Norepinephrine-stimulated HSCs Secrete SFRP1 to Promote HCC Progression Following Chronic Stress Via Augmentation of a Wnt16B/β-catenin Positive Feedback Loop

Overview

Journal J Exp Clin Cancer Res

Publisher Biomed Central

Specialty Oncology

Date 2020 Apr 16

PMID 32293507

Citations 14

Authors

Xia-Hui Lin

Hua-Hua Liu

Shu-Jung Hsu

Rui Zhang

Jie Chen

Jun Chen

Dong-Mei Gao

Jie-Feng Cui

Zheng-Gang Ren

Rong-Xin Chen

Affiliations

Soon will be listed here.

Abstract

Background: Sustained adrenergic signaling secondary to chronic stress promotes cancer progression; however, the underlying mechanisms for this phenomenon remain unclear. Hepatocellular carcinoma (HCC) frequently develops within fibrotic livers rich in activated hepatic stellate cells (HSCs). Here, we examined whether the stress hormone norepinephrine (NE) could accelerate HCC progression by modulating HSCs activities.

Methods: HCC cells were exposed to conditioned medium (CM) from NE-stimulated HSCs. The changes in cell migration and invasion, epithelial-mesenchymal transition, parameters of cell proliferation, and levels of cancer stem cell markers were analyzed. Moreover, the in vivo tumor progression of HCC cells inoculated with HSCs was studied in nude mice subjected to chronic restraint stress.

Results: CM from NE-treated HSCs significantly promoted cell migration and invasion, epithelial-mesenchymal transition (EMT), and expression of cell proliferation-related genes and cancer stem cell markers in HCC cells. These pro-tumoral effects were markedly reduced by depleting secreted frizzled related protein 1 (sFRP1) in CM. The pro-tumoral functions of sFRP1 were dependent on β-catenin activation, and sFRP1 augmented the binding of Wnt16B to its receptor FZD7, resulting in enhanced β-catenin activity. Additionally, sFRP1 enhanced Wnt16B expression, reinforcing an autocrine feedback loop of Wnt16B/β-catenin signaling. The expression of sFRP1 in HSCs promoted HCC progression in an in vivo model under chronic restraint stress, which was largely attenuated by sFRP1 knockdown.

Conclusions: We identify a new mechanism by which chronic stress promotes HCC progression. In this model, NE activates HSCs to secrete sFRP1, which cooperates with a Wnt16B/β-catenin positive feedback loop. Our findings have therapeutic implications for the treatment of chronic stress-promoted HCC progression.

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References

Oben J, Roskams T, Yang S, Lin H, Sinelli N, Torbenson M . Hepatic fibrogenesis requires sympathetic neurotransmitters. Gut. 2004; 53(3):438-45. PMC: 1773985. DOI: 10.1136/gut.2003.026658. View

Liu N, Zhang X, Liang C, Yao D, Liu L, Zhao D . [Dynamic changes of alpha-AR, beta1-AR and beta2-AR expression during hepatic fibrogenesis]. Zhonghua Gan Zang Bing Za Zhi. 2009; 17(9):653-6. View

Krizhanovsky V, Yon M, Dickins R, Hearn S, Simon J, Miething C . Senescence of activated stellate cells limits liver fibrosis. Cell. 2008; 134(4):657-67. PMC: 3073300. DOI: 10.1016/j.cell.2008.06.049. View

Wurtman R . Stress and the adrenocortical control of epinephrine synthesis. Metabolism. 2002; 51(6 Suppl 1):11-4. DOI: 10.1053/meta.2002.33185. View

Chida Y, Sudo N, Kubo C . Does stress exacerbate liver diseases?. J Gastroenterol Hepatol. 2006; 21(1 Pt 2):202-8. DOI: 10.1111/j.1440-1746.2006.04110.x. View

Kang N, Gores G, Shah V . Hepatic stellate cells: partners in crime for liver metastases?. Hepatology. 2011; 54(2):707-13. PMC: 3145026. DOI: 10.1002/hep.24384. View

