Top

Journal of Cancer Research and Clinical Oncology

Published in:

01-12-2020 | Hepatocellular Carcinoma | Original Article – Cancer Research

Senescent hepatic stellate cells caused by deoxycholic acid modulates malignant behavior of hepatocellular carcinoma

Authors: Phuong Thao Nguyen, Keishi Kanno, Quoc Thang Pham, Yuka Kikuchi, Masaki Kakimoto, Tomoki Kobayashi, Yuichiro Otani, Nobusuke Kishikawa, Mutsumi Miyauchi, Koji Arihiro, Masanori Ito, Susumu Tazuma

Published in: Journal of Cancer Research and Clinical Oncology | Issue 12/2020

Abstract

Purpose

Deoxycholic acid (DCA), a secondary bile acid, is reportedly increased in the serum of patients with nonalcoholic steatohepatitis and animals with experimentally induced hepatocellular carcinoma (HCC), but its contribution to malignant behaviors of HCC has not been precisely clarified. This study aimed to examine the effect of DCA on hepatic stellate cells (HSCs), a major component of nonparenchymal cells in the liver, and its subsequent indirect effect on HCC cells.

Methods

LX2 cells, a human HSC line, were treated with DCA in vitro. Then, HuH7 cells, a human hepatoma cell line, were incubated in conditioned media of DCA-treated LX2 to investigate the subsequent effect focusing on malignant behaviors.

Results

DCA resulted in cellular senescence in LX2 with the decreased cell proliferation via cell cycle arrest at G0/1 phase, together with the induction of senescence-associated secretory phenotype (SASP) factors. To investigate the influence of SASP factors secreted by HSCs in response to DCA, HCC cells were treated with conditioned media that promoted cell migration and invasion via induction of epithelial mesenchymal transition. These changes were attenuated in the presence of neutralizing antibody against IL8 or TGFβ. Pathological analysis of surgical specimens from HCC patients revealed that senescent HSCs were detected in the stroma surrounding HCC.

Conclusion

Our data suggest an important role of HSC senescence caused by DCA for the malignant biological behaviors of HCC via induction of SASP factors, particularly IL8 and TGFβ.

Available only for authorised users

Aranha MM, Cortez-Pinto H, Costa A, da Silva IB, Camilo ME, de Moura MC, Rodrigues CM (2008) Bile acid levels are increased in the liver of patients with steatohepatitis. Eur J Gastroenterol Hepatol 20:519–525. https://doi.org/10.1097/MEG.0b013e3282f4710aCrossRefPubMed

Ascha MS, Hanouneh IA, Lopez R, Tamimi TA, Feldstein AF, Zein NN (2010) The incidence and risk factors of hepatocellular carcinoma in patients with nonalcoholic steatohepatitis. Hepatology 51:1972–1978. https://doi.org/10.1002/hep.23527CrossRefPubMed

Bilusic M et al (2019) Phase I trial of HuMax-IL8 (BMS-986253), an anti-IL-8 monoclonal antibody, in patients with metastatic or unresectable solid tumors. J Immunother Cancer. https://doi.org/10.1186/s40425-019-0706-xCrossRefPubMedPubMedCentral

Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A (2018) Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 68:394–424. https://doi.org/10.3322/caac.21492CrossRef

Campisi J (2005) Senescent cells, tumor suppression, and organismal aging: good citizens, bad neighbors. Cell 120:513–522. https://doi.org/10.1016/j.cell.2005.02.003CrossRefPubMed

Cook JW, Kennaway EI, Kennaway NM (1940) Production of tumours in mice by deoxycholic acid. Nature 145:627–627. https://doi.org/10.1038/145627a0CrossRef

Coppe JP et al (2008) Senescence-associated secretory phenotypes reveal cell-nonautonomous functions of oncogenic RAS and the p53 tumor suppressor. PLoS Biol 6:2853–2868. https://doi.org/10.1371/journal.pbio.0060301CrossRefPubMed

d'Adda di Fagagna F (2008) Living on a break: cellular senescence as a DNA-damage response. Nat Rev Cancer 8:512–522. https://doi.org/10.1038/nrc2440CrossRefPubMed

