Elevation of Plasminogen Activator Inhibitor-1 Promotes Differentiation of Cancer Stem-Like Cell State by Hepatitis C Virus Infection

被引:5
作者
Nam, Da-eun [1 ]
Angelucci, Angelina [1 ]
Choi, Dahsom [1 ]
Leigh, Arnold [1 ]
Seong, Hae Chang [1 ]
Hahn, Young S. [1 ,2 ]
机构
[1] Univ Virginia, Beirne B Carter Ctr Immunol Res, Charlottesville, VA 22904 USA
[2] Univ Virginia, Dept Microbiol Immunol & Canc Biol, Charlottesville, VA 22904 USA
基金
美国国家卫生研究院;
关键词
HCV; PAI-1; CSC; miRNAs; miR-30c; EPITHELIAL-MESENCHYMAL TRANSITION; HEPATOCELLULAR-CARCINOMA; MATRIX METALLOPROTEINASES; CLINICAL-SIGNIFICANCE; ADHESION MOLECULE; LIVER-CIRRHOSIS; EXPRESSION; AKT; MARKER; PAI-1;
D O I
10.1128/JVI.02057-20
中图分类号
Q93 [微生物学];
学科分类号
071005 ; 100705 ;
摘要
Plasminogen activator inhibitor-1 (PAI-1) is a critical factor that regulates protein synthesis and degradation. Increased PAI-1 levels are detectable in the serum of patients with chronic hepatitis C virus (HCV) liver disease. The differentiation state and motility of HCV-induced cancer stem-like cells (CSCs) play a major role in severe liver disease progression. However, the role of PAI-1 in the pathological process of chronic liver diseases remains unknown. In this study, we determined how PAI-1 affects the differentiation of CSC state in hepatocytes upon HCV infection. We found that HCV infection induced the expression of PAI-1 while decreasing miR30c expression in Huh7.5.1 cells. Similar results were obtained from isolated hepatocytes from humanized-liver mice after HCV infection. Moreover, decreased miR-30c expression in HCV-infected hepatocytes was associated with the increased levels of PAI-1 mRNA and protein. Notably, the increased PAI-1 levels resulted in the activation of protein kinase B/AKT, a major mediator of cell proliferation in HCV-infected hepatocytes, along with the increased expression of CSC markers such as human differentiated protein (CD) 133, epithelial cell adhesion molecule (EpCAM), octamer 4 (Oct4), Nanog, cyclin D1, and MYC. Moreover, blockade of PAI-1 activity by miR-30c mimic and anti-PAI-1 monoclonal antibody (Mab) abrogated the AKT activation with decreased expression of CSC markers. Our findings suggest that HCV infection induces the CSC state via PAI-1-mediated AKT activation in hepatocytes. This finding implies that manipulation of PAI-1 activity could provide potential therapeutics to prevent the development of HCV-associated chronic liver diseases. IMPORTANCE The progression of chronic liver disease by HCV infection is considered a major risk factor for hepatocellular carcinoma (HCC), one of the major causes of death from cancer. Recent studies have demonstrated that increased CSC properties in HCV-infected hepatocytes are associated with the progression of HCC. Since protein and microRNA (miRNA) production by HCV-infected hepatocytes can play various roles in physiological processes, investigating these factors can potentially lead to new therapeutic targets. However, the mechanism of HCV-associated progression of hepatocytes to CSC remains unclear. Here, we identify the roles of PAI-1 and miR30c in the progression of CSC during HCV infection in hepatocytes. Our data show that increased secretion of PAI-1 following HCV infection promotes this CSC state and activation of AKT. We report that the inhibition of PAI-1 by an miR-30c mimic reduces HCV-associated CSC properties in hepatocytes. Taken together, targeting this interaction of secreted PAI-1 and miR-30c in HCV-infected hepatocytes may provide a potential therapeutic intervention against the progression to chronic liver diseases and HCC.
引用
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页数:19
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共 77 条
[1]   Extracellular Matrix Secretion by Cardiac Fibroblasts Role of MicroRNA-29b and MicroRNA-30c [J].
Abonnenc, Melanie ;
Nabeebaccus, Adam A. ;
Mayr, Ursula ;
Barallobre-Barreiro, Javier ;
Dong, Xuebin ;
Cuello, Friederike ;
Sur, Sumon ;
Drozdov, Ignat ;
Langley, Sarah R. ;
Lu, Ruifang ;
Stathopoulou, Konstantina ;
Didangelos, Athanasios ;
Yin, Xiaoke ;
Zimmermann, Wolfram-Hubertus ;
Shah, Ajay M. ;
Zampetaki, Anna ;
Mayr, Manuel .
