Please wait a minute...
Frontiers of Medicine

ISSN 2095-0217

ISSN 2095-0225(Online)

CN 11-5983/R

Postal Subscription Code 80-967

2018 Impact Factor: 1.847

Front Med    2014, Vol. 8 Issue (1) : 24-32     DOI: 10.1007/s11684-014-0312-8
REVIEW |
Osteopontin is a promoter for hepatocellular carcinoma metastasis: a summary of 10 years of studies
Lunxiu Qin()
Department of Surgery, Huashan Hospital, Fudan University, Shanghai 200040, China
Download: PDF(298 KB)   HTML
Export: BibTeX | EndNote | Reference Manager | ProCite | RefWorks
Abstract  

In this review, we summarize the novel findings from our series of studies on the leading metastasis-related gene, osteopontin (OPN). In our previous gene expression profiling study, OPN was identified as one of the leading genes associated with the metastasis of hepatocellular carcinoma (HCC). We focused on OPN to evaluate its prognostic values and important roles in HCC metastasis. A retrospective study of large cohorts of HCC patients demonstrated that plasma OPN level was one of the leading independent prognostic factors for HCC patients, even in the early stage of HCC, and could serve as a surrogate serologic biomarker for monitoring the treatment response and tumor recurrence after HCC resection. Using both in vitro and in vivo investigations, we found that OPN has an important role in metastasis and tumor growth of HCC and is an attractive potential therapeutic target for combating HCC metastasis. We also found that OPN+ HCC cells have much more amplifications at chromosomal regions, and promoter polymorphisms are important in the regulation of OPN expression and tumor growth and lung metastasis of HCC.

