The role of IL-17 in obesity-associated prostate cancer progression

IL-17 在肥胖相关前列腺癌进展中的作用

• 批准号: 10614371
• 负责人: Zongbing You
• 金额: --
• 依托单位: SOUTHEAST LOUISIANA VETERANS HEALTH CARE
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-10-01 至 2024-03-02
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10614371
• 关键词: Adult; American; American Cancer Society; Animal Model; Binding; Blood; Body Weight; Cancer Etiology; Cancer Patient; Cessation of life; Clinical; Development; Diabetes Mellitus; Diagnosis; Disease; Gene Expression; Genes; Glycogen Synthase Kinase 3; Health; Healthcare; High Fat Diet; Hormones; Human; Hyperinsulinism; IL17 gene; Incidence; Inflammation; Inflammatory; Insulin; Insulin Resistance; Insulin Signaling Pathway; Knock-in; Knock-out; Knockout Mice; Knowledge; Link; Malignant Neoplasms; Malignant neoplasm of prostate; Mediating; Modeling; Molecular; Mus; Mutation; Non-Insulin-Dependent Diabetes Mellitus; Obese Mice; Obesity; Overweight; Pathologic; Patients; Phosphatidylinositols; Phosphorylation; Phosphorylation Site; Phosphotransferases; Plasma; Prevalence; Prevention; Prostate; Prostate Cancer therapy; Proteins; Reporting; Research; Risk; Role; Signal Pathway; Signal Transduction; Specimen; Surveys; Testing; Thinness; Ubiquitination; Veterans; cancer diagnosis; castration resistant prostate cancer; clinically significant; cytokine; diabetic; diet-induced obesity; epidemiology study; glycogen synthase kinase 3 beta; high risk; inhibitor; insulin signaling; men; mortality; multicatalytic endopeptidase complex; mutant; novel; obese person; prostate cancer progression; prostate cancer risk; receptor; response; tumor

About 35.5% American men are obese and obesity has been positively associated with high-grade prostate cancer, castration-resistant prostate cancer, and prostate cancer-specific mortality. Obesity has been associated with a 50% increased risk of pathological progression in prostate cancer patients under active surveillance. However, the molecular mechanisms underlying the association between obesity and prostate cancer progression remain as a significant knowledge gap to be filled. It is known that obese people often develop type 2 diabetes (T2D) with increased blood levels of insulin and inflammatory cytokines such as interleukin-17 (IL-17). We have previously demonstrated that IL-17 promotes development of hormone-naïve and castration-resistant prostate cancer in Pten-null mice. Our preliminary studies found that prostate cancer formation rate was increased by approximately 82% in high-fat diet-induced obese Pten-null mice compared to lean Pten-null mice. We have demonstrated that insulin enhances IL-17-induced gene expression through inhibition of glycogen synthase kinase 3 (GSK3). Moreover, we have originally found that GSK3 binds to and phosphorylates IL-17 receptor A (IL-17RA) at residue T780, leading to ubiquitination and proteasome-mediated degradation of IL-17RA. In obese mice, hyperinsulinemia activated phosphoinositide 3-kinase (PI3K)/Akt to phosphorylate GSK3α at S21 and GSK3β at S9, thus inhibiting GSK3 activity; subsequently, IL-17RA phosphorylation by GSK3 is reduced, resulting in increased levels of IL-17RA protein, followed by enhanced IL-17 signaling and increased expression of multiple IL-17 downstream genes. These findings suggest that IL- 17 signaling and insulin signaling crosstalk via GSK3, which is a novel mechanism by which obesity drives prostate cancer progression. Based on these findings, we have formulated a central hypothesis that GSK3 is an intrinsic inhibitor of IL-17 signaling, and in obesity with T2D, high levels of insulin enhance IL-17-mediated responses through inhibiting GSK3 activities, thereby promoting prostate cancer progression. We propose to test our central hypothesis through achieving the following three specific aims: Aim 1) Determine GSK3’s role in regulating IL-17’s pro-tumor function in Pten-null obese mice. We will use two animal models: a) we will create Gsk3α;Pten and Gsk3β;Pten double knockout mice with wild-type IL-17ra; we expect to find a decrease in IL-17RA phosphorylation by GSK3, a decrease in IL-17RA degradation, and an increase in IL-17-mediated inflammation in mouse prostate, resulting in an increase in prostate cancer incidence; b) we will create IL-17ra T779A knockin mutant (IL-17raKI/KI) mice that will not respond to GSK3-mediated phosphorylation of IL-17RA, thus allowing assessment of IL-17-independent functions of GSK3; mouse T779 is homologous to human T780 on IL-17RA; we expect to find no significant differences in prostate cancer formation comparing Gsk3α;Pten and Gsk3β;Pten double knockout mice with Gsk3 wild-type Pten-null mice with IL-17RA T779A mutation. Aim 2) Define the molecular mechanisms by which GSK3 inhibits IL-17 signaling. We will determine if IL-17RA phosphorylation at T780 by GSK3 requires a primed phosphorylation and if there are other GSK3 phosphorylation sites on IL-17RA. Aim 3) Assess the association between GSK3/IL-17 status and prostate cancer in obese/diabetic men. We will assess GSK3/IL-17 status in 500 prostate cancer specimens from patients with normal body weight, overweight, and obesity, with or without T2D; we will assess the associations between GSK3/IL-17 status and the clinical variables. Successful completion of the proposed studies will provide novel molecular mechanisms of how obesity drives prostate cancer progression, which will significantly advance the knowledge and reveal new targets in the prevention and treatment of prostate cancer.

