Cellular Oncology最新文献

{"title":"Correction to: Microbial metabolite trimethylamine-N-oxide induces intestinal carcinogenesis through inhibiting farnesoid X receptor signaling","authors":"Wanru Zhang, Xiali Qin, Kexin Zhang, Jiahui Ma, Mengfan Li, Ge Jin, Xiang Liu, Sinan Wang, Bangmao Wang, Jing Wu, Tianyu Liu, Weilong Zhong, Hailong Cao","doi":"10.1007/s13402-024-00937-7","DOIUrl":"https://doi.org/10.1007/s13402-024-00937-7","url":null,"abstract":"","PeriodicalId":9690,"journal":{"name":"Cellular Oncology","volume":"14 1","pages":""},"PeriodicalIF":6.6,"publicationDate":"2024-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140613794","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Integrated analysis of single-cell RNA-seq and bulk RNA-seq reveals immune suppression subtypes and establishes a novel signature for determining the prognosis in lung adenocarcinoma","authors":"Shengqiang Mao, Yilong Wang, Ningning Chao, Lingyan Zeng, Li Zhang","doi":"10.1007/s13402-024-00948-4","DOIUrl":"https://doi.org/10.1007/s13402-024-00948-4","url":null,"abstract":"<h3 data-test=\"abstract-sub-heading\">Background</h3><p>Lung adenocarcinoma (LUAD) is the most common histological type of lung cancer with lower survival rates. Recent advancements in targeted therapies and immunotherapies targeting immune checkpoints have achieved remarkable success, there is still a large percentage of LUAD that lacks available therapeutic options. Due to tumor heterogeneity, the diagnosis and treatment of LUAD are challenging. Exploring the biology of LUAD and identifying new biomarker and therapeutic targets options are essential.</p><h3 data-test=\"abstract-sub-heading\">Method</h3><p>We performed single-cell RNA sequencing (scRNA-seq) of 6 paired primary and adjacent LUAD tissues, and integrative omics analysis of the scRNA-seq, bulk RNA-seq and whole-exome sequencing data revealed molecular subtype characteristics. Our experimental results confirm that <i>CDC25C</i> gene can serve as a potential marker for poor prognosis in LUAD.</p><h3 data-test=\"abstract-sub-heading\">Results</h3><p>We investigated aberrant gene expression in diverse cell types in LUAD via the scRNA-seq data. Moreover, multi-omics clustering revealed four subgroups defined by transcriptional profile and molecular subtype 4 (MS4) with poor survival probability, and immune cell infiltration signatures revealed that MS4 tended to be the immunosuppressive subtype. Our study revealed that the <i>CDC25C</i> gene can be a distinct prognostic biomarker that indicates immune infiltration levels and response to immunotherapy in LUAD patients. Our experimental results concluded that <i>CDC25C</i> expression affects lung cancer cell invasion and migration, might play a key role in regulating Epithelial-Mesenchymal Transition (EMT) pathways.</p><h3 data-test=\"abstract-sub-heading\">Conclusions</h3><p>Our multi-omics result revealed a comprehensive set of molecular attributes associated with prognosis-related genes in LUAD at the cellular and tissue level. Identification of a subtype of immunosuppressive TME and prognostic signature for LUAD. We identified the cell cycle regulation gene <i>CDC25C</i> affects lung cancer cell invasion and migration, which can be used as a potential biomarker for LUAD.</p>","PeriodicalId":9690,"journal":{"name":"Cellular Oncology","volume":"16 1","pages":""},"PeriodicalIF":6.6,"publicationDate":"2024-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140587090","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Establishment, characterization, and biobanking of 36 pancreatic cancer organoids: prediction of metastasis in resectable pancreatic cancer","authors":"Soon-Chan Kim, Ha-Young Seo, Ja-Oh Lee, Ju Eun Maeng, Young-Kyoung Shin, Sang Hyub Lee, Jin-Young Jang, Ja-Lok Ku","doi":"10.1007/s13402-024-00939-5","DOIUrl":"https://doi.org/10.1007/s13402-024-00939-5","url":null,"abstract":"<h3 data-test=\"abstract-sub-heading\">Purpose</h3><p>Early dissemination of primary pancreatic ductal adenocarcinoma (PDAC) is the main cause of dismal prognosis as it highly limits possible treatment options. A number of PDAC patients experience distant metastasis even after treatment due to the metastatic clones. We aimed to demonstrate the molecular architecture of borderline resectable PDAC manifests cancer dissemination of PDAC.