Int J Biol Sci 2021; 17(9):2294-2307. doi:10.7150/ijbs.57915 This issue Cite

Research Paper

CircHIPK3 regulates pulmonary fibrosis by facilitating glycolysis in miR-30a-3p/FOXK2-dependent manner

Qi Xu*, Demin Cheng*, Guanru Li*, Yi Liu, Ping Li, Wenqing Sun, Dongyu Ma, Chunhui Ni

Center for Global Health, Key Laboratory of Modern Toxicology of Ministry of Education, Department of Occupational Medical and Environmental Health, School of Public Health, Nanjing Medical University, Nanjing 211166, China.
*These authors contributed equally to this work and should be considered co-first authors.

Citation:
Xu Q, Cheng D, Li G, Liu Y, Li P, Sun W, Ma D, Ni C. CircHIPK3 regulates pulmonary fibrosis by facilitating glycolysis in miR-30a-3p/FOXK2-dependent manner. Int J Biol Sci 2021; 17(9):2294-2307. doi:10.7150/ijbs.57915. https://www.ijbs.com/v17p2294.htm
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Abstract

Graphic abstract

Pulmonary fibrosis develops when myofibroblasts and extracellular matrix excessively accumulate in the injured lung, but what drives fibrosis is not fully understood. Glycolysis has been linked to cell growth and proliferation, and several studies have shown enhanced glycolysis promotes pulmonary fibrosis. However, detailed studies describing this switch remain limited. Here, we identified that TGF-β1 effectively increased the expression of circHIPK3 in lung fibroblasts, and circHIPK3 inhibition attenuated the activation, proliferation, and glycolysis of fibroblasts in vitro. Dual-luciferase reporter gene assays, RNA immunoprecipitation (RIP), and RNA pull-down assays showed that circHIPK3 could function as a sponge of miR-30a-3p and inhibit its expression. Furthermore, FOXK2, a driver transcription factor of glycolysis, was identified to be a direct target of miR-30a-3p. Mechanistically, circHIPK3 could enhance the expression of FOXK2 via sponging miR-30a-3p, thereby facilitating fibroblast glycolysis and activation. Besides, miR-30a-3p overexpression or FOXK2 knockdown blocked fibroblast activation induced by TGF-β1 and abrogated the profibrotic effects of circHIPK3. Moreover, circHIPK3 and miR-30a-3p were also dysregulated in fibrotic murine lung tissues induced by silica. Adeno-associated virus (AAV)-mediated circHIPK3 silence or miR-30a-3p overexpression alleviated silica-induced pulmonary fibrosis in vivo. In conclusion, our results identified circHIPK3/miR-30a-3p/FOXK2 regulatory pathway as an important glycolysis cascade in pulmonary fibrosis.

Keywords: silicosis, glycolysis, circHIPK3, ceRNA, FOXK2


Citation styles

APA
Xu, Q., Cheng, D., Li, G., Liu, Y., Li, P., Sun, W., Ma, D., Ni, C. (2021). CircHIPK3 regulates pulmonary fibrosis by facilitating glycolysis in miR-30a-3p/FOXK2-dependent manner. International Journal of Biological Sciences, 17(9), 2294-2307. https://doi.org/10.7150/ijbs.57915.

ACS
Xu, Q.; Cheng, D.; Li, G.; Liu, Y.; Li, P.; Sun, W.; Ma, D.; Ni, C. CircHIPK3 regulates pulmonary fibrosis by facilitating glycolysis in miR-30a-3p/FOXK2-dependent manner. Int. J. Biol. Sci. 2021, 17 (9), 2294-2307. DOI: 10.7150/ijbs.57915.

NLM
Xu Q, Cheng D, Li G, Liu Y, Li P, Sun W, Ma D, Ni C. CircHIPK3 regulates pulmonary fibrosis by facilitating glycolysis in miR-30a-3p/FOXK2-dependent manner. Int J Biol Sci 2021; 17(9):2294-2307. doi:10.7150/ijbs.57915. https://www.ijbs.com/v17p2294.htm

CSE
Xu Q, Cheng D, Li G, Liu Y, Li P, Sun W, Ma D, Ni C. 2021. CircHIPK3 regulates pulmonary fibrosis by facilitating glycolysis in miR-30a-3p/FOXK2-dependent manner. Int J Biol Sci. 17(9):2294-2307.

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