约35.5%的美国男性肥胖，肥胖与高级别前列腺癌呈正相关

项目成果

Defect of IL17 Signaling, but Not Centrinone, Inhibits the Development of Psoriasis and Skin Papilloma in Mouse Models.

• DOI: 10.3390/biomedicines10081976
• 发表时间: 2022-08-15
• 期刊: Biomedicines
• 影响因子: 4.7

Intra-arterial injection to create bone metastasis of prostate cancer in mice.

动脉内注射在小鼠体内产生前列腺癌骨转移。

• 发表时间: 2020
• 期刊: American journal of clinical and experimental urology
• 影响因子: 1.2
• 作者: Zhong,Lin;Miller,HaiyanD;Zhang,Yongfeng;Jin,Ben;Ge,Dongxia;You,Zongbing
• 通讯作者: You,Zongbing

PD-L1 instead of PD-1 status is associated with the clinical features in human primary prostate tumors.

PD-L1（而不是 PD-1）状态与人类原发性前列腺肿瘤的临床特征相关。

• 发表时间: 2019
• 期刊: American journal of clinical and experimental urology
• 影响因子: 1.2
• 作者: Xian,Peng;Ge,Dongxia;Wu,VictorJ;Patel,Avi;Tang,WendellW;Wu,Xiaocheng;Zhang,Kun;Li,Li;You,Zongbing
• 通讯作者: You,Zongbing

Genome and transcriptome profiling of FBXW family in human prostate cancer.

人类前列腺癌 FBXW 家族的基因组和转录组分析。

• 发表时间: 2020
• 期刊: American journal of clinical and experimental urology
• 影响因子: 1.2
• 作者: Lan,Ruoxin;Jin,Ben;Liu,Yao-Zhong;Zhang,Kun;Niu,Tianhua;You,Zongbing
• 通讯作者: You,Zongbing

Novel discoveries in urology: big data to microbiome - highlights of the society for basic urologic research 2019 annual meeting.

泌尿外科新发现：大数据到微生物组——泌尿基础研究学会2019年年会亮点

• 发表时间: 2020
• 期刊: American journal of clinical and experimental urology
• 影响因子: 1.2
• 作者: Jin,Ben;Prins,GailS;Adam,Rosalyn;Yu,Jindan;Sfanos,KarenS;Li,Benyi;Hu,Chang-Deng;Dong,Yan;You,Zongbing
• 通讯作者: You,Zongbing