Keywords osteopontin (OPN)      hepatocellular carcinoma      metastasis      prognosis      therapeutic target      biomarker      genetic polymorphism     
Corresponding Authors: Qin Lunxiu,Email:qinlx99@163.com   
Issue Date: 26 April 2014
URL:  
http://academic.hep.com.cn/fmd/EN/10.1007/s11684-014-0312-8     OR     http://academic.hep.com.cn/fmd/EN/Y2014/V8/I1/24
Fig.1  OPN is one of the leading genes in the metastasis-related gene expression signature of HCC.
Fig.2  Association between the preoperative serum OPN levels and survival rates of HCC patients. Both the OS (left) and disease-free survival (DFS) (right) rates in patients with high preoperative OPN levels (green lines) were significantly decreased compared with those in low-OPN patients (blue lines).
Fig.3  Dynamic changes in the serum OPN levels after liver resection for HCC. (A) Dynamic change patterns of post-surgery OPN levels in the HCC patients. (B) AFP HCC patients had the same changing pattern of postoperative OPN levels. Note: 1W, 1 week; 1M, 1 month; 2M, 2 months. The OPN levels are shown as mean±SD. Boxes represent the 10th to the 90th quartile.
Fig.4  Association of postsurgery serum OPN with treatment response and tumor recurrence after HCC resection. Each dot represents an individual postsurgery OPN measurement plotted against time from surgery. Three patients (red and green lines) were observed with serially serum OPN levels at tumor relapse and after the second operative resection. The red lines denote the AFP patients, whereas the green line denotes the AFP patients.
Fig.5  Prognostic values of the genotypes and their related haplotypes at OPN promoter locus -443 for HCC patients (Kaplan-Meier analyses of 317 patients). Homozygous Ht3 is associated with the best OS (A) and significantly longer TTR (C) than the other haplotypes. Similarly, homozygous -443C genotypes are associated with longer OS and TTR than heterozygous -443 or homozygous -443T genotypes (B, D).
1 McAllister SS, Gifford AM, Greiner AL, Kelleher SP, Saelzler MP, Ince TA, Reinhardt F, Harris LN, Hylander BL, Repasky EA, Weinberg RA. Systemic endocrine instigation of indolent tumor growth requires osteopontin. Cell 2008; 133(6): 994-1005
doi: 10.1016/j.cell.2008.04.045 pmid:18555776
2 Denhardt DT, Giachelli CM, Rittling SR. Role of osteopontin in cellular signaling and toxicant injury. Annu Rev Pharmacol Toxicol 2001; 41(1): 723-749
doi: 10.1146/annurev.pharmtox.41.1.723 pmid:11264474
3 Weber GF. The metastasis gene osteopontin: a candidate target for cancer therapy. Biochim Biophys Acta 2001; 1552(2): 61-85
pmid:11825687
4 Wu CY, Wu MS, Chiang EP, Wu CC, Chen YJ, Chen CJ, Chi NH, Chen GH, Lin JT. Elevated plasma osteopontin associated with gastric cancer development, invasion and survival. Gut 2007; 56(6): 782-789
doi: 10.1136/gut.2006.109868 pmid:17148500
5 Khodavirdi AC, Song Z, Yang S, Zhong C, Wang S, Wu H, Pritchard C, Nelson PS, Roy-Burman P. Increased expression of osteopontin contributes to the progression of prostate cancer. Cancer Res 2006; 66(2): 883-888
doi: 10.1158/0008-5472.CAN-05-2816 pmid:16424021
6 Bramwell VH, Doig GS, Tuck AB, Wilson SM, Tonkin KS, Tomiak A, Perera F, Vandenberg TA, Chambers AF. Serial plasma osteopontin levels have prognostic value in metastatic breast cancer. Clin Cancer Res 2006; 12(11): 3337-3343
doi: 10.1158/1078-0432.CCR-05-2354 pmid:16740755
7 Medico E, Gentile A, Lo Celso C, Williams TA, Gambarotta G, Trusolino L, Comoglio PM. Osteopontin is an autocrine mediator of hepatocyte growth factor-induced invasive growth. Cancer Res 2001; 61(15): 5861-5868
pmid:11479227
8 Tuck AB, Hota C, Wilson SM, Chambers AF. Osteopontin-induced migration of human mammary epithelial cells involves activation of EGF receptor and multiple signal transduction pathways. Oncogene 2003; 22(8): 1198-1205
