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Journal of Hematology & Oncology
Published in: Journal of Hematology & Oncology 1/2019

Open Access 01-12-2019 | Metastasis | Research

Higher matrix stiffness as an independent initiator triggers epithelial-mesenchymal transition and facilitates HCC metastasis

Authors: Yinying Dong, Qiongdan Zheng, Zhiming Wang, Xiahui Lin, Yang You, Sifan Wu, Yaohui Wang, Chao Hu, Xiaoying Xie, Jie Chen, Dongmei Gao, Yan Zhao, Weizhong Wu, Yinkun Liu, Zhenggang Ren, Rongxin Chen, Jiefeng Cui

Published in: Journal of Hematology & Oncology | Issue 1/2019

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Abstract

Background

Increased liver stiffness exerts a detrimental role in driving hepatocellular carcinoma (HCC) malignancy and progression, and indicates a high risk of unfavorable outcomes. However, it remains largely unknown how liver matrix stiffness as an independent cue triggers epithelial-mesenchymal transition (EMT) and facilitates HCC metastasis.

Methods

Buffalo rat HCC models with different liver stiffness backgrounds and an in vitro Col I-coated cell culture system with tunable stiffness were used in the study to explore the effects of matrix stiffness on EMT occurrence and its underlying molecular mechanism. Clinical significance of liver stiffness and key molecules required for stiffness-induced EMT were validated in HCC cohorts with different liver stiffness.

Results

HCC xenografts grown in higher stiffness liver exhibited worse malignant phenotypes and higher lung metastasis rate, suggesting that higher liver stiffness promotes HCC invasion and metastasis. Cell tests in vitro showed that higher matrix stiffness was able to strikingly strengthen malignant phenotypes and independently induce EMT occurrence in HCC cells, and three signaling pathways converging on Snail expression participated in stiffness-mediated effect on EMT including integrin-mediated S100A11 membrane translocation, eIF4E phosphorylation, and TGF β1 autocrine. Additionally, the key molecules required for stiffness-induced EMT were highly expressed in tumor tissues of HCC patients with higher liver stiffness and correlated with poor tumor differentiation and higher recurrence.

