Research progress on the role of retinoic acid receptor-related orphan receptor α in tumorigenesis and development_West China Medical Journal

Authors：

XU Fan , GUO Fangyuan , HE Yan ,  WEI Xiangqun

Department of Gynecology, the Affiliated Hospital of Yunnan University, Kunming, Yunnan 650000, P. R. China;

Corresponding author：

WEI Xiangqun, Email: 386055834@qq.com

Keywords：

Retinoic acid receptor-related orphan receptor α; tumor; gene regulation

DOI：

10.7507/1002-0179.202108046

Video：

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As a member of the nuclear receptor superfamily, retinoic acid receptor-related orphan receptor α (RORα) is involved in a variety of pathophysiological processes by regulating the expression of related genes. RORα plays an important role in biological rhythm, metabolism, vascular hyperplasia and inflammation, which are closely related to the occurrence and development of tumors. This review focuses on the biological characteristics of RORα and its role and mechanism in tumorigenesis and development, so as to provide new ideas for tumor-related research.

Citation： XU Fan, GUO Fangyuan, HE Yan, WEI Xiangqun. Research progress on the role of retinoic acid receptor-related orphan receptor α in tumorigenesis and development. West China Medical Journal, 2022, 37(9): 1419-1423. doi: 10.7507/1002-0179.202108046 Copy

