Low serum gastrin associated with ER+ breast cancer development via inactivation of CCKBR/ERK/P65 signaling

Meng, Lili; Wang, Jinglong; Xu, Shaohua; Zu, Lidong; Yan, Zhao-Wen; Zhang, Jianbing; Han, Yuxiao; Fu, Guo‐Hui

doi:10.1186/s12885-018-4717-7

Cited by 8 publications

(6 citation statements)

References 54 publications

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“…However, it might also inhibit tumor growth. Therefore, the concrete role of gastrin in tumorigenesis might be organand/or molecular subtype-dependent manner (19,20). Further studies are warranted to elucidate the role of SEMA5B and GAST in HNSCC tumorigenesis.…”

Section: Discussionmentioning

confidence: 99%

Development and Validation of a Robust Immune Prognostic Signature for Head and Neck Squamous Cell Carcinoma

et al. 2020

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Head and neck squamous cell carcinoma (HNSCC) is among the most destructive of tumors, leading to considerable morbidity and mortality. Abnormal immune microenvironment is closely associated with tumor progression. This study aimed to construct a robust immune prognostic model for HNSCC. The RNA-seq transcriptome data and clinical information of HNSCC were downloaded from The Cancer Genome Atlas (TCGA) database. The key pathways and transcriptional factors (TFs) that are correlated with significantly altered immune related genes were identified. A robust immune prognostic model was constructed and further validated using a discovery-validation cohort design. An immune prognostic signature-based nomogram model was also developed. We have identified 400 significantly changed immune related genes in HNSCC. In addition, functional analysis of the altered immune related genes revealed many biological functions and pathways that might affect the tumor immune microenvironment. FOXP3, SNAI2, and STAT1 were identified as the hub TFs for regulating immunological changes in HNSCC. Moreover, an immune related gene-based prognostic signature significantly associated with the overall survival (OS) of HNSCC was constructed in the discovery cohort, and successfully validated in the validation cohort. Finally, a nomogram model based on immune prognostic signature was built and exhibited good performance for predicting the OS of HNSCC. In conclusion, the immune prognostic model is robust for predicting the prognosis of HNSCC and may evolve as a promising tool for risk evaluation and therapeutic selection.

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Section: Discussionmentioning

confidence: 99%

Development and Validation of a Robust Immune Prognostic Signature for Head and Neck Squamous Cell Carcinoma

et al. 2020

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“…The activated ERK was reported to promote IkBa phosphorylation and subsequently induce NF-kB (Rel) nuclear translocation in glioblastoma cells and murine colitis (39,40). The cholecystokinin B receptor (CCKBR) in breast cancer cells could activate the ERK/P65 pathway (41). After ERK was inhibited, P65 activity was found to be reduced in MKN28 cells (42).…”

Section: Discussionmentioning

confidence: 99%

CgCLec-HTM–Mediated Signaling Pathway Regulates Lipopolysaccharide-Induced CgIL-17 and CgTNF Production in Oyster

Sun

Wang

Huang

et al. 2019

The Journal of Immunology

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The immune signaling pathway mediated by Dectin-1 is important in mammals to modulate the production of IL-17 and TNF-a. Recently, IL-17 and TNF have also been characterized in invertebrates to play crucial roles in antibacterial immune responses, although the immune recognition and regulation mechanisms to produce IL-17 and TNF are still not well investigated. In the current study, a novel C-type lectin receptor (named CgCLec-HTM) with a signal peptide, a carbohydrate recognition domain, a transmembrane domain, and a nonclassical ITAM (hemITAM) in the cytoplasmic tail was identified from oyster Crassostrea gigas. CgCLec-HTM could bind LPS and various bacteria. After binding to its ligands, CgCLec-HTM was associated with the Src homology 2 (SH2) domain of spleen tyrosine kinase (CgSyk) by the hemITAM in its cytoplasmic tail to promote ERK (CgERK) phosphorylation. The activated CgERK could interact with CgRel to induce CgRel nuclear translocation. The CgRel in the nucleus eventually induced the transcription of CgIL-17s and CgTNF. The results demonstrated that CgCLec-HTM with a broad binding spectrum of bacteria could be associated with CgSyk to transfer immune signals into the intracellular ERK-Rel pathway to induce CgIL-17 and CgTNF production.