Conclusions

Higher matrix stiffness as an initiator triggers epithelial-mesenchymal transition (EMT) in HCC cells independently, and three signaling pathways converging on Snail expression contribute to this pathological process. This work highlights a significant role of biomechanical signal in triggering EMT and facilitating HCC invasion and metastasis.
Appendix
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Literature
1.
Yang JD, Nakamura I, Roberts LR. The tumor microenvironment in hepatocellular carcinoma: current status and therapeutic targets. Semin Cancer Biol. 2011;21(1):35–43.PubMedCrossRef
2.
Oskarsson T. Extracellular matrix components in breast cancer progression and metastasis. Breast. 2013;Suppl 2:S66–72.CrossRef
3.
Cretu A, Brooks PC. Impact of the non-cellular tumor microenvironment on metastasis: potential therapeutic and imaging opportunities. J Cell Physiol. 2007;213(2):391–402.PubMedCrossRef
4.
Levental KR, Yu H, Kass L, Lakins JN, Egeblad M, Erler JT, Fong SF, Csiszar K, Giaccia A, Weninger W, Yamauchi M, Gasser DL, Weaver VM. Matrix crosslinking forces tumor progression by enhancing integrin signaling. Cell. 2009;139(5):891–906.PubMedPubMedCentralCrossRef
5.
Leight JL, Wozniak MA, Chen S, Lynch ML, Chen CS. Matrix rigidity regulates a switch between TGF-β1-induced apoptosis and epithelial-mesenchymal transition. Mol Biol Cell. 2012;23(5):781–91.PubMedPubMedCentralCrossRef
6.
7.
Engler AJ, Sen S, Sweeney HL, Discher DE. Matrix elasticity directs stem cell lineage specification. Cell. 2006;126(4):677–89.CrossRefPubMed
8.
Klein EA, Yin L, Kothapalli D, Castagnino P, Byfield FJ, Xu T, Levental I, Hawthorne E, Janmey PA, Assoian RK. Cell-cycle control by physiological matrix elasticity and in vivo tissue stiffening. Curr Biol. 2009;19(18):1511–8.PubMedPubMedCentralCrossRef
9.
Tilghman RW, Cowan CR, Mih JD, Koryakina Y, Gioeli D, Slack-Davis JK, Blackman BR, Tschumperlin DJ, Parsons JT. Matrix rigidity regulates cancer cell growth and cellular phenotype. PLoS One. 2010;5(9):e12905.PubMedPubMedCentralCrossRef
10.
Tilghman RW, Blais EM, Cowan CR, Sherman NE, Grigera PR, Jeffery ED, Fox JW, Blackman BR, Tschumperlin DJ, Papin JA, Parsons JT. Matrix rigidity regulates cancer cell growth by modulating cellular metabolism and protein synthesis. PLoS One. 2012;7(5):e37231.PubMedPubMedCentralCrossRef
11.
Kshitiz PJ, Kim P, Helen W, Engler AJ, Levchenko A, Kim DH. Control of stem cell fate and function by engineering physical microenvironments. Integr Biol (Camb). 2012;4(9):1008–18.CrossRef
12.
Keely PJ. Mechanisms by which the extracellular matrix and integrin signaling act to regulate the switch between tumor suppression and tumor promotion. J Mammary Gland Biol Neoplasia. 2011;16(3):205–19.PubMedCrossRef
13.
Yeung T, Georges PC, Flanagan LA, Marg B, Ortiz M, Funaki M, Zahir N, Ming W, Weaver V, Janmey PA. Effects of substrate stiffness on cell morphology, cytoskeletal structure, and adhesion. Cell Motil Cytoskeleton. 2005;60(1):24–34.CrossRefPubMed
14.
Fattovich G, Stroffolini T, Zagni I, Donato F. Hepatocellular carcinoma in cirrhosis: incidence and risk factors. Gastroenterology. 2004;127(5 Suppl 1):S35–50.PubMedCrossRef
15.
Greten TF, Papendorf F, Bleck JS, Kirchhoff T, Wohlberedt T, Kubicka S, Klempnauer J, Galanski M, Manns MP. Survival rate in patients with hepatocellular carcinoma: a retrospective analysis of 389 patients. Br J Cancer. 2005;92(10):1862–8.PubMedPubMedCentralCrossRef
16.
Jung KS, Kim SU, Choi GH, Park JY, Park YN, do Kim Y, Ahn SH, Chon CY, Kim KS, Choi EH, Choi JS, Han KH. Prediction of recurrence after curative resection of hepatocellular carcinoma using liver stiffness measurement (FibroScan®). Ann Surg Oncol. 2012;19:4278–86.PubMedCrossRef
17.
Cescon M, Colecchia A, Cucchetti A, Peri E, Montrone L, Ercolani G, Festi D, Pinna AD. Value of transient elastography measured with FibroScan in predicting the outcome of hepatic resection for hepatocellular carcinoma. Ann Surg. 2012;256:706–12.PubMedCrossRef
18.
Schrader J, Gordon-Walker TT, Aucott RL, van Deemter M, Quaas A, Walsh S, Benten D, Forbes SJ, Wells RG, Iredale JP. Matrix stiffness modulates proliferation, chemotherapeutic response, and dormancy in hepatocellular carcinoma cells. Hepatology. 2011;53:1192–205.PubMedCrossRef