1.	Gu D, Li S, Ben S, et al. Circadian clock pathway genes associated with colorectal cancer risk and prognosis. Arch Toxicol, 2018, 92(8): 2681-2689.
2.	Zheng X, Wu K, Liao S, et al. MicroRNA-transcription factor network analysis reveals miRNAs cooperatively suppress RORA in oral squamous cell carcinoma. Oncogenesis, 2018, 7(10): 79.
3.	Markiewicz A, Brożyna AA, Podgórska E, et al. Vitamin D receptors (VDR), hydroxylases CYP27B1 and CYP24A1 and retinoid-related orphan receptors (ROR) level in human uveal tract and ocular melanoma with different melanization levels. Sci Rep, 2019, 9(1): 9142.
4.	Zhu Y, McAvoy S, Kuhn R, et al. RORA, a large common fragile site gene, is involved in cellular stress response. Oncogene, 2006, 25(20): 2901-2098.
5.	Wu Y, Tao B, Zhang T, et al. Pan-cancer analysis reveals disrupted circadian clock associates with T cell exhaustion. Front Immunol, 2019, 10: 2451.
6.	Wendeu-Foyet MG, Cénée S, Koudou Y, et al. Circadian genes polymorphisms, night work and prostate cancer risk: findings from the EPICAP study. Int J Cancer, 2020, 147(11): 3119-3129.
7.	Feng Y, Zhang S, Li L, et al. The cis-trans binding strength defined by motif frequencies facilitates statistical inference of transcriptional regulation. BMC Bioinformatics, 2019, 20(Suppl 7): 201.
8.	Lee JM, Kim H, Baek SH. Unraveling the physiological roles of retinoic acid receptor-related orphan receptor α. Exp Mol Med, 2021, 53(9): 1278-1286.
9.	高登科, 赵泓淙, 董浩, 等. 山羊 RORα 基因的克隆、表达载体构建及功能分析. 畜牧兽医学报, 2022, 53(6): 1779-1794.
10.	Bollinger T, Schibler U. Circadian rhythms - from genes to physiology and disease. Swiss Med Wkly, 2014, 144: w13984.
11.	Zhu B, Gates LA, Stashi E, et al. Coactivator-dependent oscillation of chromatin accessibility dictates circadian gene amplitude via REV-ERB loading. Mol Cell, 2015, 60(5): 769-783.
12.	Kadiri S, Monnier C, Ganbold M, et al. The nuclear retinoid-related orphan receptor-α regulates adipose tissue glyceroneogenesis in addition to hepatic gluconeogenesis. Am J Physiol Endocrinol Metab, 2015, 309(2): E105-E114.
13.	Ramos LO, Samblas M, Milagro FI, et al. Circadian gene methylation profiles are associated with obesity, metabolic disturbances and carbohydrate intake. Chronobiol Int, 2018, 35(7): 969-981.
14.	Byun JK, Choi YK, Kang YN, et al. Retinoic acid-related orphan receptor alpha reprograms glucose metabolism in glutamine-deficient hepatoma cells. Hepatology, 2015, 61(3): 953-964.
15.	Sun XM, Dongol S, Qiu CP, et al. miR-652 promotes tumor proliferation and metastasis by targeting RORA in endometrial cancer. Molecular Cancer Research, 2018, 16(12): 1927-1939.
16.	Jakel H, Nowak M, Helleboid-Chapman A, et al. Is apolipoprotein A5 a novel regulator of triglyceride-rich lipoproteins?. Ann Med, 2006, 38(1): 2-10.
17.	Xiao L, Wang J, Li J, et al. RORα inhibits adipocyte-conditioned medium-induced colorectal cancer cell proliferation and migration and chick embryo chorioallantoic membrane angiopoiesis. Am J Physiol Cell Physiol, 2015, 308(5): C385-C396.
18.	Moretti RM, Montagnani MM, Sala A, et al. Activation of the orphan nuclear receptor RORalpha counteracts the proliferative effect of fatty acids on prostate cancer cells: crucial role of 5-lipoxygenase. Int J Cancer, 2004, 112(1): 87-93.