Evangelou K, Gorgoulis VG (2017) Sudan Black B, the specific histochemical stain for lipofuscin: a novel method to detect senescent cells. Methods Mol Biol 1534:111–119. https://doi.org/10.1007/978-1-4939-6670-7_10CrossRefPubMed

Fabregat I, Roncero C, Fernandez M (2007) Survival and apoptosis: a dysregulated balance in liver cancer. Liver Int 27:155–162. https://doi.org/10.1111/j.1478-3231.2006.01409.xCrossRefPubMed

Frey N, Venturelli S, Zender L, Bitzer M (2018) Cellular senescence in gastrointestinal diseases: from pathogenesis to therapeutics. Nat Rev Gastroenterol Hepatol 15:81–95. https://doi.org/10.1038/nrgastro.2017.146CrossRefPubMed

Friedman SL (2008) Hepatic stellate cells: protean, multifunctional, and enigmatic cells of the liver. Physiol Rev 88:125–172. https://doi.org/10.1152/physrev.00013.2007CrossRefPubMedPubMedCentral

Fu XT et al (2015) Macrophage-secreted IL-8 induces epithelial-mesenchymal transition in hepatocellular carcinoma cells by activating the JAK2/STAT3/Snail pathway. Int J Oncol 46:587–596. https://doi.org/10.3892/ijo.2014.2761CrossRefPubMed

Guo M et al (2013) The role of vimentin intermediate filaments in cortical and cytoplasmic mechanics. Biophys J 105:1562–1568. https://doi.org/10.1016/j.bpj.2013.08.037CrossRefPubMedPubMedCentral

Honma N, Genda T, Matsuda Y, Yamagiwa S, Takamura M, Ichida T, Aoyagi Y (2006) MEK/ERK signaling is a critical mediator for integrin-induced cell scattering in highly metastatic hepatocellular carcinoma cells. Lab Invest 86:687–696. https://doi.org/10.1038/labinvest.3700427CrossRefPubMed

Huang WD et al (2006) Nuclear receptor-dependent bile acid signaling is required for normal liver regeneration. Science 312:233–236. https://doi.org/10.1126/science.1121435CrossRefPubMed

Hustedt N, Durocher D (2016) The control of DNA repair by the cell cycle. Nat Cell Biol 19:1–9. https://doi.org/10.1038/ncb3452CrossRefPubMed

Jemal A et al (2017) Annual report to the nation on the status of cancer, 1975–2014. Featuring Survival J Natl Cancer Inst. https://doi.org/10.1093/jnci/djx030CrossRefPubMed

Karimian A, Ahmadi Y, Yousefi B (2016) Multiple functions of p21 in cell cycle, apoptosis and transcriptional regulation after DNA damage. DNA Repair (Amst) 42:63–71. https://doi.org/10.1016/j.dnarep.2016.04.008CrossRef

Kaul Z, Cesare AJ, Huschtscha LI, Neumann AA, Reddel RR (2012) Five dysfunctional telomeres predict onset of senescence in human cells. Embo Rep 13:52–59. https://doi.org/10.1038/embor.2011.227CrossRef

Kim JH (2020) Interleukin-8 in the tumor immune niche: lessons from comparative oncology. Adv Exp Med Biol 1240:25–33. https://doi.org/10.1007/978-3-030-38315-2_2CrossRefPubMed

Kim I, Morimura K, Shah Y, Yang Q, Ward JM, Gonzalez FJ (2007) Spontaneous hepatocarcinogenesis in farnesoid X receptor-null mice vol 28. Carcinogenesis. https://doi.org/10.1093/carcin/bgl249CrossRefPubMed

