The leukemia inhibitory factor regulates fibroblast growth factor receptor 4 transcription in gastric cancer.

IF 6.6 2区 医学 Q1 Medicine Cellular Oncology Pub Date : 2024-04-01 Epub Date: 2023-11-09 DOI:10.1007/s13402-023-00893-8
Cristina Di Giorgio, Rachele Bellini, Antonio Lupia, Carmen Massa, Ginevra Urbani, Martina Bordoni, Silvia Marchianò, Rosalinda Rosselli, Rosa De Gregorio, Pasquale Rapacciuolo, Valentina Sepe, Elva Morretta, Maria Chiara Monti, Federica Moraca, Luigi Cari, Khan Rana Sami Ullah, Nicola Natalizi, Luigina Graziosi, Eleonora Distrutti, Michele Biagioli, Bruno Catalanotti, Annibale Donini, Angela Zampella, Stefano Fiorucci
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Abstract

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.

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白血病抑制因子在癌症中调节成纤维细胞生长因子受体4的转录。
目的:胃腺癌(GC)是全球癌症相关死亡率的第三大原因,可用的治疗方案仍处于次优状态。成纤维细胞生长因子受体(FGFR)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,并且在幽门螺杆菌感染的肠GC中记录了FGFR4的STAT3依赖性调节。因此,FGFR4的调节可能有助于治疗GC。方法:为了研究哪些因素可以调节GC中的FGFR4信号,我们对GC患者活检、人类患者来源的类器官(PDO)和癌症细胞系进行了RNA-seq分析。结果:我们报道了FGFR4的表达/功能受到白血病抑制因子(LIF)的调节,LIF是一种IL-6相关的致癌细胞因子,以JAK1/STAT3依赖的方式。转录组学分析揭示了在31个GC的探索性队列的组织中LIFR和FGFR4的表达之间的直接相关性,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)消除LIF诱导的STAT3磷酸化以及pSTAT3向FGFR4启动子的募集。此外,roblitinib或siRNA对FGFR4的抑制消除了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。LIR-201处理细胞消除了FGFR4的生理配体FGF19的致癌潜力。结论:这些数据揭示了LIF/LIFR对FGFR4先前未被认识的调节机制,并证明LIF和FGF19在GC细胞中共同调节致癌STAT3。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Cellular Oncology
Cellular Oncology Biochemistry, Genetics and Molecular Biology-Cancer Research
CiteScore
10.40
自引率
1.50%
发文量
0
审稿时长
16 weeks
期刊介绍: The Official Journal of the International Society for Cellular Oncology Focuses on translational research Addresses the conversion of cell biology to clinical applications Cellular Oncology publishes scientific contributions from various biomedical and clinical disciplines involved in basic and translational cancer research on the cell and tissue level, technical and bioinformatics developments in this area, and clinical applications. This includes a variety of fields like genome technology, micro-arrays and other high-throughput techniques, genomic instability, SNP, DNA methylation, signaling pathways, DNA organization, (sub)microscopic imaging, proteomics, bioinformatics, functional effects of genomics, drug design and development, molecular diagnostics and targeted cancer therapies, genotype-phenotype interactions. A major goal is to translate the latest developments in these fields from the research laboratory into routine patient management. To this end Cellular Oncology forms a platform of scientific information exchange between molecular biologists and geneticists, technical developers, pathologists, (medical) oncologists and other clinicians involved in the management of cancer patients. In vitro studies are preferentially supported by validations in tumor tissue with clinicopathological associations.
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