KASMEJ

Kastamonu Medical Journal regularly publishes internationally qualified issues in the field of Medicine in the light of up-to-date information.

EndNote Style
Index
Original Article
Expression of TGR5 (GPBAR1) and NOX5 in renal tumor subtypes: ımmunohistochemical and RT-PCR analysis
Aims: This study aimed to determine the expressions of TGR5 (G protein-coupled bile acid receptor 1) and NADPH oxidase 5 (NOX5) in renal cancer subtypes.
Methods: In formalin-fixed, paraffin-embedded tissue sections of renal tumor subtypes, TGR5 and NOX5 protein expressions were measured by immunohistochemical staining and mRNA expressions were measured by RT-PCR.
Results: Our results showed that TGR5 and NOX5 exhibited differences in their expression levels in RCC subtypes, and that TGR5 expression was upregulated in papillary RCC (r=0.53, p<0.01). A positive correlation of TGR5 with NOX5 was detected in the same subtype (r=0.49, p<0.01). After COCOR analysis, a statistically significant difference was found in the TGR5-NOX5 correlation between papillary RCC and clear cell RCC subtypes (z=1.92, p=0.02). At the same time, expression profiles showed that TGR5 was highly expressed in all groups except clear cell RCC compared to normal kidney tissue, but among these, TGR5 had the diagnostic power to distinguish papillary RCC from other groups (AUC=0.94, 95% CI: 0.64–0.95, p=0.005).
Conclusion: The present findings indicate the potential of TGR5 as a diagnostic biomarker for papillary RCC, while suggesting that it may have a functional role in regulating the tumor microenvironment together with NOX5.


1. Sanganeria BS, Misra R, Shukla KK. Molecular diagnostics in renal cancer. Molecular Diagnostics in Cancer Patients. Singapore: Springer. 2019;199-218.
2. T&uuml;rk A, Aslan H, Balaban M, Demirkol MK, Tarhan F. B&ouml;breğin renal h&uuml;creli kanserlerinde klinik ve histopatolojik &ouml;zellikler. J Kartal TR. 2014;25(2):124-126.
3. Freitas AS, Costa M, Pontes O, et al. Selective cytotoxicity of portuguese propolis ethyl acetate fraction towards renal cancer cells. Molecules. 2022;27(13):4001. doi:10.3390/molecules27134001
4. Li F, Aljahdali IAM, Zhang R, Nastiuk KL, Krolewski JJ, Ling X. Kidney cancer biomarkers and targets for therapeutics: survivin (BIRC5), XIAP, MCL-1, HIF1&alpha;, HIF2&alpha;, NRF2, MDM2, MDM4, p53, KRAS and AKT in renal cell carcinoma. J Exp Clin Cancer Res. 2021;40(1):254. doi:10.1186/s13046-021-02026-1
5. Singh D. Current updates and future perspectives on the management of renal cell carcinoma. Life Sci. 2021;264:118632. doi:10.1016/j.lfs.2020. 118632
6. Alaghehbandan R, Siadat F, Trpkov K. What&rsquo;s new in the WHO 2022 classification of kidney tumours? Pathologica. 2022;115(1):8-22. doi:10. 32074/1591-951X-818
7. Tanji N, Yokoyama M. Treatment of metastatic renal cell carcinoma and renal pelvic cancer. Clin Exp Nephrol. 2011;15(3):331-338. doi:10.1007/s10157-011-0438-9
8. Ng KL. The Etiology of Renal Cell Carcinoma and Upper Tract Urothelial Carcinoma. In Urologic Cancers; Barber, N., Ali, A., Eds.; Exon Publications: Brisbane, Australia, 2022.