Knisely AS et al (2006) Hepatocellular carcinoma in ten children under 5 years of age with bile salt export pump deficiency. Hepatology 44:478–486. https://doi.org/10.1002/hep.21287CrossRefPubMed

Kuilman T et al (2008) Oncogene-induced senescence relayed by an interleukin-dependent inflammatory network. Cell 133:1019–1031. https://doi.org/10.1016/j.cell.2008.03.039CrossRefPubMed

Liu H et al (2015) Ursodeoxycholic acid induces apoptosis in hepatocellular carcinoma xenografts in mice. World J Gastroenterol 21:10367–10374. https://doi.org/10.3748/wjg.v21.i36.10367CrossRefPubMedPubMedCentral

Llovet JM, Bruix J (2008) Molecular targeted therapies in hepatocellular carcinoma. Hepatology 48:1312–1327. https://doi.org/10.1002/hep.22506CrossRefPubMedPubMedCentral

Lowe SW, Cepero E, Evan G (2004) Intrinsic tumour suppression. Nature 432:307–315. https://doi.org/10.1038/nature03098CrossRefPubMed

Mannaerts I, Schroyen B, Verhulst S, Van Lommel L, Schuit F, Nyssen M, van Grunsven LA (2013) Gene expression profiling of early hepatic stellate cell activation reveals a role for Igfbp3 in cell migration. PLoS ONE 8:e84071. https://doi.org/10.1371/journal.pone.0084071CrossRefPubMedPubMedCentral

Mariotti A, Perotti A, Sessa C, Ruegg C (2007) N-cadherin as a therapeutic target in cancer Expert. Opin Inv Drug 16:451–465. https://doi.org/10.1517/13543784.16.4.451CrossRef

Mikula M, Proell V, Fischer AN, Mikulits W (2006) Activated hepatic stellate cells induce tumor progression of neoplastic hepatocytes in a TGF-beta dependent fashion. J Cell Physiol 209:560–567. https://doi.org/10.1002/jcp.20772CrossRefPubMedPubMedCentral

Nguyen PT, Kudo Y, Yoshida M, Iizuka S, Ogawa I, Takata T (2011) N-cadherin expression is correlated with metastasis of spindle cell carcinoma of head and neck region. J Oral Pathol Med 40:77–82. https://doi.org/10.1111/j.1600-0714.2010.00966.xCrossRefPubMed

Nguyen PT, Tsunematsu T, Yanagisawa S, Kudo Y, Miyauchi M, Kamata N, Takata T (2013) The FGFR1 inhibitor PD173074 induces mesenchymal-epithelial transition through the transcription factor AP-1. Brit J Cancer 109:2248–2258. https://doi.org/10.1038/bjc.2013.550CrossRefPubMed

Nurse P (2000) A long twentieth century of the cell cycle and beyond. Cell 100:71–78. https://doi.org/10.1016/S0092-8674(00)81684-0CrossRefPubMed

Oda K, Uto H, Mawatari S, Ido A (2015) Clinical features of hepatocellular carcinoma associated with nonalcoholic fatty liver disease: a review of human studies Clin. J Gastroenterol 8:1–9. https://doi.org/10.1007/s12328-014-0548-5CrossRef

Saga K et al (2018) Secondary unconjugated bile acids induce hepatic stellate cell activation. Int J Mol Sci. https://doi.org/10.3390/ijms19103043CrossRefPubMedPubMedCentral

Son H, Moon A (2010) Epithelial-mesenchymal transition and cell invasion. Toxicol Res 26:245–252. https://doi.org/10.5487/TR.2010.26.4.245CrossRefPubMedPubMedCentral

Sun L et al (2016) Bile acids promote diethylnitrosamine-induced hepatocellular carcinoma via increased inflammatory signaling. Am J Physiol Gastrointest Liver Physiol 311:G91–G104. https://doi.org/10.1152/ajpgi.00027.2015CrossRefPubMedPubMedCentral

