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Growth Hormone Receptor Regulation in Cancer and Chronic Diseases.

ABSTRACT: The GHR signaling pathway plays important roles in growth, metabolism, cell cycle control, immunity, homeostatic processes, and chemoresistance via both the JAK/STAT and the SRC pathways. Dysregulation of GHR signaling is associated with various diseases and chronic conditions such as acromegaly, cancer, aging, metabolic disease, fibroses, inflammation and autoimmunity. Numerous studies entailing the GHR signaling pathway have been conducted for various cancers. Diverse factors mediate the up- or down-regulation of GHR signaling through post-translational modifications. Of the numerous modifications, ubiquitination and deubiquitination are prominent events. Ubiquitination by E3 ligase attaches ubiquitins to target proteins and induces proteasomal degradation or starts the sequence of events that leads to endocytosis and lysosomal degradation. In this review, we discuss the role of first line effectors that act directly on the GHR at the cell surface including ADAM17, JAK2, SRC family member Lyn, Ubc13/CHIP, proteasome, ?TrCP, CK2, STAT5b, and SOCS2. Activity of all, except JAK2, Lyn and STAT5b, counteract GHR signaling. Loss of their function increases the GH-induced signaling in favor of aging and certain chronic diseases, exemplified by increased lung cancer risk in case of a mutation in the SOCS2-GHR interaction site. Insight in their roles in GHR signaling can be applied for cancer and other therapeutic strategies.

SUBMITTER: Strous GJ

PROVIDER: S-EPMC7708378 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Growth Hormone Receptor Regulation in Cancer and Chronic Diseases.

Strous Ger J GJ Almeida Ana Da Silva ADS Putters Joyce J Schantl Julia J Sedek Magdalena M Slotman Johan A JA Nespital Tobias T Hassink Gerco C GC Mol Jan A JA

Frontiers in endocrinology 20201118

The GHR signaling pathway plays important roles in growth, metabolism, cell cycle control, immunity, homeostatic processes, and chemoresistance <i>via</i> both the JAK/STAT and the SRC pathways. Dysregulation of GHR signaling is associated with various diseases and chronic conditions such as acromegaly, cancer, aging, metabolic disease, fibroses, inflammation and autoimmunity. Numerous studies entailing the GHR signaling pathway have been conducted for various cancers. Diverse factors mediate th ...[more]

PMID: 33312162

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Project description:BackgroundHumans with inactivating mutations in growth hormone receptor (GHR) have lower rates of cancer, including prostate cancer. Similarly, mice with inactivating Ghr mutations are protected from prostatic intraepithelial neoplasia in the C3(1)/TAg prostate cancer model. However, gaps in clinical relevance in those models persist. The current study addresses these gaps and the ongoing role of Ghr in prostate cancer using loss-of-function and gain-of-function models.MethodsConditional Ghr inactivation was achieved in the C3(1)/TAg model by employing a tamoxifen-inducible Cre and a prostate-specific Cre. In parallel, a transgenic GH antagonist was also used. Pathology, proliferation, and gene expression of 6-month old mouse prostates were assessed. Analysis of The Cancer Genome Atlas data was conducted to identify GHR overexpression in a subset of human prostate cancers. Ghr overexpression was modeled in PTEN-P2 and TRAMP-C2 mouse prostate cancer cells using stable transfectants. The growth, proliferation, and gene expression effects of Ghr overexpression was assessed in vitro and in vivo.ResultsLoss-of-function for Ghr globally or in prostatic epithelial cells reduced proliferation and stratification of the prostatic epithelium in the C3(1)/TAg model. Genes and gene sets involved in the immune system and tumorigenesis, for example, were dysregulated upon global Ghr disruption. Analysis of The Cancer Genome Atlas revealed higher GHR expression in human prostate cancers with ERG-fusion genes or ETV1-fusion genes. Modeling the GHR overexpression observed in these human prostate cancers by overexpressing Ghr in mouse prostate cancer cells with mutant Pten or T-antigen driver genes increased proliferation of prostate cancer cells in vitro and in vivo. Ghr overexpression regulated the expression of multiple genes oppositely to Ghr loss-of-function models.ConclusionsLoss-of-function and gain-of-function Ghr models, including prostatic epithelial cell specific alterations in Ghr, altered proliferation, and gene expression. These data suggest that changes in GHR activity in human prostatic epithelial cells play a role in proliferation and gene regulation in prostate cancer, suggesting the potential for disrupting GH signaling, for example by the FDA approved GH antagonist pegvisomant, may be beneficial in treating prostate cancer.

Project description:BackgroundCluster of differentiation 4 (CD4+) T cells plays a prominent role in eliminating cancer cells. The balance between T helper (Th)17 and regulatory T (Treg) cells is crucial for optimal immune response and protection against cancer. Growth hormone secretagogue receptor 1a (GHSR1a), a member of the G protein-coupled protein receptor superfamily, plays a critical role in immune cell function. The aim of our study is to investigate the role of GHSR1a in CD4+ T cell differentiation and lung cancer progression.MethodsA subcutaneous lung cancer model was used to examine the role of GHSR1a in controlling tumor growth. Lewis lung carcinoma (LLC) cells were subcutaneously implanted into Ghsr1a -/- mice and wild-type (WT) mice. The ratio of Th17 and Treg in the draining lymph node of Ghsr1a -/- mice and WT tumor-bearing mice was detected by fluorescence-activated cell sorting (FACS). The effect of GHSR1a deficiency on Th17 and Treg cell differentiation was examined using an in vitro differentiation assay. The phosphorylation of mammalian target of rapamycin (mTOR), signal transducer, and activator of transcription (STAT)3 and STAT5 signaling was detected with Western blot.ResultsWe found that the ablation of GHSR1a resulted in impaired anti-tumor immunity to control lung cancer growth in vivo. We also demonstrated that the deficiency of GHSR1a promoted a shift in the Th17/Treg balance toward enhanced Treg differentiation and inhibited Th17 differentiation both in vivo and in vitro, which suggests that GHSR1a regulates T cell lineage choices between Th17 and Treg cell commitment in the tumor microenvironment. Mechanistically, the deficiency of GHSR1a resulted in reduced phosphorylation in mTOR and STAT3, and increased phosphorylation in STAT5.ConclusionsOur findings showed the important role of GHSR1a in CD4+ T cell differentiation in the context of the lung cancer microenvironment. This research provides a novel molecular target and insights into interventions for the prevention and treatment of lung cancer.

Dataset Information

Growth Hormone Receptor Regulation in Cancer and Chronic Diseases.

Publications

Growth Hormone Receptor Regulation in Cancer and Chronic Diseases.

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