19.	Suzuki H, Yano M, Miyazawa M, et al. Association of the hypoxia-inducible factor-1α (HIF-1α) gene polymorphisms with prognosis in ovarian clear cell carcinoma. J Ovarian Res, 2019, 12(1): 7.
20.	Chauvet C, Bois-Joyeux B, Berra E, et al. The gene encoding human retinoic acid-receptor-related orphan receptor alpha is a target for hypoxia-inducible factor 1. Biochem J, 2004, 384(Pt 1): 79-85.
21.	Li H, Zhou L, Dai J. Retinoic acid receptor-related orphan receptor RORα regulates differentiation and survival of keratinocytes during hypoxia. J Cell Physiol, 2018, 233(1): 641-650.
22.	Brożyna AA, Jóźwicki W, Jetten AM, et al. On the relationship between VDR, RORα and RORγ receptors expression and HIF1-α levels in human melanomas. Exp Dermatol, 2019, 28(9): 1036-1043.
23.	Sun Y, Liu CH, Wang Z, et al. RORα modulates semaphorin 3E transcription and neurovascular interaction in pathological retinal angiogenesis. FASEB J, 2017, 31(10): 4492-4502.
24.	Kim EJ, Yoo YG, Yang WK, et al. Transcriptional activation of HIF-1 by RORalpha and its role in hypoxia signaling. Arterioscler Thromb Vasc Biol, 2008, 28(10): 1796-1802.
25.	Chauvet C, Vanhoutteghem A, Duhem C, et al. Control of gene expression by the retinoic acid-related orphan receptor alpha in HepG2 human hepatoma cells. PLoS One, 2011, 6(7): e22545.
26.	Grivennikov SI, Greten FR, Karin M. Immunity, inflammation, and cancer. Cell, 2010, 140(6): 883-899.
27.	Han S, Li Z, Han F, et al. ROR alpha protects against LPS-induced inflammation by down-regulating SIRT1/NF-kappa B pathway. Arch Biochem Biophys, 2019, 668: 1-8.
28.	Delerive P, Monté D, Dubois G, et al. The orphan nuclear receptor ROR alpha is a negative regulator of the inflammatory response. EMBO Rep, 2001, 2(1): 42-48.
29.	Huang Q, Jacquelot N, Preaudet A, et al. Type 2 innate lymphoid cells protect against colorectal cancer progression and predict improved patient survival. Cancers (Basel), 2021, 13(3): 559.
30.	Mjösberg J, Bernink J, Peters C, et al. Transcriptional control of innate lymphoid cells. Eur J Immunol, 2012, 42(8): 1916-1923.
31.	Kindermann M, Knipfer L, Obermeyer S, et al. Group 2 innate lymphoid cells (ILC2) suppress beneficial type 1 immune responses during pulmonary cryptococcosis. Front Immunol, 2020, 11: 209.
32.	Xiao L, Zhang Z, Luo X, et al. Retinoid acid receptor-related orphan receptor alpha (RORα) regulates macrophage M2 polarization via activation of AMPKα. Mol Immunol, 2016, 80: 17-23.
33.	Nejati MN, Bjørkøy TE, Ryan L, et al. RORα controls inflammatory state of human macrophages. PLoS One, 2018, 13(11): e0207374.
34.	Hams E, Roberts J, Bermingham R, et al. Role for retinoic acid-related orphan receptor alpha (RORα) expressing macrophages in diet-induced obesity. Front Immunol, 2020, 11: 1966.
35.	Dattilo M, Benzo Y, Herrera LM, et al. Regulatory mechanisms leading to differential Acyl-CoA synthetase 4 expression in breast cancer cells. Sci Rep, 2019, 9(1): 10324.
36.	Anderson AM, Kalimutho M, Harten S, et al. The metastasis suppressor RARRES3 as an endogenous inhibitor of the immunoproteasome expression in breast cancer cells. Sci Rep, 2017, 7: 39873.
37.	Kim K, Lee JM, Yu YS, et al. RORα2 requires LSD1 to enhance tumor progression in breast cancer. Sci Rep, 2017, 7(1): 11994.

