<scp>FGF</scp>19 genetic amplification as a potential therapeutic target in lung squamous cell carcinomas

Zhang, Xiaochen; Kong, Mei; Zhang, Zhen; Xu, Suzhen; Yan, F.; Wei, Liyuan; Zhou, Jianying

doi:10.1111/1759-7714.12504

Cited by 25 publications

(15 citation statements)

References 28 publications

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“…In this scenario, knockdown FGF19 is potent enough to suppress the growth of LSQ cells since mTOR is a direct downstream effector of the FGF19 signal. However, this result is slightly different from an earlier report in which downregulating FGF19 alone could not suppress tumor formation in LSQ [34]. This could be explained by the different basal levels of FGF19 in the different cell lines.…”

Section: Discussioncontrasting

confidence: 99%

Enhanced autocrine FGF19/FGFR4 signaling drives the progression of lung squamous cell carcinoma, which responds to mTOR inhibitor AZD2104

Fan

Han

et al. 2020

Oncogene

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Lung cancer occurrence and associated mortality ranks top in all countries. Despite the rapid development of targeted and immune therapies, many patients experience relapse within a few years. It is urgent to uncover the mechanisms that drive lung cancer progression and identify novel molecular targets. Our group has previously identified FGF19 as a prognostic marker and potential driver gene of lung squamous cell carcinomas (LSQ) in Chinese smoking patients. However, the underlying mechanism of how FGF19 promotes the progression of LSQ remains unclear. In this study, we characterized and confirmed that FGF19 serves as an oncogenic driver in LSQ development and progression, and reported that the amplification and high expression of FGF19 in LSQ was significantly associated with poor overall and progression-free survival. A higher serum level of FGF19 was found in lung cancer patients, which could also serve as a novel diagnostic index to screen lung cancer. Overproduction of FGF19 in LSQ cells markedly promoted cell growth, progression and metastasis, while downregulating FGF19 effectively inhibited LSQ progression in vitro and in vivo. Moreover, downregulating the receptor FGFR4 was also effective to suppress the growth and migration of LSQ cells. Since FGF19 could be induced by smoking or endoplasmic reticulum stress, to tackle the more malignant FGF19-overproducing LSQ, we reported for the first time that inhibiting mTOR pathway by using AZD2014 was effective and feasible. These findings have offered a new strategy by using anti-FGF19/FGFR4 therapy or mTOR-based therapy in FGF19-driven LSQ.

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Section: Discussioncontrasting

confidence: 99%

Enhanced autocrine FGF19/FGFR4 signaling drives the progression of lung squamous cell carcinoma, which responds to mTOR inhibitor AZD2104

Fan

Han

et al. 2020

Oncogene

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“…FGF19 has emerged as a critical regulator of cell proliferation. A high expression of FGF19 is frequently detected in cancer tissues and contributes to sustaining the hyperproliferation of cancer cells . FGF19‐deficient mice show reduced hepatocyte proliferation because of impaired cell cycle progression .…”

Section: Discussionmentioning

confidence: 99%

FGF19 sustains the high proliferative ability of keratinocytes in psoriasis through the regulation of Wnt/GSK‐3β/β‐catenin signalling via FGFR4