</p><h3 data-test=\"abstract-sub-heading\">Methods</h3><p>Here, 36 organoids isolated from primary tumor masses of PDAC patients with diverse metastatic statues are presented. Whole-exome sequencing and RNA sequencing were performed and drug responses to clinically relevant 18 compounds were assessed.</p><h3 data-test=\"abstract-sub-heading\">Results</h3><p>Our results revealed that borderline resectable PDAC organoids exhibited distinct patterns according to their metastatic potency highlighted by multiple genetic and transcriptional factors and strong variances in drug responses.</p><h3 data-test=\"abstract-sub-heading\">Conclusions</h3><p>These data suggest that the presence of metastatic PDAC can be identified by integrating molecular compositions and drug responses of borderline resectable PDAC.</p>","PeriodicalId":9690,"journal":{"name":"Cellular Oncology","volume":"51 1","pages":""},"PeriodicalIF":6.6,"publicationDate":"2024-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140579521","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The emerging role of CARM1 in cancer","authors":"Zizhuo Xie, Yuan Tian, Xiaohan Guo, Na Xie","doi":"10.1007/s13402-024-00943-9","DOIUrl":"https://doi.org/10.1007/s13402-024-00943-9","url":null,"abstract":"<p>Coactivator-associated arginine methyltransferase 1 (CARM1), pivotal for catalyzing arginine methylation of histone and non-histone proteins, plays a crucial role in developing various cancers. CARM1 was initially recognized as a transcriptional coregulator by orchestrating chromatin remodeling, transcription regulation, mRNA splicing and stability. This diverse functionality contributes to the recruitment of transcription factors that foster malignancies. Going beyond its established involvement in transcriptional control, CARM1-mediated methylation influences a spectrum of biological processes, including the cell cycle, metabolism, autophagy, redox homeostasis, and inflammation. By manipulating these physiological functions, CARM1 becomes essential in critical processes such as tumorigenesis, metastasis, and therapeutic resistance. Consequently, it emerges as a viable target for therapeutic intervention and a possible biomarker for medication response in specific cancer types. This review provides a comprehensive exploration of the various physiological functions of CARM1 in the context of cancer. Furthermore, we discuss potential CARM1-targeting pharmaceutical interventions for cancer therapy.</p>","PeriodicalId":9690,"journal":{"name":"Cellular Oncology","volume":"12 1","pages":""},"PeriodicalIF":6.6,"publicationDate":"2024-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140579410","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Downregulation of GPX8 in hepatocellular carcinoma: impact on tumor stemness and migration","authors":"Chen-Yang Tao, Xiao-Ling Wu, Shu-Shu Song, Zheng Tang, Yu-Fu Zhou, Meng-Xin Tian, Xi-Fei Jiang, Yuan Fang, Gui-Qi Zhu, Run Huang, Wei-Feng Qu, Jun Gao, Tian-Hao Chu, Rui Yang, Jia-Feng Chen, Qian-Fu Zhao, Zhen-Bin Ding, Zhi Dai, Jian Zhou, Wei-Ren Liu, Ying-Hong Shi, Jia Fan","doi":"10.1007/s13402-024-00934-w","DOIUrl":"https://doi.org/10.1007/s13402-024-00934-w","url":null,"abstract":"<h3 data-test=\"abstract-sub-heading\">Purpose</h3><p>GPX8, which is found in the endoplasmic reticulum lumen, is a member of the Glutathione Peroxidases (GPXs) family. Its role in hepatocellular carcinoma (HCC) is unknown.