19.
Dong Y, Xie X, Wang Z, Hu C, Zheng Q, Wang Y, Chen R, Xue T, Chen J, Gao D, Wu W, Ren Z, Cui J. Increasing matrix stiffness upregulates vascular endothelial growth factor expression in hepatocellular carcinoma cells mediated by integrin β1. Biochem Biophys Res Commun. 2014;444:427–32.PubMedCrossRef
20.
You Y, Zheng Q, Dong Y, Wang Y, Zhang L, Xue T, Xie X, Hu C, Wang Z, Chen R, Wang Y, Cui J, Ren Z. Higher matrix stiffness upregulates osteopontin expression in hepatocellular carcinoma cells mediated by integrin β1/GSK3β/β-catenin signaling pathway. PLoS One. 2015;10:e0134243.PubMedPubMedCentralCrossRef
21.
You Y, Zheng Q, Dong Y, Xie X, Wang Y, Wu S, Zhang L, Wang Y, Xue T, Wang Z, Chen R, Wang Y, Cui J, Ren Z. Matrix stiffness-mediated effects on stemness characteristics occurring in HCC cells. Oncotarget. 2016;7:32221–31.PubMedPubMedCentral
22.
Zhao G, Cui J, Qin Q, Zhang J, Liu L, Deng S, Wu C, Yang M, Li S, Wang C. Mechanical stiffness of liver tissues in relation to integrin β1 expression may influence the development of hepatic cirrhosis and hepatocellular carcinoma. J Surg Oncol. 2010;102:482–9.PubMedCrossRef
23.
Wu S, Zheng Q, Xing X, Dong Y, Wang Y, You Y, Chen R, Hu C, Chen J, Gao D, Zhao Y, Wang Z, Xue T, Ren Z, Cui J. Matrix stiffness-upregulated LOXL2 promotes fibronectin production, MMP9 and CXCL12 expression and BMDCs recruitment to assist pre-metastatic niche formation. J Exp Clin Cancer Res. 2018;37(1):99.PubMedPubMedCentralCrossRef
24.
O'Connor JW, Gomez EW. Biomechanics of TGFβ-induced epithelial-mesenchymal transition: implications for fibrosis and cancer. Clin Transl Med. 2014;3:23.PubMedPubMedCentralCrossRef
25.
Thiery JP, Acloque H, Huang RY, Nieto MA. Epithelial-mesenchymal transitions in development and disease. Cell. 2009;139:871–90.PubMedCrossRef
26.
Lee K, Chen QK, Lui C, Cichon MA, Radisky DC, Nelson CM. Matrix compliance regulates Rac1b localization, NADPH oxidase assembly, and epithelial-mesenchymal transition. Mol Biol Cell. 2012;23:4097–108.PubMedPubMedCentralCrossRef
27.
Wong VW, Vergniol J, Wong GL, Foucher J, Chan HL, Le Bail B, Choi PC, Kowo M, Chan AW, Merrouche W, Sung JJ, de Lédinghen V. Diagnosis of fibrosis and cirrhosis using liver stiffness measurement in nonalcoholic fatty liver disease. Hepatology. 2010;51:454–62.PubMedCrossRef
28.
Karicheva O, Rodriguez-Vargas JM, Wadier N, Martin-Hernandez K, Vauchelles R, Magroun N, Tissier A, Schreiber V, Dantzer F. PARP3 controls TGFβ and ROS driven epithelial-to-mesenchymal transition and stemness by stimulating a TG2-Snail-E-cadherin axis. Oncotarget. 2016;7:64109–23.PubMedPubMedCentralCrossRef
29.
Romagnoli M, Belguise K, Yu Z, Wang X, Landesman-Bollag E, Seldin DC, Chalbos D, Barillé-Nion S, Jézéquel P, Seldin ML, Sonenshein GE. Epithelial-to-mesenchymal transition induced by TGF-β1 is mediated by Blimp-1-dependent repression of BMP-5. Cancer Res. 2012;72:6268–78.PubMedPubMedCentralCrossRef
30.
Le LT, Cazares O, Mouw JK, Chatterjee S, Macias H, Moran A, Ramos J, Keely PJ, Weaver VM, Hinck L. Loss of miR-203 regulates cell shape and matrix adhesion through ROBO1/Rac/FAK in response to stiffness. J Cell Biol. 2016;212:707–19.PubMedPubMedCentralCrossRef
31.
Mouw JK, Yui Y, Damiano L, Bainer RO, Lakins JN, Acerbi I, Ou G, Wijekoon AC, Levental KR, Gilbert PM, Hwang ES, Chen YY, Weaver VM. Tissue mechanics modulate microRNA-dependent PTEN expression to regulate malignant progression. Nat Med. 2014;20:360–7.PubMedPubMedCentralCrossRef
32.
Park MS, Han KH, Kim SU. Non-invasive prediction of development of hepatocellular carcinoma using transient elastography in patients with chronic liver disease. Expert Rev Gastroenterol Hepatol. 2014;8:501–11.PubMedCrossRef
33.
Yu X, Zech T, McDonald L, Gonzalez EG, Li A, Macpherson I, Schwarz JP, Spence H, Futó K, Timpson P, Nixon C, Ma Y, Anton IM, Visegrády B, Insall RH, Oien K, Blyth K, Norman JC, Machesky LM. N-WASP coordinates the delivery and F-actin-mediated capture of MT1-MMP at invasive pseudopods. J Cell Biol. 2012;199:527–44.PubMedPubMedCentralCrossRef
34.
