Purpose

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.

Methods

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.

Results

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.

Conclusions

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.

Graphical abstract

中文翻译：

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白血病抑制因子调节胃癌成纤维细胞生长因子受体4转录

目的

胃腺癌（GC）是全球癌症相关死亡的第三大原因，而现有的治疗选择仍然不够理想。成纤维细胞生长因子受体 (FGFR) 是致癌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，并且在幽门螺杆菌感染的肠道 GC 中已记录了 FGFR4 的 STAT3 依赖性调节。因此，调节 FGFR4 可能有助于治疗 GC。

方法

为了研究哪些因素可以调节 GC 中的 FGFR4 信号传导，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。

结果

我们报告 FGFR4 表达/功能受白血病抑制因子 (LIF)（一种 IL-6 相关致癌细胞因子）以 JAK1/STAT3 依赖性方式调节。转录组分析揭示了 31 名 GC 探索性队列组织中 LIFR 和 FGFR4 表达之间的直接相关性，并通过两个外部 GC 验证队列证实了这些发现。LIFR 抑制剂 (LIR-201) 可消除 LIF 诱导的 STAT3 磷酸化以及将 pSTAT3 募集到 FGFR4 启动子上。此外，Roblitinib 或 siRNA 对 FGFR4 的抑制消除了 GC 细胞中 STAT3 磷酸化和 LIF 的致癌作用，表明 FGFR4 是 LIF/LIFR 复合物的下游靶标。用 LIR-201 处理细胞可消除 FGF19（FGFR4 的生理配体）的致癌潜力。

结论

这些数据共同揭示了 LIF/LIFR 之前未被发现的 FGFR4 调节机制，并证明 LIF 和 FGF19 集中在 GC 细胞中致癌 STAT3 的调节上。

图形概要