Inhibitory effect of PPARγ on NR0B1 in tumorigenesis of lung adenocarcinoma

Susaki,Yoshiyuki; Inoue,Masayoshi; Minami,Masato; Sawabata,Noriyoshi; Shintani,Yasushi; Nakagiri,Tomoyuki; Funaki,Soichiro; Aozasa,Katsuyuki; Okumura,Meinoshin; Morii,Eiichi

doi:10.3892/ijo.2012.1571

Inhibitory effect of PPARγ on NR0B1 in tumorigenesis of lung adenocarcinoma

Authors:
- Yoshiyuki Susaki
- Masayoshi Inoue
- Masato Minami
- Noriyoshi Sawabata
- Yasushi Shintani
- Tomoyuki Nakagiri
- Soichiro Funaki
- Katsuyuki Aozasa
- Meinoshin Okumura
- Eiichi Morii
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Affiliations: Department of Pathology, Osaka University Graduate School of Medicine, Suita 565-0871, Japan, Department of General Thoracic Surgery, Osaka University Graduate School of Medicine, Suita 565-0871, Japan
Published online on: July 25, 2012 https://doi.org/10.3892/ijo.2012.1571
Pages: 1278-1284

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Abstract

NR0B1, an orphan nuclear receptor, is expressed in side population cells and its knockdown reduces tumorigenic and anti-apoptotic potential in lung adenocarcinoma. Peroxisome proliferator-activated receptor γ (PPARγ) is another member of the nuclear receptor family which induces apoptosis in lung cancer. The interaction of NR0B1 with PPARγ was examined. The transactivation ability of PPARγ was inhibited by NR0B1 in lung adenocarcinoma, and the N-terminal region of NR0B1 containing LxxLL motifs mediated its inhibition. Co-immunoprecipitation experiments revealed that this N-terminal region of NR0B1 was essential for the physical interaction with PPARγ. Aldehyde dehydrogenase (ALDH) activity and ALDH3A1 expression, which are correlated with tumorigenic potential of lung adenocarcinoma, increased when NR0B1 expression was induced, but its increase was inhibited by PPARγ overexpression. ALDH activity increased by treatment with PPARγ inhibitor, and the increase was further enhanced when the expression of NR0B1 was induced. Furthermore, the high NR0B1 and low PPARγ expression was a negative prognostic factor in Pathological-Stage IA clinical cases. These results indicate the reciprocal relationship between NR0B1 and PPARγ on the malignant grade of lung adenocarcinoma.