doi: 10.1038/sj.onc.1206209 pmid:12606946
9 Ariztia EV, Subbarao V, Solt DB, Rademaker AW, Iyer AP, Oltvai ZN. Osteopontin contributes to hepatocyte growth factor-induced tumor growth and metastasis formation. Exp Cell Res 2003; 288(2): 257-267
doi: 10.1016/S0014-4827(03)00118-6 pmid:12915117
10 Sharp JA, Sung V, Slavin J, Thompson EW, Henderson MA. Tumor cells are the source of osteopontin and bone sialoprotein expression in human breast cancer. Lab Invest 1999; 79(7): 869-877
pmid:10418827
11 Urquidi V, Sloan D, Kawai K, Agarwal D, Woodman AC, Tarin D, Goodison S. Contrasting expression of thrombospondin-1 and osteopontin correlates with absence or presence of metastatic phenotype in an isogenic model of spontaneous human breast cancer metastasis. Clin Cancer Res 2002; 8(1): 61-74
pmid:11801541
12 Chen H, Ke Y, Oates AJ, Barraclough R, Rudland PS. Isolation of and effector for metastasis-inducing DNAs from a human metastatic carcinoma cell line. Oncogene 1997; 14(13): 1581-1588
doi: 10.1038/sj.onc.1200993 pmid:9129149
13 Oates AJ, Barraclough R, Rudland PS. The identification of osteopontin as a metastasis-related gene product in a rodent mammary tumour model. Oncogene 1996; 13(1): 97-104
pmid:8700559
14 Ye QH, Qin LX, Forgues M, He P, Kim JW, Peng AC, Simon R, Li Y, Robles AI, Chen Y, Ma ZC, Wu ZQ, Ye SL, Liu YK, Tang ZY, Wang XW. Predicting hepatitis B virus-positive metastatic hepatocellular carcinomas using gene expression profiling and supervised machine learning. Nat Med 2003; 9(4): 416-423
doi: 10.1038/nm843 pmid:12640447
15 Zhang H, Ye QH, Ren N, Zhao L, Wang YF, Wu X, Sun HC, Wang L, Zhang BH, Liu YK, Tang ZY, Qin LX. The prognostic significance of preoperative plasma levels of osteopontin in patients with hepatocellular carcinoma. J Cancer Res Clin Oncol 2006; 132(11): 709-717
doi: 10.1007/s00432-006-0119-3 pmid:16786357
16 Huang H, Zhang XF, Zhou HJ, Xue YH, Dong QZ, Ye QH, Qin LX. Expression and prognostic significance of osteopontin and caspase-3 in hepatocellular carcinoma patients after curative resection. Cancer Sci 2010; 101(5): 1314-1319
doi: 10.1111/j.1349-7006.2010.01524.x pmid:20345480
17 Sun J, Xu HM, Zhou HJ, Dong QZ, Zhao Y, Fu LY, Hei ZY, Ye QH, Ren N, Jia HL, Qin LX. The prognostic significance of preoperative plasma levels of osteopontin in patients with TNM stage-I of hepatocellular carcinoma. J Cancer Res Clin Oncol 2010; 136(1): 1-7
doi: 10.1007/s00432-009-0629-x pmid:19593583
18 Zhou C, Zhou HJ, Zhang XF, Lou LL, Ye QH, Zheng Y, Wang J, Zhu HT, Dong QZ, Jia HL, Zhu WW, Guo L, Zhao Y, Gao DM, Qin LX. Postoperative serum osteopontin level is a novel monitor for treatment response and tumor recurrence after resection of hepatitis B-related hepatocellular carcinoma. Ann Surg Oncol 2013; 20(3): 929-937
doi: 10.1245/s10434-012-2749-9 pmid:23203407
19 Sun BS, Dong QZ, Ye QH, Sun HJ, Jia HL, Zhu XQ, Liu DY, Chen J, Xue Q, Zhou HJ, Ren N, Qin LX. Lentiviral-mediated miRNA against osteopontin suppresses tumor growth and metastasis of human hepatocellular carcinoma. Hepatology 2008; 48(6): 1834-1842
doi: 10.1002/hep.22 531 pmid:18972404
20 Xue YH, Zhang XF, Dong QZ, Sun J, Dai C, Zhou HJ, Ren N, Jia HL, Ye QH, Qin LX. Thrombin is a therapeutic target for metastatic osteopontin-positive hepatocellular carcinoma. Hepatology 2010; 52(6): 2012-2022
doi: 10.1002/hep.23942 pmid:20890897
21 Wu JC, Sun BS, Ren N, Ye QH, Qin LX. Genomic aberrations in hepatocellular carcinoma related to osteopontin expression detected by array-CGH. J Cancer Res Clin Oncol 2010; 136(4): 595-601
doi: 10.1007/s00432-009-0695-0 pmid:19834740
22 Dong QZ, Zhang XF, Zhao Y, Jia HL, Zhou HJ, Dai C, Sun HJ, Qin Y, Zhang WD, Ren N, Ye QH, Qin LX. Osteopontin promoter polymorphisms at locus–443 significantly affect the metastasis and prognosis of human hepatocellular carcinoma. Hepatology 2013; 57(3): 1024-1034