1. Gu D, Li S, Ben S, et al. Circadian clock pathway genes associated with colorectal cancer risk and prognosis. Arch Toxicol, 2018, 92(8): 2681-2689.
2. Zheng X, Wu K, Liao S, et al. MicroRNA-transcription factor network analysis reveals miRNAs cooperatively suppress RORA in oral squamous cell carcinoma. Oncogenesis, 2018, 7(10): 79.
3. Markiewicz A, Brożyna AA, Podgórska E, et al. Vitamin D receptors (VDR), hydroxylases CYP27B1 and CYP24A1 and retinoid-related orphan receptors (ROR) level in human uveal tract and ocular melanoma with different melanization levels. Sci Rep, 2019, 9(1): 9142.
4. Zhu Y, McAvoy S, Kuhn R, et al. RORA, a large common fragile site gene, is involved in cellular stress response. Oncogene, 2006, 25(20): 2901-2098.
5. Wu Y, Tao B, Zhang T, et al. Pan-cancer analysis reveals disrupted circadian clock associates with T cell exhaustion. Front Immunol, 2019, 10: 2451.
6. Wendeu-Foyet MG, Cénée S, Koudou Y, et al. Circadian genes polymorphisms, night work and prostate cancer risk: findings from the EPICAP study. Int J Cancer, 2020, 147(11): 3119-3129.
7. Feng Y, Zhang S, Li L, et al. The cis-trans binding strength defined by motif frequencies facilitates statistical inference of transcriptional regulation. BMC Bioinformatics, 2019, 20(Suppl 7): 201.
8. Lee JM, Kim H, Baek SH. Unraveling the physiological roles of retinoic acid receptor-related orphan receptor α. Exp Mol Med, 2021, 53(9): 1278-1286.
9. 高登科, 赵泓淙, 董浩, 等. 山羊 RORα 基因的克隆、表达载体构建及功能分析. 畜牧兽医学报, 2022, 53(6): 1779-1794.
10. Bollinger T, Schibler U. Circadian rhythms - from genes to physiology and disease. Swiss Med Wkly, 2014, 144: w13984.
11. Zhu B, Gates LA, Stashi E, et al. Coactivator-dependent oscillation of chromatin accessibility dictates circadian gene amplitude via REV-ERB loading. Mol Cell, 2015, 60(5): 769-783.
12. Kadiri S, Monnier C, Ganbold M, et al. The nuclear retinoid-related orphan receptor-α regulates adipose tissue glyceroneogenesis in addition to hepatic gluconeogenesis. Am J Physiol Endocrinol Metab, 2015, 309(2): E105-E114.
13. Ramos LO, Samblas M, Milagro FI, et al. Circadian gene methylation profiles are associated with obesity, metabolic disturbances and carbohydrate intake. Chronobiol Int, 2018, 35(7): 969-981.
14. Byun JK, Choi YK, Kang YN, et al. Retinoic acid-related orphan receptor alpha reprograms glucose metabolism in glutamine-deficient hepatoma cells. Hepatology, 2015, 61(3): 953-964.
15. Sun XM, Dongol S, Qiu CP, et al. miR-652 promotes tumor proliferation and metastasis by targeting RORA in endometrial cancer. Molecular Cancer Research, 2018, 16(12): 1927-1939.
16. Jakel H, Nowak M, Helleboid-Chapman A, et al. Is apolipoprotein A5 a novel regulator of triglyceride-rich lipoproteins?. Ann Med, 2006, 38(1): 2-10.
17. Xiao L, Wang J, Li J, et al. RORα inhibits adipocyte-conditioned medium-induced colorectal cancer cell proliferation and migration and chick embryo chorioallantoic membrane angiopoiesis. Am J Physiol Cell Physiol, 2015, 308(5): C385-C396.
18. Moretti RM, Montagnani MM, Sala A, et al. Activation of the orphan nuclear receptor RORalpha counteracts the proliferative effect of fatty acids on prostate cancer cells: crucial role of 5-lipoxygenase. Int J Cancer, 2004, 112(1): 87-93.
19. Suzuki H, Yano M, Miyazawa M, et al. Association of the hypoxia-inducible factor-1α (HIF-1α) gene polymorphisms with prognosis in ovarian clear cell carcinoma. J Ovarian Res, 2019, 12(1): 7.
20. Chauvet C, Bois-Joyeux B, Berra E, et al. The gene encoding human retinoic acid-receptor-related orphan receptor alpha is a target for hypoxia-inducible factor 1. Biochem J, 2004, 384(Pt 1): 79-85.
21. Li H, Zhou L, Dai J. Retinoic acid receptor-related orphan receptor RORα regulates differentiation and survival of keratinocytes during hypoxia. J Cell Physiol, 2018, 233(1): 641-650.
22. Brożyna AA, Jóźwicki W, Jetten AM, et al. On the relationship between VDR, RORα and RORγ receptors expression and HIF1-α levels in human melanomas. Exp Dermatol, 2019, 28(9): 1036-1043.
23. Sun Y, Liu CH, Wang Z, et al. RORα modulates semaphorin 3E transcription and neurovascular interaction in pathological retinal angiogenesis. FASEB J, 2017, 31(10): 4492-4502.
24. Kim EJ, Yoo YG, Yang WK, et al. Transcriptional activation of HIF-1 by RORalpha and its role in hypoxia signaling. Arterioscler Thromb Vasc Biol, 2008, 28(10): 1796-1802.
25. Chauvet C, Vanhoutteghem A, Duhem C, et al. Control of gene expression by the retinoic acid-related orphan receptor alpha in HepG2 human hepatoma cells. PLoS One, 2011, 6(7): e22545.
26. Grivennikov SI, Greten FR, Karin M. Immunity, inflammation, and cancer. Cell, 2010, 140(6): 883-899.
27. Han S, Li Z, Han F, et al. ROR alpha protects against LPS-induced inflammation by down-regulating SIRT1/NF-kappa B pathway. Arch Biochem Biophys, 2019, 668: 1-8.
28. Delerive P, Monté D, Dubois G, et al. The orphan nuclear receptor ROR alpha is a negative regulator of the inflammatory response. EMBO Rep, 2001, 2(1): 42-48.
29. Huang Q, Jacquelot N, Preaudet A, et al. Type 2 innate lymphoid cells protect against colorectal cancer progression and predict improved patient survival. Cancers (Basel), 2021, 13(3): 559.
30. Mjösberg J, Bernink J, Peters C, et al. Transcriptional control of innate lymphoid cells. Eur J Immunol, 2012, 42(8): 1916-1923.
31. Kindermann M, Knipfer L, Obermeyer S, et al. Group 2 innate lymphoid cells (ILC2) suppress beneficial type 1 immune responses during pulmonary cryptococcosis. Front Immunol, 2020, 11: 209.
32. Xiao L, Zhang Z, Luo X, et al. Retinoid acid receptor-related orphan receptor alpha (RORα) regulates macrophage M2 polarization via activation of AMPKα. Mol Immunol, 2016, 80: 17-23.
33. Nejati MN, Bjørkøy TE, Ryan L, et al. RORα controls inflammatory state of human macrophages. PLoS One, 2018, 13(11): e0207374.
34. Hams E, Roberts J, Bermingham R, et al. Role for retinoic acid-related orphan receptor alpha (RORα) expressing macrophages in diet-induced obesity. Front Immunol, 2020, 11: 1966.
35. Dattilo M, Benzo Y, Herrera LM, et al. Regulatory mechanisms leading to differential Acyl-CoA synthetase 4 expression in breast cancer cells. Sci Rep, 2019, 9(1): 10324.
36. Anderson AM, Kalimutho M, Harten S, et al. The metastasis suppressor RARRES3 as an endogenous inhibitor of the immunoproteasome expression in breast cancer cells. Sci Rep, 2017, 7: 39873.
37. Kim K, Lee JM, Yu YS, et al. RORα2 requires LSD1 to enhance tumor progression in breast cancer. Sci Rep, 2017, 7(1): 11994.

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