9. Nam H, Kundu A, Karki S, et al. The TGF-&beta;/HDAC7 axis suppresses TCA cycle metabolism in renal cancer. JCI Insight. 2021;6(22):e148438. doi:10.1172/jci.insight.148438
10. Wu G, Li X, Liu Y, Li Q, Xu Y, Wang Q. Study on HOXBs of clear cell renal cell carcinoma and detection of new molecular target. J Oncol. 2021;2021:5541423. doi:10.1155/2021/5541423
11. Yang CY, Wang J, Zhang JQ, Cai HM. Human circular RNA hsa_circRNA_101705 (circTXNDC11) regulates renal cancer progression by regulating MAPK/ERK pathway. Bioengineered. 2021;12(1):4432-4441. doi:10.1080/21655979.2021.1955579
12. Wang H, Chong T, Li BY, Chen XS, Zhen WB. Evaluating the clinical significance of SHMT2 and its co-expressed gene in human kidney cancer. Biol Res. 2020;53(1):46. doi:10.1186/s40659-020-00314-2
13. Guo C, Chen WD, Wang YD. TGR5, not only a metabolic regulator. Front Physiol. 2016;7:646. doi:10.3389/fphys.2016.00646
14. Erice O, Labiano I, Arbelaiz A, et al. Differential effects of FXR or TGR5 activation in cholangiocarcinoma progression. Biochim Biophys Acta Mol Basis Dis. 2018;1864(4 Pt B):1335-1344. doi:10.1016/j.bbadis.2017.08. 016
15. Keitel V, Reinehr R, Gatsios P, et al. The G-protein coupled bile salt receptor TGR5 is expressed in liver sinusoidal endothelial cells. Hepatology. 2007;45(3):695-704. doi:10.1002/hep.21458
16. Tiwari A, Maiti P. TGR5: an emerging bile acid G-protein-coupled receptor target for the potential treatment of metabolic disorders. Drug Discov Today. 2009;14(9-10):523-530. doi:10.1016/j.drudis.2009.02.005
17. Kawamata Y, Fujii R, Hosoya M, et al. A G protein-coupled receptor responsive to bile acids. J Biol Chem. 2003;278(11):9435-9440. doi:10. 1074/jbc.M209706200
18. Qi Y, Duan G, Wei D, Zhao C, Ma Y. The bile acid membrane receptor TGR5 in cancer: friend or foe? Molecules. 2022;27(16):5292. doi:10.3390/molecules27165292
19. Li H, Zhao J, Shi X. GPBAR1 promotes proliferation of serous ovarian cancer by inducing Smad4 ubiquitination. Appl Immunohistochem Mol Morphol. 2021;29(7):519-526. doi:10.1097/PAI.0000000000000917
20. Hov JR, Keitel V, Schrumpf E, H&auml;ussinger D, Karlsen TH. TGR5 sequence variation in primary sclerosing cholangitis. Dig Dis. 2011;29(1):78-84. doi:10.1159/000324138
21. Wang YD, Chen WD, Huang W. FXR, a target for different diseases. Histol Histopathol. 2008;23(5):621-627. doi:10.14670/HH-23.621
22. Li D, Cao W. Bile acid receptor TGR5, NADPH oxidase NOX5-S and CREB mediate bile acid-induced DNA damage in Barrett&rsquo;s esophageal adenocarcinoma cells. Sci Rep. 2016;6:31538. doi:10.1038/srep31538
23. Tsuei J, Chau T, Mills D, Wan YJ. Bile acid dysregulation, gut dysbiosis, and gastrointestinal cancer. Exp Biol Med (Maywood). 2014;239(11):1489-1504. doi:10.1177/1535370214538743
24. Huo X, Juergens S, Zhang X, et al. Deoxycholic acid causes DNA damage while inducing apoptotic resistance through NF-&kappa;B activation in benign Barrett&rsquo;s epithelial cells. Am J Physiol Gastrointest Liver Physiol. 2011;301(2):G278-G286. doi:10.1152/ajpgi.00092.2011
25. Reich M, Deutschmann K, Sommerfeld A, et al. TGR5 is essential for bile acid-dependent cholangiocyte proliferation in vivo and in vitro. Gut. 2016;65(3):487-501. doi:10.1136/gutjnl-2015-309458
26. Sarmiento-Salinas FL, Perez-Gonzalez A, Acosta-Casique A, et al. Reactive oxygen species: Role in carcinogenesis, cancer cell signaling and tumor progression. Life Sci. 2021;284:119942. doi:10.1016/j.lfs.2021. 119942
