Int J Biol Sci 2023; 19(8):2613-2629. doi:10.7150/ijbs.81498 This issue Cite

Research Paper

ACE2 negatively regulates the Warburg effect and suppresses hepatocellular carcinoma progression via reducing ROS-HIF1α activity

Fangyuan Dong1,3,4,5,*, Hui Li2,*, Limin Liu6,*, Lin-Li Yao2,*, Jiaofeng Wang3,4,5, Danni Xiang1, Jianxia Ma1, Gansheng Zhang1, Shan Zhang2, Jun Li2, Shu-Heng Jiang2,✉, Xiaona Hu1,3,4,5,✉, Jie Chen1,3,4,5,✉, Zhijun Bao1,3,4,5,✉

1. Department of Gastroenterology, Huadong Hospital, Shanghai Medical College, Fudan University, Shanghai 200040, P.R. China.
2. State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200240, P.R. China.
3. Shanghai Key Laboratory of Clinical Geriatric Medicine, Shanghai 200040, P.R. China.
4. National Clinical Research Center for Aging and Medicine, Shanghai 200040, P.R. China.
5. Department of Geriatrics, Huadong Hospital, Shanghai Medical College, Fudan University Shanghai 200040, P.R. China.
6. Department of Oral pathology, Ninth People's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200011, P.R. China.
*These authors contributed equally to this work.

Citation:
Dong F, Li H, Liu L, Yao LL, Wang J, Xiang D, Ma J, Zhang G, Zhang S, Li J, Jiang SH, Hu X, Chen J, Bao Z. ACE2 negatively regulates the Warburg effect and suppresses hepatocellular carcinoma progression via reducing ROS-HIF1α activity. Int J Biol Sci 2023; 19(8):2613-2629. doi:10.7150/ijbs.81498. https://www.ijbs.com/v19p2613.htm
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Abstract

Graphic abstract

Aerobic glycolysis has pleiotropic roles in the pathogenesis of hepatocellular carcinoma (HCC). Emerging studies revealed key promoters of aerobic glycolysis, however, little is known about its negative regulators in HCC. In this study, an integrative analysis identifies a repertoire of differentially expressed genes (DNASE1L3, SLC22A1, ACE2, CES3, CCL14, GYS2, ADH4, and CFHR3) that are inversely associated with the glycolytic phenotype in HCC. ACE2, a member of the rennin-angiotensin system, is revealed to be downregulated in HCC and predicts a poor prognosis. ACE2 overexpression significantly inhibits the glycolytic flux as evidenced by reduced glucose uptake, lactate release, extracellular acidification rate, and the expression of glycolytic genes. Opposite results are noticed in loss-of-function studies. Mechanistically, ACE2 metabolizes Ang II to Ang-(1-7), which activates Mas receptor and leads to the phosphorylation of Src homology 2-containing inositol phosphatase 2 (SHP-2). SHP2 activation further blocks reactive oxygen species (ROS)-HIF1α signaling. Addition of Ang-(1-7) or the antioxidant N-acetylcysteine compromises in vivo additive tumor growth and aerobic glycolysis induced by ACE2 knockdown. Moreover, growth advantages afforded by ACE2 knockdown are largely glycolysis-dependent. In clinical settings, a close link between ACE2 expression and HIF1α or the phosphorated level of SHP2 is found. Overexpression of ACE2 significantly retards tumor growth in patient-derived xenograft model. Collectively, our findings suggest that ACE2 is a negative glycolytic regulator, and targeting the ACE2/Ang-(1-7)/Mas receptor/ROS/HIF1α axis may be a promising therapeutic strategy for HCC treatment.

Keywords: Warburg effect, Liver cancer, Hypoxia-inducible factor, Metabolic reprogramming


Citation styles

APA
Dong, F., Li, H., Liu, L., Yao, L.L., Wang, J., Xiang, D., Ma, J., Zhang, G., Zhang, S., Li, J., Jiang, S.H., Hu, X., Chen, J., Bao, Z. (2023). ACE2 negatively regulates the Warburg effect and suppresses hepatocellular carcinoma progression via reducing ROS-HIF1α activity. International Journal of Biological Sciences, 19(8), 2613-2629. https://doi.org/10.7150/ijbs.81498.

ACS
Dong, F.; Li, H.; Liu, L.; Yao, L.L.; Wang, J.; Xiang, D.; Ma, J.; Zhang, G.; Zhang, S.; Li, J.; Jiang, S.H.; Hu, X.; Chen, J.; Bao, Z. ACE2 negatively regulates the Warburg effect and suppresses hepatocellular carcinoma progression via reducing ROS-HIF1α activity. Int. J. Biol. Sci. 2023, 19 (8), 2613-2629. DOI: 10.7150/ijbs.81498.

NLM
Dong F, Li H, Liu L, Yao LL, Wang J, Xiang D, Ma J, Zhang G, Zhang S, Li J, Jiang SH, Hu X, Chen J, Bao Z. ACE2 negatively regulates the Warburg effect and suppresses hepatocellular carcinoma progression via reducing ROS-HIF1α activity. Int J Biol Sci 2023; 19(8):2613-2629. doi:10.7150/ijbs.81498. https://www.ijbs.com/v19p2613.htm

CSE
Dong F, Li H, Liu L, Yao LL, Wang J, Xiang D, Ma J, Zhang G, Zhang S, Li J, Jiang SH, Hu X, Chen J, Bao Z. 2023. ACE2 negatively regulates the Warburg effect and suppresses hepatocellular carcinoma progression via reducing ROS-HIF1α activity. Int J Biol Sci. 19(8):2613-2629.

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