Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ASCO Annual Meeting 2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

2024 ASCO Annual Meeting

Keep up to date with all the top stories and latest evidence with our hub page, including official congress videos and expert takeaways.
ADVANCED SEARCH
Log in
Top
Discover Oncology
Published in: Discover Oncology 1/2023

Open Access 01-12-2023 | Pancreatic Cancer | Research

Upregulated GPRC5A disrupting the Hippo pathway promotes the proliferation and migration of pancreatic cancer cells via the cAMP-CREB axis

Authors: Weidan Fang, Xin Yu, Jun Deng, Bin Yu, Jianping Xiong, Mei Ma

Published in: Discover Oncology | Issue 1/2023

Login to get access

Abstract

Background

Pancreatic cancer has a high mortality rate worldwide, and is predicted to be third leading cause of death in the near future. However, the regulatory mechanisms that inhibit the progression of pancreatic cancer remain elusive. Currently, exploring the function and mechanisms of GPCRs (G-protein coupled receptors) is an important way to discover promising therapeutic targets for cancer.

Methods

GPRC5A expression was measured using real-time quantitative PCR, immunohistochemistry and western blot assays. Cell proliferation and migration were assessed using CCK-8, clone formation, wound-healing and transwell assays. A cytosolic/nuclear distribution experiment was used to detect the protein location transfer. A xenograft model of pancreatic cancer was established to explore the role of GPRC5A in vivo.

Results

GPRC5A expression was increased in pancreatic cancer, and disruption of GPRC5A expression inhibited tumor growth in vivo. Mechanistically, GPRC5A positively regulated the transcription of YAP1 through cAMP-CREB signaling. Moreover, we show that the proliferation and migration induced by GPRC5A in pancreatic cancer could be rescued by inhibiting YAP1 expression.