</p><h3 data-test=\"abstract-sub-heading\">Methods</h3><p>Immunohistochemical staining was used to detect the protein levels of GPX8 in HCC tissue microarrays. A short hairpin RNA lentivirus was used to knock down GPX8, and the main signaling pathways were investigated using transcriptome sequencing and a phosphorylated kinase array. The sphere formation assays, cloning-formation assays and cell migration assays were used to evaluate the stemness and migration ability of HCC cells. Identifying the GPX8-interacting proteins was accomplished through immunoprecipitation and protein mass spectrometry.</p><h3 data-test=\"abstract-sub-heading\">Results</h3><p>The GPX8 protein levels were downregulated in HCC patients. Low expression of GPX8 protein was related to early recurrence and poor prognosis in HCC patients. GPX8 knockdown could enhance the stemness and migration ability of HCC cells. Consistently, Based on transcriptome analysis, multiple signaling pathways that include the PI3K-AKT and signaling pathways that regulate the pluripotency of stem cells, were activated after GPX8 knockdown. The downregulation of GPX8 could increase the expression of the tumor stemness markers KLF4, OCT4, and CD133. The in vivo downregulation of GPX8 could also promote the subcutaneous tumor-forming and migration ability of HCC cells. MK-2206, which is a small-molecule inhibitor of AKT, could reverse the tumor-promoting effects both in vivo and in vitro. We discovered that GPX8 and the 71-kDa heat shock cognate protein (Hsc70) have a direct interaction. The phosphorylation of AKT encouraged the translocation of Hsc70 into the nucleus and the expression of the PI3K p110 subunit, thereby increasing the downregulation of GPX8.</p><h3 data-test=\"abstract-sub-heading\">Conclusion</h3><p>The findings from this study demonstrate the anticancer activity of GPX8 in HCC by inactivating the Hsc70/AKT pathway. The results suggest a possible therapeutic target for HCC.</p>","PeriodicalId":9690,"journal":{"name":"Cellular Oncology","volume":"48 1","pages":""},"PeriodicalIF":6.6,"publicationDate":"2024-04-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140579404","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dexmedetomidine promotes colorectal cancer progression via Piwil2 signaling","authors":"Jing Dong, Ji Che, Yuanyuan Wu, Yixu Deng, Xuliang Jiang, Zhiyong He, Jun Zhang","doi":"10.1007/s13402-024-00944-8","DOIUrl":"https://doi.org/10.1007/s13402-024-00944-8","url":null,"abstract":"<h3 data-test=\"abstract-sub-heading\">Purpose</h3><p>α2-adrenoceptor agonist dexmedetomidine (DEX) has been reported to promote tumorigenesis. Stem-cell protein Piwil2 is associated with cancer progression. Whether Piwil2 plays a role in tumor-promoting effects of DEX is unknown.</p><h3 data-test=\"abstract-sub-heading\">Methods</h3><p>We examined the expression of Piwil2 in human colorectal cancer (CRC) cell lines with/without DEX treatment. We also studied the roles of Piwil2 in proliferation, invasion, migration, as well as expressions of epithelial-mesenchymal transition (EMT)-related proteins in DEX-treated in vitro and in vivo CRC models. And the experiments with genetic and pharmacological treatments were conducted to investigate the underlying molecular mechanism.</p><h3 data-test=\"abstract-sub-heading\">Results</h3><p>RNA-sequencing (RNA-seq) analysis found Piwil2 is one of most upregulated genes upon DEX treatment in CRC cells. Furthermore, Piwil2 protein levels significantly increased in DEX-treated CRC cancer cells, which promoted proliferation, invasion, and migration in both CRC cell lines and human tumor xenografts model. Mechanistically, DEX increased nuclear factor E2-related factor 2 (Nrf2) expression, which enhanced Piwil2 transcription via binding to its promoter. Furthermore, in vitro experiments with Piwil2 knockdown or Siah2 inhibition indicated that DEX promoted EMT process and tumorigenesis through Siah2/PHD3/HIF1α pathway. The experiments with another α2-adrenoceptor agonist Brimonidine and antagonists yohimbine and atipamezole also suggested the role of Piwil2 signaling in tumor-promoting effects via an α2 adrenoceptor-dependent manner.