7A11, ki-67, and 4HNE, but overexpression of SLC7A11 reversed this process. In summary, our investigation has shown that c-Fos acts as a transcriptional regulator of SLC7A11, which may enhance tumour growth in pancreatic cancer by inhibiting ferroptosis. These results indicate that c-Fos might be a promising target for treating ferroptosis in PAAD.
细胞原癌基因 C-Fos 通过与原癌基因 c-Jun 二聚化形成 AP-1 转录因子；该因子上调与不同恶性肿瘤相关的基因转录。然而，其在胰腺导管腺癌（PAAD）中的功能仍知之甚少。在这项研究中，通过生物信息学分析、RT-PCR 和 WB 发现 PAAD 细胞和组织中 C-Fos 增加。在两种 PAAD 细胞系 PANC-1 和 BxPC-3 中，我们使用短发夹 RNA（shRNA）进行了 C-Fos 敲低研究。功能分析表明，PAAD 细胞中 C-Fos 的缺失抑制细胞增殖并促进铁死亡。染色质免疫沉淀（ChIP）和双荧光素酶实验表明，C-Fos 与 SLC7A11 启动子区域结合，刺激其转录，为该过程提供了机制上的见解。此外，SLC7A11 通过阻断 PAAD 细胞中 C-Fos 敲低引起的增殖和铁死亡下降。此外，建立了异种移植裸鼠模型以研究 c-Fos 在体内对肿瘤发生的影响。c-Fos 的缺失可以抑制 PC 肿瘤的生长和 SLC7A11、ki-67 和 4HNE 的表达，但 SLC7A11 的过表达逆转了这一过程。总之，我们的研究表明，C-Fos 作为 SLC7A11 的转录调节剂发挥作用，通过抑制铁死亡可能增强胰腺癌中的肿瘤生长。这些结果表明，c-Fos 可能是治疗 PAAD 中铁死亡的有前途的靶点。