Yan

et al. 2019

Clin Exp Pharma Physio

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Accumulating evidence has shown that fibroblast growth factor 19 (FGF19) plays an important role in regulating cell proliferation. Psoriasis is characterized by the hyperproliferation of keratinocytes in skin lesions. However, whether FGF19 regulates the proliferation of keratinocytes in psoriasis remains unknown. In this study, we aimed to explore the potential relevance of FGF19 in psoriasis. We found that FGF19 was highly expressed in psoriatic skin from psoriasis patients, as well as keratinocytes that were stimulated with a cocktail of cytokines (M5), which is an in vitro model of psoriasis. Functional experiments demonstrated that FGF19 overexpression promoted the growth and proliferation of keratinocytes, while FGF19 knockdown showed opposite effect. Moreover, we found that FGF19 increased the phosphorylation of glycogen synthase kinase (GSK)‐3β and promoted the expression of β‐catenin and the activation of T cell factor 4 (TCF4) transcriptional activity. Notably, blocking Wnt/β‐catenin signalling by silencing β‐catenin partially reversed FGF19‐mediated promotional effects on keratinocyte proliferation. In addition, FGFR4 inhibition significantly blocked the promotional effect of FGF19 on keratinocyte proliferation and GSK‐3β/β‐catenin/TCF4 signalling. Taken together, our results demonstrated that FGF19 contributes to sustaining the high proliferative ability of keratinocytes through promoting Wnt/GSK‐3β/β‐catenin signalling via FGFR4, highlighting the importance of FGF19 in the pathogenesis of psoriasis. Our study suggests that FGF19 may serve as a novel and potential therapeutic target for psoriasis.

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“…Cell line studies implicate FGF19 as a potential ESCC oncogene . Overexpression of FGF19 has been reported in gastric adenocarcinoma and squamous cell lung carcinoma …”

Section: Discussionmentioning

confidence: 99%

Prediagnostic circulating inflammation biomarkers and esophageal squamous cell carcinoma: A case–cohort study in Japan

Aversa

Song

Shimazu³

et al. 2019

Intl Journal of Cancer

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Esophageal squamous cell carcinoma (ESCC) is the predominant histologic subtype of esophageal cancer worldwide. Measurements of circulating inflammation-related biomarkers may inform etiology or provide noninvasive signatures for early diagnosis. We therefore examined levels of inflammation molecules for associations with ESCC risk. Using a case-cohort study designed within the Japan Public Health Center-based Prospective Study, we measured baseline plasma levels of 92 biomarkers using a multiplex assay in a subcohort of 410 randomly selected participants and 66 participants with incident ESCC (including four cases that occurred in the subcohort). ESCC hazard ratios (HRs) were calculated for 2-4 quantiles of each biomarker by Cox proportional hazards regression models with age as the time metric, adjusted for sex, smoking and alcohol use. Twenty analytes were undetectable in nearly all samples. Of the remaining 72, 12 biomarkers (FGF19, ST1A1, STAMBP, AXIN1, CASP8, NT3, CD6, CDCP1, CD5, SLAMF1, OPG and CSF1) were associated with increased ESCC risk (p trend < 0.05) with HRs per quantile 1.28-1.65. Seven biomarkers (CXCL6, CCL23, CXCL5, TGFA, CXCL1, OSM and CCL4) were inversely associated with HRs 0.57-0.72. FGF19, CASP8, STAMBP, ST1A1 and CCL-4 met statistical significance with false discovery rate correction. Associations did not differ <5 vs. ≥5 years between blood collection and ESCC diagnosis. CASP8, STAMBP and ST1A1 were strongly correlated (p < 0.05). Our study expands the range of inflammation molecules associated with the development of this highly lethal neoplasia. Correlations among these novel biomarkers suggest a possible shared pathway. These findings need replication and could further delineate ESCCs molecular mechanisms of carcinogenesis.Additional Supporting Information may be found in the online version of this article.

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FGF19 genetic amplification as a potential therapeutic target in lung squamous cell carcinomas

Cited by 25 publications

References 28 publications

Enhanced autocrine FGF19/FGFR4 signaling drives the progression of lung squamous cell carcinoma, which responds to mTOR inhibitor AZD2104

Enhanced autocrine FGF19/FGFR4 signaling drives the progression of lung squamous cell carcinoma, which responds to mTOR inhibitor AZD2104

FGF19 sustains the high proliferative ability of keratinocytes in psoriasis through the regulation of Wnt/GSK‐3β/β‐catenin signalling via FGFR4

Prediagnostic circulating inflammation biomarkers and esophageal squamous cell carcinoma: A case–cohort study in Japan

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