</p><h3 data-test=\"abstract-sub-heading\">Conclusion</h3><p>DEX promotes CRC progression may via activating α2 adrenoceptor-dependent Nrf2/Piwil2/Siah2 pathway and thus EMT process. Our work provides a novel insight into the mechanism underlying tumor-promoting effects of α2-adrenoceptor agonists.</p>","PeriodicalId":9690,"journal":{"name":"Cellular Oncology","volume":"31 1","pages":""},"PeriodicalIF":6.6,"publicationDate":"2024-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140579523","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Hedgehog ligand and receptor cooperatively regulate EGFR stability and activity in non-small cell lung cancer","authors":"Aidi Huang, Junyao Cheng, Yuan Zhan, Feifei Zhou, Yanlu Xuan, Yiting Wang, Qingjie Chen, Hailong Wang, Xinping Xu, Shiwen Luo, Minzhang Cheng","doi":"10.1007/s13402-024-00938-6","DOIUrl":"https://doi.org/10.1007/s13402-024-00938-6","url":null,"abstract":"<h3 data-test=\"abstract-sub-heading\">Purpose</h3><p>The hyperactivation of epidermal growth factor receptor (EGFR) plays a crucial role in non-small cell lung cancer (NSCLC). Hedgehog (Hh) signaling has been implicated in the tumorigenesis and progression of various cancers, however, its function in NSCLC cells remains controversial. Herein, we present a novel finding that challenges the current understanding of Hh signaling in tumor growth.</p><h3 data-test=\"abstract-sub-heading\">Methods</h3><p>Expression of Hh ligands and receptor were assessed using TCGA datasets, immunoblotting and immunohistochemical. Biological function of Hh ligands and receptor in NSCLC were tested using colony formation, cell count kit-8 (CCK-8) and xenograft assays. Biochemical effect of Hh ligands and receptor on regulating EGFR stability and activity were checked via immunoblotting.</p><h3 data-test=\"abstract-sub-heading\">Results</h3><p>Expression of Hh ligands and receptor was suppressed in NSCLC tissues, and the lower expression levels of these genes were associated with poor prognosis. Ptch1 binds to EGFR and facilitates its poly-ubiquitylation and degradation independent of downstream transcriptional signaling. Moreover, Hh ligands cooperate with Ptch1 to regulate the protein stability and activity of EGFR. This unique mechanism leads to a suppressive effect on NSCLC tumor growth.</p><h3 data-test=\"abstract-sub-heading\">Conclusion</h3><p>Non-canonical Hh signaling pathway, involving cooperation between Hh ligands and their receptor Ptch1, facilitates the degradation of EGFR and attenuates its activity in NSCLC. These findings provide novel insights into the regulation of EGFR protein stability and activity, offer new diagnostic indicators for molecular typing of NSCLC and identify potential targets for targeted therapy of this challenging disease.</p>","PeriodicalId":9690,"journal":{"name":"Cellular Oncology","volume":"105 1","pages":""},"PeriodicalIF":6.6,"publicationDate":"2024-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140579529","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The microbiota and renal cell carcinoma.","authors":"Ke Wu, Yaorong Li, Kangli Ma, Weiguang Zhao, Zhixian Yao, Zhong Zheng, Feng Sun, Xingyu Mu, Zhihong Liu, Junhua Zheng","doi":"10.1007/s13402-023-00876-9","DOIUrl":"10.1007/s13402-023-00876-9","url":null,"abstract":"<p><p>Renal cell carcinoma (RCC) accounts for about 2% of cancer diagnoses and deaths worldwide. Recent studies emphasized the critical involvement of microbial populations in RCC from oncogenesis, tumor growth, and response to anticancer therapy. Microorganisms have been shown to be involved in various renal physiological and pathological processes by influencing the immune system function, metabolism of the host and pharmaceutical reactions. These findings have extended our understanding and provided more possibilities for the diagnostic or therapeutic development of microbiota, which could function as screening, prognostic, and predictive biomarkers, or be manipulated to prevent RCC progression, boost anticancer drug efficacy and lessen the side effects of therapy. This review aims to present an overview of the roles of microbiota in RCC, including pertinent mechanisms in microbiota-related carcinogenesis, the potential use of the microbiota as RCC biomarkers, and the possibility of modifying the microbiota for RCC prevention or treatment. According to these scientific findings, the clinical translation of microbiota is expected to improve the diagnosis and treatment of RCC.