Effects of activin A on migration and aerobic glycolysis of gastric cancer cells

doi:10.16138/j.1673-6087.2022.04.009

Abstract

Abstract:

Objective To investigate the role of activin A, a member of transforming growth factor-β superfamily cytokine, in regulating migration and aerobic glycolysis of gastric cancer cells, and the prognostic value of the expression of its coding gene inhibin βA(INHBA) in survival of gastric cancer patients. Methods The gastric cells were first titrated with various concentration of activin A and the expression of pSmad2/3 was examined by Western blot(WB) to determine the concentration range of activin A used in the study. The effect of activin A on the migration of gastric cancer cells was monitored by transwell and wound healing assays. The lactate production and glucose uptake of gastric cancer cells were followed to evaluate the role of activin A on the regulation of aerobic glycolysis. The association between activin A and epithelial mesenchymal transformation(EMT)/glycolysis related genes was analyzed in the Cancer Genome Atlas (TCGA) gastric cancer database, and further validated by WB studies. The expression of INHBA in gastric cancer and normal mucosa tissue were analyzed in TCGA, Gene Expression Omnibus(GEO) and other publicly available databases to explore the association of INHBA expression level with patients’ survival. Results The activin A at 20 ng/mL sufficiently upregulate the level of pSmad2/3, and the concentration was thus used in the study. Activin A promoted migration and aerobic glycolysis of gastric cancer cells. There was a significant positive correlation between the expression of INHBA and several EMT related genes, hypoxia inducible factor-1 α(HIF1A), glucose transporter 3 (GLUT3) [SNAI1: r=0.47, P=0;SNAI2: r=0.51, P=0; VIM: r=0.37, P=2.1×10^-14; matrix metalloproteinase(MMP)2: r=0.64, P=0; MMP9: r=0.27, P=2.8×10^-8; HIF1A: r=0.45, P=0; SLC2A3: r=0.42, P=0]. After treatment with activin A, the expression of snail, slug, vimentin, MMP2 and GLUT3 increased significantly(P<0.05). The expression of INHBA in gastric cancer was significantly higher than that in normal gastric mucosa tissue, and the prognosis of patients with higher expression of INHBA was poor. Conclusions Activin A can promote migration and aerobic glycolysis, which might attribute to its upregulation of EMT related genes and GLUT3. High level of INHBA is indicative of prognosis for gastric cancer patients.

Key words: Gastric cancer, Activin A, Migration, Glycolysis

CLC Number:

R735.2

ZHAO Liqin, GUO Weijian, YU Nuoya, WU Junwei, ZHANG Jun. Effects of activin A on migration and aerobic glycolysis of gastric cancer cells[J]. Journal of Internal Medicine Concepts & Practice, 2022, 17(04): 317-323.

Figures/Tables 5

References 19

[1]	Sung H, Ferlay J, Siegel RL, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries[J]. CA Cancer J Clin, 2021, 71(3): 209-249. doi: 10.3322/caac.21660 URL
[2]	郑荣寿, 孙可欣, 张思维, 等. 2015年中国恶性肿瘤流行情况分析[J]. 中华肿瘤杂志, 2019, 41(1): 19-28.
[3]	Baracos VE, Martin L, Korc M, et al. Cancer-associated cachexia[J]. Nat Rev Dis Primers, 2018, 4: 17105. doi: 10.1038/nrdp.2017.105 pmid: 29345251
[4]	Morianos I, Papadopoulou G, Semitekolou M, et al. Activin-A in the regulation of immunity in health and disease[J]. J Autoimmun, 2019, 104: 102314.
[5]	Ries A, Schelch K, Falch D, et al. Activin A: an emerging target for improving cancer treatment?[J]. Expert Opin Ther Targets, 2020, 24(10): 985-996. doi: 10.1080/14728222.2020.1799350 URL
[6]	Thissen JP, Loumaye A. Role of activin A and myostatin in cancer cachexia[J]. Ann Endocrinol (Paris), 2013, 74(2): 79-81. doi: 10.1016/j.ando.2013.03.004 URL
[7]	Lee SJ, Lehar A, Meir JU, et al. Targeting myostatin/activin A protects against skeletal muscle and bone loss during spaceflight[J]. Proc Natl Acad Sci U S A, 2020, 117(38): 23942-23951. doi: 10.1073/pnas.2014716117 URL
[8]	Ghosh AC, O’Connor MB. Systemic activin signaling independently regulates sugar homeostasis, cellular metabolism, and pH balance in Drosophila melanogaster[J]. Proc Natl Acad Sci U S A, 2014, 111(15): 5729-5734. doi: 10.1073/pnas.1319116111 URL
[9]	Zhao L, Zhang J, Qu X, et al. Microsatellite instability-related ACVR2A mutations partially account for decreased lymph node metastasis in MSI-H gastric cancers[J]. Onco Targets Ther, 2020, 13: 3809-3821. doi: 10.2147/OTT.S247757 URL
[10]	Kaneda H, Arao T, Matsumoto K, et al. Activin A inhibits vascular endothelial cell growth and suppresses tumour angiogenesis in gastric cancer[J]. Br J Cancer, 2011, 105(8): 1210-1217. doi: 10.1038/bjc.2011.348 URL
[11]	Kim YI, Lee HJ, Khang I, et al. Selective inhibition of cell growth by activin in SNU-16 cells[J]. World J Gastroenterol, 2006, 12(19): 3000-3005. doi: 10.3748/wjg.v12.i19.3000 URL
[12]	Dean M, Davis DA, Burdette JE. Activin A stimulates migration of the fallopian tube epithelium, an origin of high-grade serous ovarian cancer, through non-canonical signaling[J]. Cancer Lett, 2017, 391: 114-124. doi: 10.1016/j.canlet.2017.01.011 URL
[13]	Jung BH, Beck SE, Cabral J, et al. Activin type 2 receptor restoration in MSI-H colon cancer suppresses growth and enhances migration with activin[J]. Gastroenterology, 2007, 132(2): 633-644. doi: 10.1053/j.gastro.2006.11.018 URL
[14]	Hanahan D. Hallmarks of cancer: new dimensions[J]. Cancer Discov, 2022, 12(1): 31-46. doi: 10.1158/2159-8290.CD-21-1059 URL
[15]	Vander Heiden MG, Cantley LC, Thompson CB. Understanding the Warburg effect: the metabolic requirements of cell proliferation[J]. Science, 2009, 324(5930): 1029-1033. doi: 10.1126/science.1160809 URL
[16]	Hanahan D, Coussens LM. Accessories to the crime: functions of cells recruited to the tumor microenvironment[J]. Cancer Cell, 2012, 21(3): 309-322. doi: 10.1016/j.ccr.2012.02.022 URL
[17]	Gill KS, Fernandes P, O’Donovan TR, et al. Glycolysis inhibition as a cancer treatment and its role in an anti-tumour immune response[J]. Biochim Biophys Acta, 2016, 1866(1): 87-105.
[18]	Huang Y, Chen ZC, Lu T, et al. HIF-1α switches the functionality of TGF-β signaling via changing the partners of smads to drive glucose metabolic reprogramming in non-small cell lung cancer[J]. J Exp Clin Cancer Res, 2021, 40(1): 398.
[19]	Chan DA, Sutphin PD, Nguyen P, et al. Targeting GLUT1 and the Warburg effect in renal cell carcinoma by chemical synthetic lethality[J]. Sci Transl Med, 2011, 3(94): 94ra70.