Taura K et al (2008) Hepatic stellate cells secrete angiopoietin 1 that induces angiogenesis in liver fibrosis. Gastroenterology 135:1729–1738. https://doi.org/10.1053/j.gastro.2008.07.065CrossRefPubMed

van Zijl F et al (2009) Hepatic tumor-stroma crosstalk guides epithelial to mesenchymal transition at the tumor edge. Oncogene 28:4022–4033. https://doi.org/10.1038/onc.2009.253CrossRefPubMedPubMedCentral

Xing S et al (2018) Isoviolanthin extracted from dendrobium officinale reverses TGF-beta1-mediated epithelial(-)mesenchymal transition in hepatocellular carcinoma cells via deactivating the TGF-beta/Smad and PI3K/Akt/mTOR signaling pathways. Int J Mol Sci. https://doi.org/10.3390/ijms19061556CrossRefPubMedPubMedCentral

Xu J, Lamouille S, Derynck R (2009) TGF-beta-induced epithelial to mesenchymal transition. Cell Res 19:156–172. https://doi.org/10.1038/cr.2009.5CrossRefPubMedPubMedCentral

Yamada S, Takashina Y, Watanabe M, Nagamine R, Saito Y, Kamada N, Saito H (2018) Bile acid metabolism regulated by the gut microbiota promotes non-alcoholic steatohepatitis-associated hepatocellular carcinoma in mice. Oncotarget 9:9925–9939. https://doi.org/10.18632/oncotarget.24066CrossRefPubMedPubMedCentral

Yin C, Evason KJ, Asahina K, Stainier DY (2013) Hepatic stellate cells in liver development, regeneration, and cancer. J Clin Invest 123:1902–1910. https://doi.org/10.1172/JCI66369CrossRefPubMedPubMedCentral

Yoshimoto S et al (2013) Obesity-induced gut microbial metabolite promotes liver cancer through senescence secretome. Nature 499:97–101. https://doi.org/10.1038/nature12347CrossRefPubMed

Title: Senescent hepatic stellate cells caused by deoxycholic acid modulates malignant behavior of hepatocellular carcinoma
Authors: Phuong Thao Nguyen
Keishi Kanno
Quoc Thang Pham
Yuka Kikuchi
Masaki Kakimoto
Tomoki Kobayashi
Yuichiro Otani
Nobusuke Kishikawa
Mutsumi Miyauchi
Koji Arihiro
Masanori Ito
Susumu Tazuma
Publication date: 01-12-2020
Publisher: Springer Berlin Heidelberg
Keywords: Hepatocellular Carcinoma
Hepatocellular Carcinoma
Published in: Journal of Cancer Research and Clinical Oncology / Issue 12/2020
Print ISSN: 0171-5216
Electronic ISSN: 1432-1335
DOI: https://doi.org/10.1007/s00432-020-03374-9

Live Webinar | 27-06-2024 | 18:00 (CEST)

Keynote webinar | Spotlight on medication adherence

Reserve your place

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

WHO estimates that half of all patients worldwide are non-adherent to their prescribed medication. The consequences of poor adherence can be catastrophic, on both the individual and population level.

Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.

Prof. Kevin Dolgin

Prof. Florian Limbourg

Prof. Anoop Chauhan

Developed by: Springer Medicine

Obesity Clinical Trial Summary

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Purpose

Methods

Results

Conclusion

Please log in to get access to this content

Other articles of this Issue 12/2020

UV-type specific alteration of miRNA expression and its association with tumor progression and metastasis in SCC cell lines

EPS15–NTRK1: a novel NTRK1 oncogenic fusion in patient with lung adenocarcinoma

Patient expectations are better for immunotherapy than traditional chemotherapy for cancer

Gamma-delta T cells stimulate IL-6 production by pancreatic stellate cells in pancreatic ductal adenocarcinoma

Implications of flavonoids as potential modulators of cancer neovascularity

Surgical outcomes of second primary lung cancer after the extrapulmonary malignancy

Keynote webinar | Spotlight on medication adherence

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

At a glance: The STEP trials