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“…PDE4B is mainly present in immune and epithelial cells and has a role modulating inflammation and epithelial integrity 96 while CCKBR encodes a G-protein coupled receptor for gastrin and cholecystokinin. Even though CCKBR has not been targeted for treatment of endometriosis, a recent study has demonstrated that reduction of gastrin is associated with inactivation of CCKBR/ERK/P65 signalling in estrogen receptor positive breast cancer cells, and lower expression of gastrin and CCKBR was correlated to worse prognosis in breast cancer 97 . Therefore, the involvement of gastrin and CCKBR in estrogen metabolism may implicate this gene as a potential drug target for endometriosis.…”

Section: Discussionmentioning

confidence: 99%

Evidence of shared genetic factors in the aetiology of gastrointestinal disorders and endometriosis and clinical implications for disease management

Hockey

Doust

et al. 2022

Preprint

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In clinical practice, the co-existence of endometriosis and gastrointestinal symptoms is often observed; however, the factors driving this link remain largely unknown. Here, using large-scale multifaceted data including observational, genetic, and pharmaceutical datasets, we report a positive phenotypic and genetic association of endometriosis with peptic ulcer disease (PUD), gastro-oesophageal reflux disease (GORD), a combined GORD/PUD Medicated (GPM) phenotype and irritable bowel syndrome (IBS), but not with inflammatory bowel disease (IBD). Mendelian randomization analysis identified a causal effect of the GPM phenotype on endometriosis and a bidirectional causal association between endometriosis and IBS. Cross-trait meta-analysis and colocalization along with comprehensive functional annotation confirmed two shared genetic loci (FN1, TACSTD2) for endometriosis with IBS and twelve loci (ETAA1, HOXC4, RERG, SEMA3F, SPAG16, HIST1H2BC, RAB5B, CCKBRandPDE4B) with GORD and PUD. Shared genetic loci may contribute to risk of both endometriosis and digestive disorders through the involvement of DNA damage, estrogen regulated cell-proliferation and inflammation, and barrier dysfunction. Analyses of medication usage identified a higher use of drugs for IBS, GORD and PUD in women diagnosed with endometriosis as well as a higher use of hormone therapies in women diagnosed with IBS, GORD and PUD but not for IBD, which strongly supports the co-occurrence of these conditions and highlights the potential for drug repositioning and caution around drug contraindications in clinical practice. Taken together, the combined evidence robustly suggests a shared disease aetiology and provides important clinical implications for diagnostic and treatment decisions for endometriosis and digestive disorders.WHAT IS ALREADY KNOWN ON THIS TOPIC?Both endometriosis and gastrointestinal disorders affect a large proportion of people worldwide and the co-existence of endometriosis and gastrointestinal symptoms (eg, abnormal pain, bloating, constipation) is often observed in clinical practice.The association of these two diseases was supported but also limited to previous observational evidence which highlights a three-fold increase in the prevalence of irritable bowel syndrome (IBS) in women with endometriosis.Observational study is easily subject to measurement error, confounding and reverse causation. Therefore, it is important to assess the association using multidimensional datasets and more accurate approaches, such as the use of genetic data in a mendelian randomisation framework as well as the analysis from a perspective of medication usage.WHAT THIS STUDY ADDSGenetic risk factors for endometriosis and gastrointestinal disorders, two leading causes of discomfort and chronic pelvic pain, are correlated.Mendelian randomisation analyses supported a causal relationship between genetic predisposition to gastrointestinal disorders (gastro-oesophageal reflux disease (GORD) and peptic ulcer diseases (PUD)) and endometriosis risk, and evidence for a bidirectional causal relationship between endometriosis and IBS, which might explain in part the co-occurrence of these diseases.The identification of shared risk loci highlighted biological pathways that may contribute to the pathogenesis of both diseases, including estrogen regulation and inflammation, as well as potential therapeutic drug targets such asCCKBRandPDE4B.The higher use of drugs for IBS, GORD and PUD in women diagnosed with endometriosis as well as the higher use of hormone therapies in women diagnosed with IBS, GORD and PUD, support the co-occurrence of these conditions and shared disease aetiology but also highlights the potential for drug repositioning and caution around drug contraindications.Graphical abstract

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Low serum gastrin associated with ER+ breast cancer development via inactivation of CCKBR/ERK/P65 signaling

Cited by 8 publications

References 54 publications

Development and Validation of a Robust Immune Prognostic Signature for Head and Neck Squamous Cell Carcinoma

Development and Validation of a Robust Immune Prognostic Signature for Head and Neck Squamous Cell Carcinoma

CgCLec-HTM–Mediated Signaling Pathway Regulates Lipopolysaccharide-Induced CgIL-17 and CgTNF Production in Oyster

Evidence of shared genetic factors in the aetiology of gastrointestinal disorders and endometriosis and clinical implications for disease management

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