Peroxisome proliferator‑activated receptor‑α expression is associated with histological type in human gastric carcinoma

Morinishi,Tatsuya; Tokuhara,Yasunori; Kajihara,Kazuki; Kawakami,Shunsei; Tanaka,Shinichi; Ohsaki,Hiroyuki; Matsunaga,Toru; Ibuki,Emi; Hirakawa,Eiichiro

doi:10.3892/mco.2021.2484

Peroxisome proliferator‑activated receptor‑α expression is associated with histological type in human gastric carcinoma

Authors:
- Tatsuya Morinishi
- Yasunori Tokuhara
- Kazuki Kajihara
- Shunsei Kawakami
- Shinichi Tanaka
- Hiroyuki Ohsaki
- Toru Matsunaga
- Emi Ibuki
- Eiichiro Hirakawa
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Affiliations: Laboratory of Pathology, Department of Medical Technology, Kagawa Prefectural University of Health Sciences, Takamatsu, Kagawa 761‑0123, Japan, Department of Medical Technology, Faculty of Health Science and Technology, Kawasaki University of Medical Welfare, Kurashiki, Okayama 701‑0193, Japan, Laboratory of Pathology, Department of Medical Biophysics, Kobe University Graduate School of Health Sciences, Kobe, Hyogo 654‑0142, Japan, Department of Diagnostic Pathology, University Hospital, Faculty of Medicine, Kagawa University, Miki, Kagawa 761‑0793, Japan
Published online on: December 24, 2021 https://doi.org/10.3892/mco.2021.2484
Article Number: 51
Copyright: © Morinishi et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Gastric carcinoma is one of the most common types of cancer worldwide and a leading cause of cancer‑related mortality. Gastric carcinoma is histologically subdivided into differentiated and undifferentiated carcinoma, with the latter including poorly differentiated carcinoma and signet ring cell carcinoma (SRCC). Poorly differentiated carcinoma and SRCC have a worse prognosis compared with differentiated carcinoma. Peroxisome proliferator‑activated receptors (PPARs) are nuclear hormone receptors and the PPAR‑α subtype regulates important cellular functions, including cell proliferation, energy metabolism, oxidative stress, immune responses and cell differentiation. The aim of the present study was to elucidate the associations between clinicopathological factors and PPAR‑α expression in patients with gastric carcinoma. The immunohistochemical staining of specimens obtained from 57 patients showed that PPAR‑α expression was slightly weaker in undifferentiated carcinoma than in differentiated carcinoma (P<0.01). PPAR‑α expression also significantly differed between poorly differentiated carcinoma (both positive and negative: 14/20, 70%) and SRCC (not expressed: 0/7, 0%) (P<0.01). However, PPAR‑α expression was not significantly affected by age, lymph node invasion, venous invasion, lymph node metastasis, depth of invasion or stage. Collectively, the present results demonstrated that the downregulated expression of PPAR‑α may play a key role in the biological transformation of tumors. Therefore, PPAR‑α appears to be an important protein related to histology and may hold promise as a prognostic marker. Further studies with a larger number of subjects are needed to elucidate the relationship between PPAR‑α expression and tumor progression and to analyze long‑term clinical survival.