Conclusions

GPRC5A interacts with the Hippo pathway to promote the progression of pancreatic cancer. These findings reveal an important crosstalk model and provide potential targets for pancreatic cancer therapy.
Appendix
Available only for authorised users
Literature
1.
Rahib L, Smith BD, Aizenberg R, Rosenzweig AB, Fleshman JM, Matrisian LM. Projecting cancer incidence and deaths to 2030: the unexpected burden of thyroid, liver, and pancreas cancers in the United States. Cancer Res. 2014;74(11):2913–21.CrossRef
2.
Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, Bray F. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021;71(3):209–49.CrossRef
3.
Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68(6):394–424.CrossRef
4.
Liu Y, An S, Ward R, Yang Y, Guo XX, Li W, Xu TR. G protein-coupled receptors as promising cancer targets. Cancer Lett. 2016;376(2):226–39.CrossRef
5.
Lappano R, Maggiolini M. G protein-coupled receptors: novel targets for drug discovery in cancer. Nat Rev Drug Discov. 2011;10(1):47–60.CrossRef
6.
Jiang X, Xu X, Wu M, Guan Z, Su X, Chen S, Wang H, Teng L. GPRC5A: an emerging biomarker in human cancer. Biomed Res Int. 2018;2018:1823726.CrossRef
7.
Zhong S, Yin H, Liao Y, Yao F, Li Q, Zhang J, Jiao H, Zhao Y, Xu D, Liu S, et al. Lung tumor suppressor GPRC5A binds EGFR and restrains its effector signaling. Cancer Res. 2015;75(9):1801–14.CrossRef
8.
Wang T, Jing B, Xu D, Liao Y, Song H, Sun B, Guo W, Xu J, Li K, Hu M, et al. PTGES/PGE2 signaling links immunosuppression and lung metastasis in Gprc5a-knockout mouse model. Oncogene. 2020;39(15):3179–94.CrossRef
9.
Zhou H, Telonis AG, Jing Y, Xia NL, Biederman L, Jimbo M, Blanco F, Londin E, Brody JR, Rigoutsos I. GPRC5A is a potential oncogene in pancreatic ductal adenocarcinoma cells that is upregulated by gemcitabine with help from HuR. Cell Death Dis. 2016;7: e2294.CrossRef
10.
Jahny E, Yang H, Liu B, Jahnke B, Lademann F, Knosel T, Rummele P, Grutzmann R, Aust DE, Pilarsky C, et al. The G protein-coupled receptor RAI3 is an independent prognostic factor for pancreatic cancer survival and regulates proliferation via STAT3 phosphorylation. PLoS ONE. 2017;12(1): e0170390.CrossRef
11.
Liu B, Yang H, Pilarsky C, Weber GF. The effect of GPRC5a on the proliferation, migration ability, chemotherapy resistance, and phosphorylation of GSK-3beta in pancreatic cancer. Int J Mol Sci. 2018;19(7):1870.CrossRef
12.
Harvey KF, Zhang X, Thomas DM. The Hippo pathway and human cancer. Nat Rev Cancer. 2013;13(4):246–57.CrossRef
13.
Meng Z, Moroishi T, Guan KL. Mechanisms of Hippo pathway regulation. Genes Dev. 2016;30(1):1–17.CrossRef
14.
Rozengurt E, Sinnett-Smith J, Eibl G. Yes-associated protein (YAP) in pancreatic cancer: at the epicenter of a targetable signaling network associated with patient survival. Signal Transduct Target Ther. 2018;3:11.CrossRef
15.
Vallejo A, Perurena N, Guruceaga E, Mazur PK, Martinez-Canarias S, Zandueta C, Valencia K, Arricibita A, Gwinn D, Sayles LC, et al. An integrative approach unveils FOSL1 as an oncogene vulnerability in KRAS-driven lung and pancreatic cancer. Nat Commun. 2017;8:14294.CrossRef
16.
Zanconato F, Forcato M, Battilana G, Azzolin L, Quaranta E, Bodega B, Rosato A, Bicciato S, Cordenonsi M, Piccolo S. Genome-wide association between YAP/TAZ/TEAD and AP-1 at enhancers drives oncogenic growth. Nat Cell Biol. 2015;17(9):1218–27.CrossRef
17.
Wu N, Nguyen Q, Wan Y, Zhou T, Venter J, Frampton GA, DeMorrow S, Pan D, Meng F, Glaser S, et al. The Hippo signaling functions through the Notch signaling to regulate intrahepatic bile duct development in mammals. Lab Invest. 2017;97(7):843–53.CrossRef
18.
Yu FX, Zhao B, Panupinthu N, Jewell JL, Lian I, Wang LH, Zhao J, Yuan H, Tumaneng K, Li H, et al. Regulation of the Hippo-YAP pathway by G-protein-coupled receptor signaling. Cell. 2012;150(4):780–91.CrossRef
19.
20.
Wang K, Huang W, Chen R, Lin P, Zhang T, Ni YF, Li H, Wu J, Sun XX, Geng JJ, et al. Di-methylation of CD147-K234 promotes the progression of NSCLC by enhancing lactate export. Cell Metab. 2021;33(1):160-173 e166.CrossRef
21.
Yao Y, Liu Z, Huang S, Huang C, Cao Y, Li L, Guo H, Liu F, Huang S, Liao Q, et al. The E3 ubiquitin ligase, FBXW5, promotes the migration and invasion of gastric cancer through the dysregulation of the Hippo pathway. Cell Death Discov. 2022;8(1):79.CrossRef
22.
Wang J, Chen M, Wang M, Zhao W, Zhang C, Liu X, Cai M, Qiu Y, Zhang T, Zhou H, et al. The novel ER stress inducer Sec C triggers apoptosis by sulfating ER cysteine residues and degrading YAP via ER stress in pancreatic cancer cells. Acta Pharm Sin B. 2022;12(1):210–27.CrossRef
23.
Zhang W, Nandakumar N, Shi Y, Manzano M, Smith A, Graham G, Gupta S, Vietsch EE, Laughlin SZ, Wadhwa M, et al. Downstream of mutant KRAS, the transcription regulator YAP is essential for neoplastic progression to pancreatic ductal adenocarcinoma. Sci Signal. 2014;7(324):ra42.CrossRef
24.
Zhang Q, Zhang Y, Parsels JD, Lohse I, Lawrence TS, Pasca di Magliano M, Sun Y, Morgan MA. Fbxw7 deletion accelerates Kras(G12D)-driven pancreatic tumorigenesis via Yap accumulation. Neoplasia. 2016;18(11):666–73.CrossRef
25.
Zheng Y, Pan D. The Hippo signaling pathway in development and disease. Dev Cell. 2019;50(3):264–82.CrossRef
26.
Kimple ME, Keller MP, Rabaglia MR, Pasker RL, Neuman JC, Truchan NA, Brar HK, Attie AD. Prostaglandin E2 receptor, EP3, is induced in diabetic islets and negatively regulates glucose- and hormone-stimulated insulin secretion. Diabetes. 2013;62(6):1904–12.CrossRef
27.
Ali DC, Naveed M, Gordon A, Majeed F, Saeed M, Ogbuke MI, Atif M, Zubair HM, Changxing L. beta-Adrenergic receptor, an essential target in cardiovascular diseases. Heart Fail Rev. 2020;25(2):343–54.CrossRef
28.
Zhang H, Kong Q, Wang J, Jiang Y, Hua H. Complex roles of cAMP-PKA-CREB signaling in cancer. Exp Hematol Oncol. 2020;9(1):32.CrossRef
29.
Zhang T, Zhang J, You X, Liu Q, Du Y, Gao Y, Shan C, Kong G, Wang Y, Yang X, et al. Hepatitis B virus X protein modulates oncogene Yes-associated protein by CREB to promote growth of hepatoma cells. Hepatology. 2012;56(6):2051–9.CrossRef
30.
Wang J, Ma L, Weng W, Qiao Y, Zhang Y, He J, Wang H, Xiao W, Li L, Chu Q, et al. Mutual interaction between YAP and CREB promotes tumorigenesis in liver cancer. Hepatology. 2013;58(3):1011–20.CrossRef
31.
Deng J, Fujimoto J, Ye XF, Men TY, Van Pelt CS, Chen YL, Lin XF, Kadara H, Tao Q, Lotan D, et al. Knockout of the tumor suppressor gene Gprc5a in mice leads to NF-kappaB activation in airway epithelium and promotes lung inflammation and tumorigenesis. Cancer Prev Res (Phila). 2010;3(4):424–37.CrossRef
32.
Tao Q, Fujimoto J, Men T, Ye X, Deng J, Lacroix L, Clifford JL, Mao L, Van Pelt CS, Lee JJ, et al. Identification of the retinoic acid-inducible Gprc5a as a new lung tumor suppressor gene. J Natl Cancer Inst. 2007;99(22):1668–82.CrossRef
33.
Hao Y, Chun A, Cheung K, Rashidi B, Yang X. Tumor suppressor LATS1 is a negative regulator of oncogene YAP. J Biol Chem. 2008;283(9):5496–509.CrossRef
34.
Oka T, Mazack V, Sudol M. Mst2 and Lats kinases regulate apoptotic function of Yes kinase-associated protein (YAP). J Biol Chem. 2008;283(41):27534–46.CrossRef
35.
Cho-Chung YS. Role of cyclic AMP receptor proteins in growth, differentiation, and suppression of malignancy: new approaches to therapy. Cancer Res. 1990;50(22):7093–100.
36.
Yu FX, Zhang Y, Park HW, Jewell JL, Chen Q, Deng Y, Pan D, Taylor SS, Lai ZC, Guan KL. Protein kinase A activates the Hippo pathway to modulate cell proliferation and differentiation. Genes Dev. 2013;27(11):1223–32.CrossRef
37.
Hauser AS, Attwood MM, Rask-Andersen M, Schioth HB, Gloriam DE. Trends in GPCR drug discovery: new agents, targets and indications. Nat Rev Drug Discov. 2017;16(12):829–42.CrossRef
Metadata
Title
Upregulated GPRC5A disrupting the Hippo pathway promotes the proliferation and migration of pancreatic cancer cells via the cAMP-CREB axis
Authors
Weidan Fang
Xin Yu
Jun Deng
Bin Yu
Jianping Xiong
Mei Ma
Publication date
01-12-2023
Publisher
Springer US
Published in
Discover Oncology / Issue 1/2023
Print ISSN: 1868-8497
Electronic ISSN: 2730-6011
DOI
https://doi.org/10.1007/s12672-023-00626-1