</p>","PeriodicalId":9690,"journal":{"name":"Cellular Oncology","volume":" ","pages":"397-413"},"PeriodicalIF":6.6,"publicationDate":"2024-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"50157137","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"FAP is a prognostic marker, but not a viable therapeutic target for clinical translation in HNSCC.","authors":"Jie Liu, Yeling Ouyang, Zijin Xia, Wenhao Mai, Hongrui Song, Fang Zhou, Lichun Shen, Kaiting Chen, Xiaochen Li, Shi-Min Zhuang, Jing Liao","doi":"10.1007/s13402-023-00888-5","DOIUrl":"10.1007/s13402-023-00888-5","url":null,"abstract":"<p><strong>Purpose: </strong>PD-1 targeted immunotherapy has imparted a survival benefit to advanced head and neck squamous cell carcinoma (HNSCC), but less than 20% patients produce a durable response to this therapy. Here we aimed to investigate the potential biomarkers for predicting the clinical outcome and resistance to PD-1 targeted immunotherapy in HNSCC patients, and to examine the involvement of FAP⁺ cancer-associated fibroblasts (CAFs).</p><p><strong>Methods: </strong>Bioinformatics methods were applied to analyze multiple datasets and explore the role of PD-1 and FAP in HNSCC. Immunohistochemistry was used to detect the expression of FAP protein. Fap gene knockout mice (Fap^-/-) and L929 cells with different levels of Fap overexpression (L929-Fap-Low/High) were established to demonstrate the role of FAP⁺ CAFs in tumor development and immune checkpoint blockade (ICB) resistance.</p><p><strong>Results: </strong>The expression level of PD-1 gene was positively correlated with better overall survival and therapeutic response to PD-1 blockade in HNSCC, but not all tumors with high expression of both PD-1 and PD-L1 were responsive. Moreover, FAP gene was overexpressed in pan-cancer tissues, and could serve as a prognostic biomarker for several cancers, including HNSCC. However, FAP protein was undetectable in mouse MTCQ1 tumors and barely expressed in human HNSCC tumors. Furthermore, FAP⁺ CAFs did not promote tumor growth or enhance the resistance to PD-1 inhibitor treatment.</p><p><strong>Conclusion: </strong>Although FAP⁺ CAFs have attracted increasing attention for their role in cancer, the feasibility and efficacy of FAP-targeting therapies for HNSCC remain doubtful.</p>","PeriodicalId":9690,"journal":{"name":"Cellular Oncology","volume":" ","pages":"623-638"},"PeriodicalIF":6.6,"publicationDate":"2024-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"49674707","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The leukemia inhibitory factor regulates fibroblast growth factor receptor 4 transcription in gastric cancer.","authors":"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","doi":"10.1007/s13402-023-00893-8","DOIUrl":"10.1007/s13402-023-00893-8","url":null,"abstract":"<p><strong>Purpose: </strong>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.</p><p><strong>Methods: </strong>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.</p><p><strong>Results: </strong>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.</p><p><strong>Conclusions: </strong>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.</p>","PeriodicalId":9690,"journal":{"name":"Cellular Oncology","volume":" ","pages":"695-710"},"PeriodicalIF":6.6,"publicationDate":"2024-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11090936/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"72013629","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}