García E, Ragazzini C, Yu X, Cuesta-García E, Bernardino de la Serna J, Zech T, Sarrió D, Machesky LM, Antón IM. WIP and WICH/WIRE co-ordinately control invadopodium formation and maturation in human breast cancer cell invasion. Sci Rep. 2016;6:23590.PubMedPubMedCentralCrossRef
35.
Shankar J, Messenberg A, Chan J, Underhill TM, Foster LJ, Nabi IR. Pseudopodial actin dynamics control epithelial-mesenchymal transition in metastatic cancer cells. Cancer Res. 2010;70:3780–90.PubMedCrossRef
36.
Wei SC, Fattet L, Tsai JH, Guo Y, Pai VH, Majeski HE, Chen AC, Sah RL, Taylor SS, Engler AJ, Yang J. Matrix stiffness drives epithelial -mesenchymal transition and tumour metastasis through a TWIST1-G3BP2 mechanotransduction pathway. Nat Cell Biol. 2015;17:678–88.PubMedPubMedCentralCrossRef
37.
Ohuchida K, Mizumoto K, Ohhashi S, Yamaguchi H, Konomi H, Nagai E, Yamaguchi K, Tsuneyoshi M, Tanaka M. S100A11, a putative tumor suppressor gene, is overexpressed in pancreatic carcinogenesis. Clin Cancer Res. 2006;12:5417–22.PubMedCrossRef
38.
Luo X, Xie H, Long X, Zhou M, Xu Z, Shi B, Jiang H, Li Z. EGFRvIII mediates hepatocellular carcinoma cell invasion by promoting S100 calcium binding protein A11 expression. PLoS One. 2013;8:e83332.PubMedPubMedCentralCrossRef
39.
Niu Y, Shao Z, Wang H, Yang J, Zhang F, Luo Y, Xu L, Ding Y, Zhao L. LASP1-S100A11 axis promotes colorectal cancer aggressiveness by modulating TGFβ/Smad signaling. Sci Rep. 2016;6:26112.PubMedPubMedCentralCrossRef
40.
Woo T, Okudela K, Mitsui H, Tajiri M, Rino Y, Ohashi K, Masuda M. Up-regulation of S100A11 in lung adenocarcinoma - its potential relationship with cancer progression. PLoS One. 2015;10:e0142642.PubMedPubMedCentralCrossRef
41.
Lim SO, Gu JM, Kim MS, Kim HS, Park YN, Park CK, Cho JW, Park YM, Jung G. Epigenetic changes induced by reactive oxygen species in hepatocellular carcinoma: methylation of the E-cadherin promoter. Gastroenterology. 2008;135:2128–40.PubMedCrossRef
42.
Liu RR, Lv YS, Tang YX, Wang YF, Chen XL, Zheng XX, Xie SZ, Cai Y, Yu J, Zhang XN. Eukaryotic translation initiation factor 5A2 regulates the migration and invasion of hepatocellular carcinoma cells via pathways involving reactive oxygen species. Oncotarget. 2016;7:24348–60.PubMedPubMedCentral
43.
Jiang XM, Yu XN, Huang RZ, Zhu HR, Chen XP, Xiong J, Chen ZY, Huang XX, Shen XZ, Zhu JM. Prognostic significance of eukaryotic initiation factor 4E in hepatocellular carcinoma. J Cancer Res Clin Oncol. 2016;142:2309–17.PubMedCrossRef
44.
Khosravi S, Tam KJ, Ardekani GS, Martinka M, McElwee KJ, Ong CJ. eIF4E is an adverse prognostic marker of melanoma patient survival by increasing melanoma cell invasion. J Invest Dermatol. 2015;135:1358–67.PubMedCrossRef
45.
Smith KA, Zhou B, Avdulov S, Benyumov A, Peterson M, Liu Y, Okon A, Hergert P, Braziunas J, Wagner CR, Borok Z, Bitterman PB. Transforming growth factor-β1 induced epithelial mesenchymal transition is blocked by a chemical antagonist of translation factor eIF4E. Sci Rep. 2015;5:18233.PubMedPubMedCentralCrossRef
46.
Robichaud N, del Rincon SV, Huor B, Alain T, Petruccelli LA, Hearnden J, Goncalves C, Grotegut S, Spruck CH, Furic L, Larsson O, Muller WJ, Miller WH, Sonenberg N. Phosphorylation of eIF4E promotes EMT and metastasis via translational control of SNAIL and MMP-3. Oncogene. 2015;34:2032–42.PubMedCrossRef
47.
Tang J, Li Y, Wang J, Wen Z, Lai M, Zhang H. Molecular mechanisms of microRNAs in regulating epithelial-mesenchymal transitions in human cancers. Cancer Lett. 2016;371:301–13.PubMedCrossRef
48.
Taylor MA, Sossey-Alaoui K, Thompson CL, Danielpour D, Schiemann WP. TGF-β upregulates miR-181a expression to promote breast cancer metastasis. J Clin Invest. 2013;123:150–63.PubMedCrossRef
Metadata
Title
Higher matrix stiffness as an independent initiator triggers epithelial-mesenchymal transition and facilitates HCC metastasis
Authors
Yinying Dong
Qiongdan Zheng
Zhiming Wang
Xiahui Lin
Yang You
Sifan Wu
Yaohui Wang
Chao Hu
Xiaoying Xie
Jie Chen
Dongmei Gao
Yan Zhao
Weizhong Wu
Yinkun Liu
Zhenggang Ren
Rongxin Chen
Jiefeng Cui
Publication date
01-12-2019
Publisher
BioMed Central
Published in
Journal of Hematology & Oncology / Issue 1/2019
Electronic ISSN: 1756-8722
DOI
https://doi.org/10.1186/s13045-019-0795-5

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