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A growth hormone receptor SNP promotes lung cancer by impairment of SOCS2-mediated degradation.

ABSTRACT: Both humans and mice lacking functional growth hormone (GH) receptors are known to be resistant to cancer. Further, autocrine GH has been reported to act as a cancer promoter. Here we present the first example of a variant of the GH receptor (GHR) associated with cancer promotion, in this case lung cancer. We show that the GHRP495T variant located in the receptor intracellular domain is able to prolong the GH signal in vitro using stably expressing mouse pro-B-cell and human lung cell lines. This is relevant because GH secretion is pulsatile, and extending the signal duration makes it resemble autocrine GH action. Signal duration for the activated GHR is primarily controlled by suppressor of cytokine signalling 2 (SOCS2), the substrate recognition component of the E3 protein ligase responsible for ubiquitinylation and degradation of the GHR. SOCS2 is induced by a GH pulse and we show that SOCS2 binding to the GHR is impaired by a threonine substitution at Pro 495. This results in decreased internalisation and degradation of the receptor evident in TIRF microscopy and by measurement of mature (surface) receptor expression. Mutational analysis showed that the residue at position 495 impairs SOCS2 binding only when a threonine is present, consistent with interference with the adjacent Thr494. The latter is key for SOCS2 binding, together with nearby Tyr487, which must be phosphorylated for SOCS2 binding. We also undertook nuclear magnetic resonance spectroscopy approach for structural comparison of the SOCS2 binding scaffold Ile455-Ser588, and concluded that this single substitution has altered the structure of the SOCS2 binding site. Importantly, we find that lung BEAS-2B cells expressing GHRP495T display increased expression of transcripts associated with tumour proliferation, epithelial-mesenchymal transition and metastases (TWIST1, SNAI2, EGFR, MYC and CCND1) at 2?h after a GH pulse. This is consistent with prolonged GH signalling acting to promote cancer progression in lung cancer.

SUBMITTER: Chhabra Y

PROVIDER: S-EPMC5799715 | biostudies-literature | 2018 Jan

REPOSITORIES: biostudies-literature

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A growth hormone receptor SNP promotes lung cancer by impairment of SOCS2-mediated degradation.

Chhabra Y Y Wong H Y HY Nikolajsen L F LF Steinocher H H Papadopulos A A Tunny K A KA Meunier F A FA Smith A G AG Kragelund B B BB Brooks A J AJ Waters M J MJ

Oncogene 20171002 4

Both humans and mice lacking functional growth hormone (GH) receptors are known to be resistant to cancer. Further, autocrine GH has been reported to act as a cancer promoter. Here we present the first example of a variant of the GH receptor (GHR) associated with cancer promotion, in this case lung cancer. We show that the GHRP495T variant located in the receptor intracellular domain is able to prolong the GH signal in vitro using stably expressing mouse pro-B-cell and human lung cell lines. Thi ...[more]

PMID: 28967904

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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.

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A growth hormone receptor SNP promotes lung cancer by impairment of SOCS2-mediated degradation.

Publications

A growth hormone receptor SNP promotes lung cancer by impairment of SOCS2-mediated degradation.

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