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1	Alberg AJ, Ford JG and Samet JM; American College of Chest Physicians: Epidemiology of lung cancer: ACCP evidence-based clinical practice guidelines (2nd edition). Chest. 132:29S–55S. 2007. View Article : Google Scholar : PubMed/NCBI
2	Committee for Scientific Affairs; Sakata R, Fujii Y and Kuwano H: Thoracic and cardiovascular surgery in Japan during 2009: Annual report by The Japanese Association for Thoracic Surgery. Gen Thorac Cardiovasc Surg. 59:636–667. 2011. View Article : Google Scholar : PubMed/NCBI
3	Sawabata N, Miyaoka E, Asamura H, et al: Japanese lung cancer registry study of 11,663 surgical cases in 2004. J Thorac Oncol. 6:1229–1235. 2011. View Article : Google Scholar : PubMed/NCBI
4	Zanaria E, Muscatelli F, Bardoni B, et al: An unusual member of the nuclear hormone receptor superfamily responsible for X-linked adrenal hypoplasia congenita. Nature. 372:635–645. 1994. View Article : Google Scholar : PubMed/NCBI
5	Swain A, Zanaria E, Hacker A, Lovell-Badge R and Camerino G: Mouse Dax1 expression is consistent with a role in sex determination as well as in adrenal and hypothalamus function. Nat Genet. 12:404–409. 1996. View Article : Google Scholar : PubMed/NCBI
6	Burris TP, Guo W and McCabe ERB: The gene responsible for adrenal hypoplasia congenita, DAX1, encodes a nuclear hormone receptor that defines a new class within the superfamily. Recent Prog Horm Res. 51:241–260. 1996.PubMed/NCBI
7	Ikeda Y, Swain A, Weber TJ, et al: Steroidogenic factor 1 and Dax-1 colocalization in multiple cell lineages: potential links in endocrine development. Mol Endocrinol. 10:1261–72. 1996.PubMed/NCBI
8	Lessnick SL, Dacwag CS and Golub TR: The Ewing’s sarcoma oncoprotein EWS/FLI induces a p53-dependent growth arrest in primary human fibroblasts. Cancer Cell. 1:393–401. 2002.
9	Lalli E, Melner MH, Stocco DM and Sassone-Corsi P: DAX-1 blocks steroid production at multiple levels. Endocrinology. 139:4237–4243. 1998.PubMed/NCBI
10	Zazopoulos P, Lalli E, Stocco DM and Sassone-Corsi P: DNA binding and transcriptional repression by DAX-1 blocks steroidogenesis. Nature. 390:311–315. 1997. View Article : Google Scholar : PubMed/NCBI
11	Sugawara T, Lin D, Holt JA, et al: Structure of the human steroidogenic acute regulatory protein (StAR) gene. Biochemistry. 34:12506–12512. 1995. View Article : Google Scholar : PubMed/NCBI
12	Stocco DM and Clark BJ: Regulation of acute production of steroid in steroidgenic tissue. Endocr Rev. 17:221–244. 1996.PubMed/NCBI
13	Park YY, Ahn SW, Kim HJ, et al: An autoregulatory loop controlling orphan nuclear receptor DAX-1 gene expression by orphan nuclear receptor ERRγ. Nucleic Acids Res. 33:6756–6768. 2005.PubMed/NCBI
14	Holter E, Kotaja N, Makela S, et al: Inhibition of androgen receptor(AR) function by the reproductive orphan nuclear receptor DAX-1. Mol Endocrinol. 16:512–528. 2002. View Article : Google Scholar : PubMed/NCBI
15	Agoulnik IU, Krause WC, Bingman WE III, et al: Repressors of androgen and progesterone receptor action. J Biol Chem. 278:31136–31148. 2003. View Article : Google Scholar : PubMed/NCBI
16	Lalli E, Ohe K, Hindelang C and Sassone-Corsi P: Orphan receptor DAX-1 is a shuttling RNA binding protein associated with polyribosomes via mRNA. Mol Cell Biol. 20:4910–4921. 2000. View Article : Google Scholar : PubMed/NCBI
17	Reya T, Morrison SJ, Clarke MF and Weissman IL: Stem cells, cancer, and cancer stem cells. Nature. 414:105–111. 2001. View Article : Google Scholar : PubMed/NCBI
18	Dean M, Fojo T and Bates S: Tumor stem cells and drug resistance. Nat Rev Cancer. 5:275–284. 2005. View Article : Google Scholar
19	Lou H and Dean M: Targeted therapy for cancer stem cells: the patched pathway and ABC transporters. Oncogene. 26:1357–1360. 2007. View Article : Google Scholar : PubMed/NCBI
