Department of Medicine and Surgery, University of Perugia, Perugia, Italy.
Department of Life and Environmental Sciences, University of Cagliari, Cagliari, Italy.
Cell Oncol (Dordr). 2024 Apr;47(2):695-710. doi: 10.1007/s13402-023-00893-8. Epub 2023 Nov 9.
The gastric adenocarcinoma (GC) represents the third cause of cancer-related mortality worldwide, and available therapeutic options remain sub-optimal. The Fibroblast growth factor receptors (FGFRs) are oncogenic transmembrane tyrosine kinase receptors. FGFR inhibitors have been approved for the treatment of various cancers and a STAT3-dependent regulation of FGFR4 has been documented in the H.pylori infected intestinal GC. Therefore, the modulation of FGFR4 might be useful for the treatment of GC.
To investigate wich factors could modulate FGFR4 signalling in GC, we employed RNA-seq analysis on GC patients biopsies, human patients derived organoids (PDOs) and cancer cell lines.
We report that FGFR4 expression/function is regulated by the leukemia inhibitory factor (LIF) an IL-6 related oncogenic cytokine, in JAK1/STAT3 dependent manner. The transcriptomic analysis revealed a direct correlation between the expression of LIFR and FGFR4 in the tissue of an exploratory cohort of 31 GC and confirmed these findings by two external validation cohorts of GC. A LIFR inhibitor (LIR-201) abrogates STAT3 phosphorylation induced by LIF as well as recruitment of pSTAT3 to the promoter of FGFR4. Furthermore, inhibition of FGFR4 by roblitinib or siRNA abrogates STAT3 phosphorylation and oncogentic effects of LIF in GC cells, indicating that FGFR4 is a downstream target of LIF/LIFR complex. Treating cells with LIR-201 abrogates oncogenic potential of FGF19, the physiological ligand of FGFR4.
Together these data unreveal a previously unregnized regulatory mechanism of FGFR4 by LIF/LIFR and demonstrate that LIF and FGF19 converge on the regulation of oncogenic STAT3 in GC cells.
胃腺癌（GC）是全球癌症相关死亡的第三大原因，可用的治疗选择仍然不理想。成纤维细胞生长因子受体（FGFRs）是致癌的跨膜酪氨酸激酶受体。FGFR 抑制剂已被批准用于治疗各种癌症，并且已经在 H.pylori 感染的肠 GC 中记录了 STAT3 依赖性 FGFR4 调节。因此，FGFR4 的调节可能对 GC 的治疗有用。
为了研究哪些因素可以调节 GC 中的 FGFR4 信号，我们对 GC 患者活检、人类患者衍生的类器官（PDO）和癌细胞系进行了 RNA-seq 分析。
我们报告说，FGFR4 的表达/功能受白血病抑制因子（LIF）调节，这是一种与 IL-6 相关的致癌细胞因子，以 JAK1/STAT3 依赖的方式调节。转录组分析显示，在 31 例 GC 的探索性队列的组织中，LIFR 和 FGFR4 的表达之间存在直接相关性，并通过 GC 的两个外部验证队列证实了这些发现。LIFR 抑制剂（LIR-201）可阻断 LIF 诱导的 STAT3 磷酸化以及 pSTAT3 向 FGFR4 启动子的募集。此外，用 roblitinib 或 siRNA 抑制 FGFR4 可阻断 GC 细胞中 LIF 的 STAT3 磷酸化和致癌作用，表明 FGFR4 是 LIF/LIFR 复合物的下游靶标。用 LIR-201 处理细胞可阻断 FGF19 的致癌潜力，FGF19 是 FGFR4 的生理配体。
这些数据揭示了 LIF/LIFR 对 FGFR4 的先前未被认识的调节机制，并表明 LIF 和 FGF19 都集中在 GC 细胞中调节致癌性 STAT3。
