Yang Pengjie, Zhu Benben, Cui Hongwei, Yu Yongjun, Yu Qin, Kong Linghui, Sun Mengfei, Liu Yuan, Han Bateer, Chen Shuchen
Department of Thoracic Surgery, Fujian Medical University Union Hospital, Fuzhou, Fujian Province, P.R. China.
Department of Thoracic Surgery, Peking University Cancer Hospital (Inner Mongolia Campus)/Affiliated Cancer Hospital of Inner Mongolia Medical University, Hohhot, Inner Mongolia Autonomous Region, P.R. China.
Cell Death Dis. 2025 May 31;16(1):425. doi: 10.1038/s41419-025-07709-7.
Kruppel-Like Factor 13 (KLF13) has strong effects on cancer occurrence and progression. Nevertheless, the role of KLF13 in oesophagal cancer (EC) remain elusive. In this study, we detected the expression of KLF13 in EC tissues and cells using immunohistochemistry, western blot, and real-time PCR, and found that KLF13 was upregulated in EC tissues and cells compared to normal controls. High expression of KLF13 indicated a poor prognosis for EC patients. Further, function studies in vitro and in vivo were performed to explore the role of KLF13 in EC cell progression. The results revealed that KLF13 knockdown suppressed EC cell proliferation, migration, epithelial-mesenchymal transition, increased cell apoptosis and cell cycle arrest in vivo and inhibited tumour growth in vitro. Conversely, KLF13 overexpression in EC cells had the opposite consequences. Mechanically, differentially expressed genes downstream of KLF13 were identified by RNA-seq and ChIP-seq. We found that there is a positive correlation between triacylglyceride and free fatty acid levels and KLF13 expression levels. A lipid-related gene, Glycosylphosphatidylinositol anchored high density lipoprotein binding protein 1 (GPIHBP1), was identified as a downstream gene of KLF13 using luciferase and chromatin immunoprecipitation assays, whose expression was positively regulated by KLF13. Finally, in vitro and in vivo recovery assays using shRNAs and overexpression plasmids confirmed that KLF13 has an oncogenic role in EC progression through GPIHBP1. Collectively, KLF13 can promote EC progression, triacylglyceride and free fatty acid metabolism through GPIHBP1. Therefore, molecular therapies targeting KLF13 and GPIHBP1 may be effective treatments against EC.
Kruppel样因子13（KLF13）对癌症的发生和发展具有显著影响。然而，KLF13在食管癌（EC）中的作用仍不明确。在本研究中，我们采用免疫组织化学、蛋白质免疫印迹和实时荧光定量PCR检测了EC组织和细胞中KLF13的表达，发现与正常对照相比，EC组织和细胞中KLF13表达上调。KLF13高表达提示EC患者预后不良。此外，进行了体内外功能研究以探讨KLF13在EC细胞进展中的作用。结果显示，敲低KLF13可抑制EC细胞增殖、迁移、上皮-间质转化，增加体内细胞凋亡和细胞周期阻滞，并抑制体外肿瘤生长。相反，EC细胞中过表达KLF13则产生相反的结果。机制上，通过RNA测序和染色质免疫沉淀测序鉴定了KLF13下游的差异表达基因。我们发现甘油三酯和游离脂肪酸水平与KLF13表达水平呈正相关。利用荧光素酶和染色质免疫沉淀试验，确定了一个脂质相关基因糖基磷脂酰肌醇锚定高密度脂蛋白结合蛋白1（GPIHBP1）为KLF13的下游基因，其表达受KLF13正向调控。最后，使用短发夹RNA和过表达质粒进行的体外和体内恢复试验证实，KLF13通过GPIHBP1在EC进展中发挥致癌作用。综上所述，KLF13可通过GPIHBP1促进EC进展、甘油三酯和游离脂肪酸代谢。因此，针对KLF13和GPIHBP1的分子疗法可能是治疗EC的有效方法。