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1	Kepil N, Batur S and Goksel S: Immunohistochemical and genetic features of mucinous and signet-ring cell carcinomas of the stomach, colon and rectum: A comparative study. Int J Clin Exp Pathol. 12:3483–3491. 2019.PubMed/NCBI
2	Katada T, Ishiguro H, Kuwabara Y, Kimura M, Mitui A, Mori Y, Ogawa R, Harata K and Fujii Y: microRNA expression profile in undifferentiated gastric cancer. Int J Oncol. 34:537–542. 2009.PubMed/NCBI
3	Adachi Y, Yasuda K, Inomata M, Sato K, Shiraishi N and Kitano S: Pathology and prognosis of gastric carcinoma: Well versus poorly differentiated type. Cancer. 89:1418–1424. 2000.PubMed/NCBI
4	Noda S, Soejima K and Inokuchi K: Clinicopathological analysis of the intestinal type and diffuse type of gastric carcinoma. Jpn J Surg. 10:277–283. 1980.PubMed/NCBI View Article : Google Scholar
5	Henson DE, Dittus C, Younes M, Nguyen H and Albores-Saavedra J: Differential trends in the intestinal and diffuse types of gastric carcinoma in the United States, 1973-2000: Increase in the signet ring cell type. Arch Pathol Lab Med. 128:765–770. 2004.PubMed/NCBI View Article : Google Scholar
6	Nakamura T, Yao T, Niho Y and Tsuneyoshi M: A clinicopathological study in young patients with gastric carcinoma. J Surg Oncol. 71:214–219. 1999.PubMed/NCBI View Article : Google Scholar
7	Pozos-Ochoa LI, Lino-Silva LS, León-Takahashi AM and Salcedo-Hernández RA: Prognosis of signet ring cell carcinoma of the colon and rectum and their distinction of mucinous adenocarcinoma with signet ring cells. A comparative study. Pathol Oncol Res. 24:609–616. 2018.PubMed/NCBI View Article : Google Scholar
8	Hyngstrom JR, Hu CY, Xing Y, You YN, Feig BW, Skibber JM, Rodriguez-Bigas MA, Cormier JN and Chang GJ: Clinicopathology and outcomes for mucinous and signet ring colorectal adenocarcinoma: Analysis from the national cancer data base. Ann Surg Oncol. 19:2814–2821. 2012.PubMed/NCBI View Article : Google Scholar
9	Nolte RT, Wisely GB, Westin S, Cobb JE, Lambert MH, Kurokawa R, Rosenfeld MG, Willson TM, Glass CK and Milburn MV: Ligand binding and co-activator assembly of the peroxisome proliferator-activated receptor-gamma. Nature. 395:137–143. 1998.PubMed/NCBI View Article : Google Scholar
10	Pozzi A, Ibanez MR, Gatica AE, Yang S, Wei S, Mei S, Falck JR and Capdevila JH: Peroxisomal proliferator-activated receptor-alpha-dependent inhibition of endothelial cell proliferation and tumorigenesis. J Biol Chem. 282:17685–17695. 2007.PubMed/NCBI View Article : Google Scholar
11	Yokoyama Y, Xin B, Shigeto T, Umemoto M, Kasai-Sakamoto A, Futagami M, Tsuchida S, Al-Mulla F and Mizunuma H: Clofibric acid, a peroxisome proliferator-activated receptor alpha ligand, inhibits growth of human ovarian cancer. Mol Cancer Ther. 6:1379–1386. 2007.PubMed/NCBI View Article : Google Scholar
12	Ramanan S, Kooshki M, Zhao W, Hsu FC and Robbins ME: PPARalpha ligands inhibit radiation-induced microglial inflammatory responses by negatively regulating NF-kappaB and AP-1 pathways. Free Radic Biol Med. 45:1695–1704. 2008.PubMed/NCBI View Article : Google Scholar
13	Wang CY, Chao YJ, Chen YL, Wang TW, Phan NN, Hsu HP, Shan YS and Lai MD: Upregulation of peroxisome proliferator-activated receptor-α and the lipid metabolism pathway promotes carcinogenesis of ampullary cancer. Int J Med Sci. 18:256–269. 2021.PubMed/NCBI View Article : Google Scholar
14	Grygiel-Górniak B: Peroxisome proliferator-activated receptors and their ligands: Nutritional and clinical implications-a review. Nutr J. 13(17)2014.PubMed/NCBI View Article : Google Scholar
15	Pandey MK, Gupta SC, Nabavizadeh A and Aggarwal BB: Regulation of cell signaling pathways by dietary agents for cancer prevention and treatment. Semin Cancer Biol. 46:158–181. 2017.PubMed/NCBI View Article : Google Scholar
16	Liu YL, Lin LC, Tung YT, Ho ST, Chen YL, Lin CC and Wu JH: Rhododendron oldhamii leaf extract improves fatty liver syndrome by increasing lipid oxidation and decreasing the lipogenesis pathway in mice. Int J Med Sci. 14:862–870. 2017.PubMed/NCBI View Article : Google Scholar
17	Kliewer SA, Forman BM, Blumberg B, Ong ES, Borgmeyer U, Mangelsdorf DJ, Umesono K and Evans RM: Differential expression and activation of a family of murine peroxisome proliferator-activated receptors. Proc Natl Acad Sci USA. 91:7355–7359. 1994.PubMed/NCBI View Article : Google Scholar
18	Japanese Gastric Cancer Association: Japanese Classification of Gastric Carcinoma. 15th ed. Tokyo, Kanehara Shuppan, 2017 (In Japanese).
19	Tokuhara Y, Morinishi T, Matsunaga T, Ohsaki H, Kushida Y, Haba R and Hirakawa E: Claudin-1, but not claudin-4, exhibits differential expression patterns between well- to moderately-differentiated and poorly-differentiated gastric adenocarcinoma. Oncol Lett. 10:93–98. 2015.PubMed/NCBI View Article : Google Scholar