20	Seo DC, Sung JM, Cho HJ, et al: Gene expression profiling of cancer stem cell in human lung adenocarcinoma A549 cells. Mol Cancer. 6:752007. View Article : Google Scholar : PubMed/NCBI
21	Saito S, Ito K, Suzuki T, et al: Orphan nuclear receptor DAX-1 in human endometrium and its disorders. Cancer Sci. 96:645–652. 2005. View Article : Google Scholar : PubMed/NCBI
22	Nakamura Y, Suzuki T, Arai Y and Sasano H: Nuclear receptor DAX1 in human prostate cancer: a novel independent biological modulator. Endocr J. 56:39–44. 2009. View Article : Google Scholar : PubMed/NCBI
23	Mendiola M, Carrillo J, García E, et al: The orphan nuclear receptor DAX1 is up-regulated by the EWS/FLI1 oncoprotein and is highly expressed in Ewing tumors. Int J Cancer. 118:1381–1389. 2006. View Article : Google Scholar : PubMed/NCBI
24	Kinsey M, Smith R and Lessnick SL: NR0B1 is required for the oncogenic phenotype mediated by EWS/FLI in Ewing’s sarcoma. Mol Cancer Res. 4:851–859. 2006.
25	Oda T, Tian T, Inoue M, et al: Tumorgenic role of orphan nuclear receptor NR0B1 in lung adenocarcinoma. Am J Pathol. 175:1235–1245. 2009. View Article : Google Scholar : PubMed/NCBI
26	Spiegelman BM: PPAR-γ: Adipogenic regulator and thiazolidinedine receptor. Diabetes. 47:507–514. 1998.
27	Tontonoz P, Hu E and Spiegelman BM: Stimulation of adipogenesis in fibroblasts by PPARγ 2, a lipid-activated transcription factor. Cell. 79:1147–1156. 1994.
28	Gearing KL, Gottlicher M, Teboul M, Widmark E and Gustafsson JA: Interaction of the peroxisome-proliferator-activated receptor and retinoid X receptor. Proc Natl Acad Sci USA. 90:1440–1444. 1993. View Article : Google Scholar : PubMed/NCBI
29	Mueller E, Sarraf P, Tontonoz P, et al: Terminal differentiation of human breast cancer through PPARγ. Mol Cell. 1:465–470. 1998.
30	Sarraf P, Mueller E, Jones D, et al: Differentiation and reversal of malignant changes in colon cancer through PPARγ. Nat Med. 4:1046–1052. 1998.PubMed/NCBI
31	Lambe KG and Tugwood JD: A human perioxisome proliferator-activated receptor-γ is activated by inducers of adipogenesis including thiazolidinedine drugs. Eur J Biochem. 239:1–7. 1996.
32	Keshamouni VG, Reddy RC, Arenberg DA, et al: Peroxisome proliferator-activated receptor-γ activation inhibits tumor progression in non-small-cell lung cancer. Oncogene. 23:100–108. 2004.
33	Satoh T, Toyoda M, Hoshino H, et al: Activation of peroxisome proliferator-activated receptor-γ stimulates the growth arrest and DNA-damage inducible 153 gene in non-small cell lung carcinoma cells. Oncogene. 21:2171–2180. 2002.
34	Li M, Lee TW, Mok TS, Warner TD, Yim AP and Chen GC: Activation of peroxisome proliferator-activated receptor-γ by troglitazone (TGZ) inhibits human lung cell growth. J Cell Biochem. 96:760–774. 2005.
35	Tsubouchi Y, Sano H, Kawahito Y, et al: Inhibition of human lung cancer cell growth by the peroxisome proliferator-activated receptor-γ agonists through induction of apoptosis. Biochem Biophys Res Commun. 270:400–405. 2000.
36	Kim GS, Lee GY, Nedumaran B, et al: The orphan nuclear receptor DAX-1 acts as a novel transcriptional corepressor of PPARγ. Biochem Biophys Res Commun. 370:264–268. 2008.PubMed/NCBI
37	Morii E and Oboki K: MITF is necessary for generation of prostaglandin D2 in mouse mast cells. J Biol Chem. 279:48293–48299. 2004. View Article : Google Scholar : PubMed/NCBI
38	Patel M, Lu L, Zander DS, Sreerama L, Coco D and Moreb JS: ALDH1A1 and ALDH3A1 expression in lung cancers: Correlation with histologic type and potential precursors. Lung Cancer. 59:340–349. 2008. View Article : Google Scholar : PubMed/NCBI
39	Muzio G, Maggiora M, Paiuzzi E, Oraldi M and Canuto RA: Aldehyde dehydrogenase ands and cell proliferation. Free Radic Biol Med. 52:735–746. 2012. View Article : Google Scholar : PubMed/NCBI