CIRCULATION RESEARCH, 2013, 113 (10) :1138-+
[2]   Ledipasvir and Sofosbuvir for Previously Treated HCV Genotype 1 Infection [J].
Afdhal, Nezam ;
Reddy, K. Rajender ;
Nelson, David R. ;
Lawitz, Eric ;
Gordon, Stuart C. ;
Schiff, Eugene ;
Nahass, Ronald ;
Ghalib, Reem ;
Gitlin, Norman ;
Herring, Robert ;
Lalezari, Jacob ;
Younes, Ziad H. ;
Pockros, Paul J. ;
Di Bisceglie, Adrian M. ;
Arora, Sanjeev ;
Subramanian, G. Mani ;
Zhu, Yanni ;
Dvory-Sobol, Hadas ;
Yang, Jenny C. ;
Pang, Phillip S. ;
Symonds, William T. ;
McHutchison, John G. ;
Muir, Andrew J. ;
Sulkowski, Mark ;
Kwo, Paul .
NEW ENGLAND JOURNAL OF MEDICINE, 2014, 370 (16) :1483-1493
[3]   Circulating microRNAs panel as a diagnostic tool for discrimination of HCV-associated hepatocellular carcinoma [J].
Ali, Hamdy E. Abouzeid ;
Hanneed, Rehab Abdel ;
Effat, Heba ;
Ahmed, Emad K. ;
Atef, Azza A. ;
Sharawi, Sabry K. ;
Ali, Mohamed ;
Elmageed, Zakaria Y. Abd ;
Wahab, Abdel Hady Abdel .
CLINICS AND RESEARCH IN HEPATOLOGY AND GASTROENTEROLOGY, 2017, 41 (04) :E51-E62
[4]   Robust expansion of human hepatocytes in Fah-/-/Rag2-/-/Il2rg-/- mice [J].
Azuma, Hisaya ;
Paulk, Nicole ;
Ranade, Aarati ;
Dorrell, Craig ;
Al-Dhalimy, Muhsen ;
Ellis, Ewa ;
Strom, Stephen ;
Kay, Mark A. ;
Finegold, Milton ;
Grompe, Markus .
NATURE BIOTECHNOLOGY, 2007, 25 (08) :903-910
[5]   EpCAM (CD326) finding its role in cancer [J].
Baeuerle, P. A. ;
Gires, O. .
BRITISH JOURNAL OF CANCER, 2007, 96 (03) :417-423
[6]   Efficient hepatitis C virus cell culture system: What a difference the host cell makes [J].
Bartenschlager, R ;
Pietschmann, T .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2005, 102 (28) :9739-9740
[7]   HCV-induced EGFR-ERK signaling promotes a pro-inflammatory and pro-angiogenic signature contributing to liver cancer pathogenesis [J].
Benkheil, Mohammed ;
Paeshuyse, Jan ;
Neyts, Johan ;
Van Haele, Matthias ;
Roskams, Tania ;
Liekens, Sandra .
BIOCHEMICAL PHARMACOLOGY, 2018, 155 :305-315
[8]   Chronic hepatitis C infection-induced liver fibrogenesis is associated with M2 macrophage activation [J].
Bility, Moses T. ;
Nio, Kouki ;
Li, Feng ;
McGivern, David R. ;
Lemon, Stanley M. ;
Feeney, Eoin R. ;
Chung, Raymond T. ;
Su, Lishan .
SCIENTIFIC REPORTS, 2016, 6
[9]   Hepatitis C Virus Induces Epithelial-Mesenchymal Transition in Primary Human Hepatocytes [J].
Bose, Sandip K. ;
Meyer, Keith ;
Di Bisceglie, Adrian M. ;
Ray, Ratna B. ;
Ray, Ranjit .
JOURNAL OF VIROLOGY, 2012, 86 (24) :13621-13628
[10]   Nonstructural 3 protein of hepatitis C virus triggers an oxidative burst in human monocytes via activation of NADPH oxidase [J].
Bureau, C ;
Bernad, J ;
Chaouche, N ;
Orfila, C ;
Béraud, M ;
Gonindard, C ;
Alric, L ;
Vinel, JP ;
Pipy, B .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2001, 276 (25) :23077-23083