20	Lin MS, Huang JX, Chen WC, Zhang BF, Fang J, Zhou Q, Hu Y and Gao HJ: Expression of PPARγ and PTEN in human colorectal cancer: An immunohistochemical study using tissue microarray methodology. Oncol Lett. 2:1219–1224. 2011.PubMed/NCBI View Article : Google Scholar
21	Dicken BJ, Bigam DL, Cass C, Mackey JR, Joy AA and Hamilton SM: Gastric adenocarcinoma: Review and considerations for future directions. Ann Surg. 241:27–39. 2005.PubMed/NCBI View Article : Google Scholar
22	Liu X, Cai H, Sheng W, Yu L, Long Z, Shi Y and Wang Y: Clinicopathological characteristics and survival outcomes of primary signet ring cell carcinoma in the stomach: Retrospective analysis of single center database. PLoS One. 10(e0144420)2015.PubMed/NCBI View Article : Google Scholar
23	Pernot S, Voron T, Perkins G, Lagorce-Pages C, Berger A and Taieb J: Signet-ring cell carcinoma of the stomach: Impact on prognosis and specific therapeutic challenge. World J Gastroenterol. 21:11428–11438. 2015.PubMed/NCBI View Article : Google Scholar
24	Jinawath N, Furukawa Y, Hasegawa S, Li M, Tsunoda T, Satoh S, Yamaguchi T, Imamura H, Inoue M, Shiozaki H and Nakamura Y: Comparison of gene-expression profiles between diffuse- and intestinal-type gastric cancers using a genome-wide cDNA microarray. Oncogene. 23:6830–6844. 2004.PubMed/NCBI View Article : Google Scholar
25	Sipponen P: Gastric cancer: Pathogenesis, risks, and prevention. J Gastroenterol. 37 (Suppl 13):S39–S44. 2002.PubMed/NCBI View Article : Google Scholar
26	Hwang CS, Ahn S, Lee BE, Lee SJ, Kim A, Choi CI, Kim DH, Jeon TY, Kim GH, Song GA and Park DY: Risk of lymph node metastasis in mixed-type early gastric cancer determined by the extent of the poorly differentiated component. World J Gastroenterol. 22:4020–4026. 2016.PubMed/NCBI View Article : Google Scholar
27	Chirieac LR, Swisher SG, Correa AM, Ajani JA, Komaki RR, Rashid A, Hamilton SR and Wu TT: Signet-ring cell or mucinous histology after preoperative chemoradiation and survival in patients with esophageal or esophagogastric junction adenocarcinoma. Clin Cancer Res. 11:2229–2236. 2005.PubMed/NCBI View Article : Google Scholar
28	Maggiora M, Oraldi M, Muzio G and Canuto RA: Involvement of PPARα and PPARγ in apoptosis and proliferation of human hepatocarcinoma HepG2 cells. Cell Biochem Funct. 28:571–577. 2010.PubMed/NCBI View Article : Google Scholar
29	Zhang N, Chu ES, Zhang J, Li X, Liang Q, Chen J, Chen M, Teoh N, Farrell G, Sung JJ and Yu J: Peroxisome proliferator activated receptor alpha inhibits hepatocarcinogenesis through mediating NF-κB signaling pathway. Oncotarget. 5:8330–8340. 2014.PubMed/NCBI View Article : Google Scholar
30	You BJ, Hour MJ, Chen LY, Luo SC, Hsu PH and Lee HZ: Fenofibrate induces human hepatoma Hep3B cells apoptosis and necroptosis through inhibition of thioesterase domain of fatty acid synthase. Sci Rep. 9(3306)2019.PubMed/NCBI View Article : Google Scholar
31	Gao J, Liu Q, Xu Y, Gong X, Zhang R, Zhou C, Su Z, Jin J, Shi H, Shi J and Hou Y: PPARα induces cell apoptosis by destructing Bcl2. Oncotarget. 6:44635–44642. 2015.PubMed/NCBI View Article : Google Scholar
32	Morinishi T, Tokuhara Y, Ohsaki H, Ibuki E, Kadota K and Hirakawa E: Activation and expression of peroxisome proliferator-activated receptor alpha are associated with tumorigenesis in colorectal carcinoma. PPAR Res. 2019(7486727)2019.PubMed/NCBI View Article : Google Scholar
33	Knapp P, Chabowski A, Błachnio-Zabielska A, Jarząbek K and Wołczyński S: Altered peroxisome-proliferator activated receptors expression in human endometrial cancer. PPAR Res. 2012(471524)2012.PubMed/NCBI View Article : Google Scholar
34	Luo Y, Chen L, Wang G, Qian G, Liu X, Xiao Y, Wang X and Qian K: PPARα gene is a diagnostic and prognostic biomarker in clear cell renal cell carcinoma by integrated bioinformatics analysis. J Cancer. 10:2319–2331. 2019.PubMed/NCBI View Article : Google Scholar
35	Yu H and Xin Y: Down-regulated expressions of PPARγ and its coactivator PGC-1 are related to gastric carcinogenesis and Lauren's classification in gastric carcinoma. Chin J Cancer Res. 25:704–714. 2013.PubMed/NCBI View Article : Google Scholar
36	Theocharis S, Kanelli H, Politi E, Margeli A, Karkandaris C, Philippides T and Koutselinis A: Expression of peroxisome proliferator activated receptor-gamma in non-small cell lung carcinoma: Correlation with histological type and grade. Lung Cancer. 36:249–255. 2002.PubMed/NCBI View Article : Google Scholar
37	Nomura S, Nakajima A, Ishimine S, Matsuhashi N, Kadowaki T and Kaminishi M: Differential expression of peroxisome proliferator-activated receptor in histologically different human gastric cancer tissues. J Exp Clin Cancer Res. 25:443–448. 2006.PubMed/NCBI
38	Tan Y, Wang M, Yang K, Chi T, Liao Z and Wei P: PPAR-α modulators as current and potential cancer treatments. Front Oncol. 11(599995)2021.PubMed/NCBI View Article : Google Scholar