Zhou Cancan, Feng Zhengyuan, Qian Weikun, Zhu Zeen, Cao Ruiqi, Wang Qiqi, Zhang Wunai, Liu Rujuan, Wu Shuai, Hao Jie, Wang Zheng, Ma Qingyong, Wu Zheng, Li Xuqi
Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, 277 West Yanta Road, Xi'an, Shaanxi, 710061, China.
Pancreas Center, Xi'an Jiaotong University, Xi'an, Shaanxi, 710061, China.
Biol Direct. 2025 Jan 14;20(1):6. doi: 10.1186/s13062-025-00595-1.
Pancreatic cancer is a lethal disease with an insidious onset, and little is known about its early molecular events. Here, we found that the sterol regulatory element-binding protein 1 (SREBP1) expression is gradually upregulated during the initiation of pancreatic cancer. Through in vitro 3D culture of pancreatic acinar cells and experiments in LSL-Kras;Pdx1-Cre (KC) mice, we found that pharmacological inhibition of SREBP1 suppressed pancreatic tumorigenesis. In vitro, either knockdown or pharmacological inhibition of SREBP1 suppressed tumor proliferation but SREBP1 overexpression promoted tumor proliferation. In LSL-Kras;Trp53;Pdx1-Cre (KPC) mice, we confirmed the tumor-promoting role of SREBP1 in pancreatic cancer progression. Mechanistically, we revealed SOX9 as a downstream target of SREPB1. SREBP1 inhibition decreased SOX9 expression in both acinar cells and pancreatic cancer cells. Indeed, we identified SREBP1 binding sites in the SOX9 promoter region and reported that SOX9 is transcriptionally regulated by SREBP1. Taken together, our findings demonstrate that SREBP1/SOX9 inhibition suppresses pancreatic cancer initiation and growth, suggesting that SREBP1 could serve as a potential target for cancer screening and treatment.
胰腺癌是一种起病隐匿的致命疾病，人们对其早期分子事件知之甚少。在此，我们发现固醇调节元件结合蛋白1（SREBP1）的表达在胰腺癌起始过程中逐渐上调。通过胰腺腺泡细胞的体外三维培养以及在LSL-Kras;Pdx1-Cre（KC）小鼠中的实验，我们发现对SREBP1的药理学抑制可抑制胰腺肿瘤发生。在体外，敲低或药理学抑制SREBP1均可抑制肿瘤增殖，而SREBP1过表达则促进肿瘤增殖。在LSL-Kras;Trp53;Pdx1-Cre（KPC）小鼠中，我们证实了SREBP1在胰腺癌进展中的促肿瘤作用。从机制上讲，我们揭示了SOX9是SREPB1的下游靶点。SREBP1抑制降低了腺泡细胞和胰腺癌细胞中SOX9的表达。实际上，我们在SOX9启动子区域鉴定到了SREBP1结合位点，并报道SOX9受SREBP1转录调控。综上所述，我们的研究结果表明，抑制SREBP1/SOX9可抑制胰腺癌的起始和生长，这表明SREBP1可作为癌症筛查和治疗的潜在靶点。
