Lung cancer suppressor gene GPRC5A mediates p53 activity in non‑small cell lung cancer cells in vitro

Jin,Er; Wang,Wenzhe; Fang,Mengdie; Wang,Limin; Wu,Kan; Zhang,Yemei; Zhang,Shirong; Ma,Shenglin

doi:10.3892/mmr.2017.7343

Lung cancer suppressor gene GPRC5A mediates p53 activity in non‑small cell lung cancer cells in vitro

Authors:
- Er Jin
- Wenzhe Wang
- Mengdie Fang
- Limin Wang
- Kan Wu
- Yemei Zhang
- Shirong Zhang
- Shenglin Ma
View Affiliations

Affiliations: Department of Respiratory Medicine, Nanjing Medical University Affiliated Hangzhou Hospital, Hangzhou First People's Hospital, Hangzhou, Zhejiang 310006, P.R. China, Center for Molecular Medicine, Zhejiang Academy of Medical Sciences, Hangzhou, Zhejiang 310012, P.R. China, Department of Medical Oncology, Nanjing Medical University Affiliated Hangzhou Hospital, Hangzhou First People's Hospital, Hangzhou, Zhejiang 310006, P.R. China
Published online on: August 23, 2017 https://doi.org/10.3892/mmr.2017.7343
Pages: 6382-6388

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Cellular tumor antigen p53 (p53) functions to maintain genomic stability and regulate cell apoptosis, while G protein‑coupled receptor class C group 5 member A (GPCR5A) is a lung cancer suppressor gene whose expression is induced by retinoids. The present in vitro study assessed the effects of p53 on the regulation of GPRC5A expression and on non‑small cell lung cancer (NSCLC) cells. Human NSCLC H1299 (p53‑null) and A549 (wild‑type p53) cell lines were subjected to p53 cDNA and small interfering (si)RNA transfection, respectively. GPRC5A expression was analyzed by reverse transcription‑quantitative polymerase chain reaction and western blotting, and cell behavior was analyzed using cell viability and apoptosis assays. The results of the present study demonstrated that knockdown of GPRC5A expression markedly upregulated tumor cell viability and reduced tumor cell apoptosis, while p53 overexpression in H1299 cells significantly increased the expression level of GPRC5A. p53 overexpression and GPRC5A induction markedly inhibited tumor cell viability and induced apoptosis, while knockdown of p53 resulted in a decrease in GPRC5A expression, inhibited tumor cell apoptosis and increased tumor cell viability. In serum‑free culture conditions, GPRC5A expression was decreased in the two cell lines; this decrease was less marked in p53 cDNA‑transfected H1299 cells and more marked in p53 siRNA‑transfected A549 cells. The results of the present study indicated that p53 antitumor activity may be mediated by GPRC5A in NSCLC cells.