Other articles of this Issue 1/2023

Discover Oncology 1/2023 Go to the issue

Review

Targeting iron metabolism in osteosarcoma

Research

Using machine learning-based radiomics to differentiate between glioma and solitary brain metastasis from lung cancer and its subtypes

Research

Glutamine is a substrate for glycosylation and CA19-9 biosynthesis through hexosamine biosynthetic pathway in pancreatic cancer

Research

Geriatric nutritional risk index as a prognostic marker of first-line immune checkpoint inhibitor combination therapy in patients with renal cell carcinoma: a retrospective multi-center study

Research

miR-17 ~ 92 suppresses proliferation and invasion of cervical cancer cells by inhibiting cell cycle regulator Cdt2

Research

Identification of Piezo1 as a potential target for therapy of colon cancer stem-like cells
Live Webinar | 27-06-2024 | 18:00 (CEST)

Keynote webinar | Spotlight on medication adherence

Reserve your place

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

WHO estimates that half of all patients worldwide are non-adherent to their prescribed medication. The consequences of poor adherence can be catastrophic, on both the individual and population level.

Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.

Prof. Kevin Dolgin
Prof. Florian Limbourg
Prof. Anoop Chauhan
Developed by: Springer Medicine
Obesity Clinical Trial Summary

At a glance: The STEP trials

Read more

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine
Image Credits