Jobling P, Pundavela J, Oliveira S, Roselli S, Walker M, Hondermarck H . Nerve-Cancer Cell Cross-talk: A Novel Promoter of Tumor Progression. Cancer Res. 2015; 75(9):1777-81. DOI: 10.1158/0008-5472.CAN-14-3180. View

Quan H, Zhou F, Nie D, Chen Q, Cai X, Shan X . Hepatitis C virus core protein epigenetically silences SFRP1 and enhances HCC aggressiveness by inducing epithelial-mesenchymal transition. Oncogene. 2013; 33(22):2826-35. DOI: 10.1038/onc.2013.225. View

Perugorria M, Olaizola P, Labiano I, Esparza-Baquer A, Marzioni M, Marin J . Wnt-β-catenin signalling in liver development, health and disease. Nat Rev Gastroenterol Hepatol. 2018; 16(2):121-136. DOI: 10.1038/s41575-018-0075-9. View

10.

Carbone E, Borges R, Eiden L, Garcia A, Hernandez-Cruz A . Chromaffin Cells of the Adrenal Medulla: Physiology, Pharmacology, and Disease. Compr Physiol. 2019; 9(4):1443-1502. DOI: 10.1002/cphy.c190003. View

11.

Szpunar M, Burke K, Dawes R, Brown E, Madden K . The antidepressant desipramine and α2-adrenergic receptor activation promote breast tumor progression in association with altered collagen structure. Cancer Prev Res (Phila). 2013; 6(12):1262-72. PMC: 3862035. DOI: 10.1158/1940-6207.CAPR-13-0079. View

12.

Clevers H . Wnt/beta-catenin signaling in development and disease. Cell. 2006; 127(3):469-80. DOI: 10.1016/j.cell.2006.10.018. View

13.

Cui B, Luo Y, Tian P, Peng F, Lu J, Yang Y . Stress-induced epinephrine enhances lactate dehydrogenase A and promotes breast cancer stem-like cells. J Clin Invest. 2019; 129(3):1030-1046. PMC: 6391112. DOI: 10.1172/JCI121685. View

14.

Liu T, Ding T, Ma Y, Wei W . Selective α1B- and α1D-adrenoceptor antagonists suppress noradrenaline-induced activation, proliferation and ECM secretion of rat hepatic stellate cells in vitro. Acta Pharmacol Sin. 2014; 35(11):1385-92. PMC: 4220077. DOI: 10.1038/aps.2014.84. View

15.

Loreal O, Levavasseur F, Fromaget C, Gros D, Guillouzo A, Clement B . Cooperation of Ito cells and hepatocytes in the deposition of an extracellular matrix in vitro. Am J Pathol. 1993; 143(2):538-44. PMC: 1887016. View

16.

Jansen A, Nguyen X, Karpitskiy V, Mettenleiter T, Loewy A . Central command neurons of the sympathetic nervous system: basis of the fight-or-flight response. Science. 1995; 270(5236):644-6. DOI: 10.1126/science.270.5236.644. View

17.

Yang E, Kim S, Donovan E, Chen M, Gross A, Webster Marketon J . Norepinephrine upregulates VEGF, IL-8, and IL-6 expression in human melanoma tumor cell lines: implications for stress-related enhancement of tumor progression. Brain Behav Immun. 2008; 23(2):267-75. PMC: 2652747. DOI: 10.1016/j.bbi.2008.10.005. View

18.

Fukui T, Kondo M, Ito G, Maeda O, Sato N, Yoshioka H . Transcriptional silencing of secreted frizzled related protein 1 (SFRP 1) by promoter hypermethylation in non-small-cell lung cancer. Oncogene. 2005; 24(41):6323-7. DOI: 10.1038/sj.onc.1208777. View

19.

Gjyshi A, Dash S, Cen L, Cheng C, Zhang C, Yoder S . Early transcriptional response of human ovarian and fallopian tube surface epithelial cells to norepinephrine. Sci Rep. 2018; 8(1):8291. PMC: 5974302. DOI: 10.1038/s41598-018-26670-4. View

20.

Ondicova K, Mravec B . Role of nervous system in cancer aetiopathogenesis. Lancet Oncol. 2010; 11(6):596-601. DOI: 10.1016/S1470-2045(09)70337-7. View