View Figures

View References

1	Jemal A, Bray F, Center MM, Ferlay J, Ward E and Forman D: Global cancer statistics. CA Cancer J Clin. 61:69–90. 2011. View Article : Google Scholar : PubMed/NCBI
2	Yang P, Allen MS, Aubry MC, Wampfler JA, Marks RS, Edell ES, Thibodeau S, Adjei AA, Jett J and Deschamps C: Clinical features of 5,628 primary lung cancer patients: Experience at mayo clinic from 1997 to 2003. Chest. 128:452–462. 2005. View Article : Google Scholar : PubMed/NCBI
3	Fridman JS and Lowe SW: Control of apoptosis by p53. Oncogene. 22:9030–9040. 2003. View Article : Google Scholar : PubMed/NCBI
4	Fukasawa K, Wiener F, Woude GF Vande and Mai S: Genomic instability and apoptosis are frequent in p53 deficient young mice. Oncogene. 15:1295–1302. 1997. View Article : Google Scholar : PubMed/NCBI
5	Cheng Y and Lotan R: Molecular cloning and characterization of a novel retinoic acid-inducible gene that encodes a putative G protein-coupled receptor. J Biol Chem. 273:35008–35015. 1998. View Article : Google Scholar : PubMed/NCBI
6	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. 99:1668–1682. 2007. View Article : Google Scholar : PubMed/NCBI
7	Ye X, Tao Q, Wang Y, Cheng Y and Lotan R: Mechanisms underlying the induction of the putative human tumor suppressor GPRC5A by retinoic acid. Cancer Biol Ther. 8:951–962. 2009. View Article : Google Scholar : PubMed/NCBI
8	Kadara H, Fujimoto J, Men T, Ye X, Lotan D, Lee JS and Lotan R: A Gprc5a tumor suppressor loss of expression signature is conserved, prevalent, and associated with survival in human lung adenocarcinomas. Neoplasia. 12:499–505. 2010. View Article : Google Scholar : PubMed/NCBI
9	Mogi A and Kuwano H: TP53 mutations in nonsmall cell lung cancer. J Biomed Biotechnol. 2011:5839292011. View Article : Google Scholar : PubMed/NCBI
10	Wu Q, Ding W, Mirza A, Van Arsdale T, Wei I, Bishop WR, Basso A, McClanahan T, Luo L, Kirschmeier P, et al: Integrative genomics revealed RAI3 is a cell growth-promoting gene and a novel P53 transcriptional target. J Biol Chem. 280:12935–12943. 2005. View Article : Google Scholar : PubMed/NCBI
11	Li S, Huang S and Peng SB: Overexpression of G protein-coupled receptors in cancer cells: Involvement in tumor progression. Int J Oncol. 27:1329–1339. 2005.PubMed/NCBI
12	Fujimoto J, Kadara H, Men T, van Pelt C, Lotan D and Lotan R: Comparative functional genomics analysis of NNK tobacco-carcinogen induced lung adenocarcinoma development in Gprc5a-knockout mice. PLoS One. 5:e118472010. View Article : Google Scholar : PubMed/NCBI
13	Barta P, Van Pelt C, Men T, Dickey BF, Lotan R and Moghaddam SJ: Enhancement of lung tumorigenesis in a Gprc5a Knockout mouse by chronic extrinsic airway inflammation. Mol Cancer. 11:42012. View Article : Google Scholar : PubMed/NCBI
14	Fujimoto J, Kadara H, Garcia MM, Kabbout M, Behrens C, Liu DD, Lee JJ, Solis LM, Kim ES, Kalhor N, et al: G-protein coupled receptor family C, group 5, member A (GPRC5A) expression is decreased in the adjacent field and normal bronchial epithelia of patients with chronic obstructive pulmonary disease and non-small-cell lung cancer. J Thorac Oncol. 7:1747–1754. 2012. View Article : Google Scholar : PubMed/NCBI
15	Nagahata T, Sato T, Tomura A, Onda M, Nishikawa K and Emi M: Identification of RAI3 as a therapeutic target for breast cancer. Endocr Relat Cancer. 12:65–73. 2005. View Article : Google Scholar : PubMed/NCBI
16	Chen X, Wong JY, Wong P and Radany EH: Low-dose valproic acid enhances radiosensitivity of prostate cancer through acetylated p53-dependent modulation of mitochondrial membrane potential and apoptosis. Mol Cancer Res. 9:448–461. 2011. View Article : Google Scholar : PubMed/NCBI
17	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI
18	Lakin ND and Jackson SP: Regulation of p53 in response to DNA damage. Oncogene. 18:7644–7655. 1999. View Article : Google Scholar : PubMed/NCBI
19	Nowsheen S and Yang ES: The intersection between DNA damage response and cell death pathways. Exp Oncol. 34:243–254. 2012.PubMed/NCBI
20	Hirano M, Zang L, Oka T, Ito Y, Shimada Y, Nishimura Y and Tanaka T: Novel reciprocal regulation of cAMP signaling and apoptosis by orphan G-protein-coupled receptor GPRC5A gene expression. Biochem Biophys Res Commun. 351:185–191. 2006. View Article : Google Scholar : PubMed/NCBI