27. Dho SH, Kim JY, Lee KP, et al. STAT5A-mediated NOX5-L expression promotes the proliferation and metastasis of breast cancer cells. Exp Cell Res. 2017;351(1):51-58. doi:10.1016/j.yexcr.2016.12.020
28. Touyz RM, Anagnostopoulou A, Rios F, Montezano AC, Camargo LL. NOX5: Molecular biology and pathophysiology. Exp Physiol. 2019; 104(5):605-616. doi:10.1113/EP086204
29. Pols TW, Noriega LG, Nomura M, Auwerx J, Schoonjans K. The bile acid membrane receptor TGR5 as an emerging target in metabolism and inflammation. J Hepatol. 2011;54(6):1263-1272. doi:10.1016/j.jhep.2010. 12.004
30. Liu X, Chen B, You W, Xue S, Qin H, Jiang H. The membrane bile acid receptor TGR5 drives cell growth and migration via activation of the JAK2/STAT3 signaling pathway in non-small cell lung cancer. Cancer Lett. 2018;412:194-207. doi:10.1016/j.canlet.2017.10.017
31. Cao W, Tian W, Hong J, et al. Expression of bile acid receptor TGR5 in gastric adenocarcinoma. Am J Physiol Gastrointest Liver Physiol. 2013; 304(4):G322-G327. doi:10.1152/ajpgi.00263.2012
32. Guo C, Qi H, Yu Y, et al. The G-protein-coupled bile acid receptor Gpbar1 (TGR5) inhibits gastric inflammation through antagonizing NF-&kappa;B signaling pathway. Front Pharmacol. 2015;6:287. doi:10.3389/fphar.2015.00287
33. Yang WJ, Han FH, Gu YP, et al. TGR5 agonist inhibits intestinal epithelial cell apoptosis via cAMP/PKA/c-FLIP/JNK signaling pathway and ameliorates dextran sulfate sodium-induced ulcerative colitis. Acta Pharmacol Sin. 2023;44(8):1649-1664. doi:10.1038/s41401-023-01081-y
34. Guan Z, Luo L, Liu S, et al. The role of TGR5 as an onco-immunological biomarker in tumor staging and prognosis by encompassing the tumor microenvironment. Front Oncol. 2022;12:953091. doi:10.3389/fonc. 2022.953091
35. Su J, Zhang Q, Qi H, et al. The G-protein-coupled bile acid receptor Gpbar1 (TGR5) protects against renal inflammation and renal cancer cell proliferation and migration through antagonizing NF-&kappa;B and STAT3 signaling pathways. Oncotarget. 2017;8(33):54378-54387. doi:10.18632/oncotarget.17533
36. Hong J, Behar J, Wands J, et al. Role of a novel bile acid receptor TGR5 in the development of oesophageal adenocarcinoma. Gut. 2010;59(2):170-180. doi:10.1136/gut.2009.188375
37. Toyooka T, Amano T, Ibuki Y. Titanium dioxide particles phosphorylate histone H2AX independent of ROS production. Mutat Res. 2012;742 (1-2):84-91. doi:10.1016/j.mrgentox.2011.12.015
38. Wagener N, Paffenholz P, Krebs M, et al. Histological subtype is an independent prognostic factor in non-metastatic renal cell carcinoma: a multicentre study. PLoS One. 2017;12(8):e0184173. doi:10.1371/journal.pone.0184173
39. Deng Y, Zhou F, Yu Y, et al. Prognostic value of papillary histologic subtype in patients with metastatic renal cell carcinoma: a systematic review and meta-analysis. BMC Cancer. 2019;19:573. doi:10.1186/s12885-019-5782-2
40. Delahunt B, Eble JN. Papillary renal cell carcinoma: a clinicopathologic and immunohistochemical study of 105 tumors. Mod Pathol. 1997;10(6): 537-544.
41. Zhao CL, Amin A, Hui Y, et al. TGR5 expression in normal kidney and renal neoplasms. Diagn Pathol. 2018;13(1):42. doi:10.1186/s13000-018-0700-5
42. Yang L, Ma TJ, Zhang YB, Wang H, An RH. Construction and analysis of lncRNA-miRNA-mRNA ceRNA network identify an eight-gene signature as a potential prognostic factor in kidney renal papillary cell carcinoma (KIRP). Altern Ther Health Med. 2022;28(6):42-51. </ol> <p>
Volume 5, Issue 4, 2025
Page : 272-277
_Footer