doi: 10.1002/hep.26103 pmid:23079960
24 Coppola D, Szabo M, Boulware D, Muraca P, Alsarraj M, Chambers AF, Yeatman TJ. Correlation of osteopontin protein expression and pathological stage across a wide variety of tumor histologies. Clin Cancer Res 2004; 10(1): 184-190
doi: 10.1158/1078-0432.CCR-1405-2 pmid:14734468
25 Sedivy R, Peters K, Kl?ppel G. Osteopontin expression in ductal adenocarcinomas and undifferentiated carcinomas of the pancreas. Virchows Arch 2005; 446(1): 41-45
doi: 10.1007/s00428-004-1142-x pmid:15568158
26 Mack PC, Redman MW, Chansky K, Williamson SK, Farneth NC, Lara PN Jr, Franklin WA, Le QT, Crowley JJ, Gandara DR; SWOG.Lower osteopontin plasma levels are associated with superior outcomes in advanced non-small-cell lung cancer patients receiving platinum-based chemotherapy: SWOG Study S0003. J Clin Oncol 2008; 26(29): 4771-4776
doi: 10.1200/JCO.2008.17.0662 pmid:18779603
27 Anborgh PH, Mutrie JC, Tuck AB, Chambers AF. Role of the metastasis-promoting protein osteopontin in the tumour microenvironment. J Cell Mol Med 2010; 14(8): 2037-2044
doi: 10.1111/j.1582-4934.2010.01115.x pmid:20597997
28 Kim J, Ki SS, Lee SD, Han CJ, Kim YC, Park SH, Cho SY, Hong YJ, Park HY, Lee M, Jung HH, Lee KH, Jeong SH. Elevated plasma osteopontin levels in patients with hepatocellular carcinoma. Am J Gastroenterol 2006; 101(9): 2051-2059
doi: 10.1111/j.1572-0241.2006.00679.x pmid:16848813
29 Pan HW, Ou YH, Peng SY, Liu SH, Lai PL, Lee PH, Sheu JC, Chen CL, Hsu HC. Overexpression of osteopontin is associated with intrahepatic metastasis, early recurrence, and poorer prognosis of surgically resected hepatocellular carcinoma. Cancer 2003; 98(1): 119-127
doi: 10.1002/cncr.11487 pmid:12833464
30 El-Tanani MK. Role of osteopontin in cellular signaling and metastatic phenotype. Front Biosci 2008; 13: 4276-4284
doi: 10.2741/3004 pmid:18508510
31 Ho PK, Hawkins CJ. Mammalian initiator apoptotic caspases. FEBS J 2005; 272(21): 5436-5453
doi: 10.1111/j.1742-4658.2005.04966.x pmid:16262685
32 Gu T, Ohashi R, Cui R, Tajima K, Yoshioka M, Iwakami S, Sasaki S, Shinohara A, Matsukawa T, Kobayashi J, Inaba Y, Takahashi K. Osteopontin is involved in the development of acquired chemo-resistance of cisplatin in small cell lung cancer. Lung Cancer 2009; 66(2): 176-183
doi: 10.1016/j.lungcan.2009.02.004 pmid:19285749
33 Graessmann M, Berg B, Fuchs B, Klein A, Graessmann A. Chemotherapy resistance of mouse WAP-SVT/t breast cancer cells is mediated by osteopontin, inhibiting apoptosis downstream of caspase-3. Oncogene 2007; 26(20): 2840-2850
doi: 10.1038/sj.onc.1210096 pmid:17160024
34 Senger DR, Perruzzi CA, Gracey CF, Papadopoulos A, Tenen DG. Secreted phosphoproteins associated with neoplastic transformation: close homology with plasma proteins cleaved during blood coagulation. Cancer Res 1988; 48(20): 5770-5774
pmid:3167835
35 Yokosaki Y, Matsuura N, Sasaki T, Murakami I, Schneider H, Higashiyama S, Saitoh Y, Yamakido M, Taooka Y, Sheppard D. The integrin alpha(9)beta(1) binds to a novel recognition sequence (SVVYGLR) in the thrombin-cleaved amino-terminal fragment of osteopontin. J Biol Chem 1999; 274(51): 36328-36334
doi: 10.1074/jbc.274.51.36328 pmid:10593924
36 Helluin O, Chan C, Vilaire G, Mousa S, DeGrado WF, Bennett JS. The activation state of αvβ3 regulates platelet and lymphocyte adhesion to intact and thrombin-cleaved osteopontin. J Biol Chem 2000; 275(24): 18337-18343
doi: 10.1074/jbc.M001529200 pmid:10751402
37 Senger DR, Perruzzi CA, Papadopoulos-Sergiou A, Van de Water L. Adhesive properties of osteopontin: regulation by a naturally occurring thrombin-cleavage in close proximity to the GRGDS cell-binding domain. Mol Biol Cell 1994; 5(5): 565-574
doi: 10.1091/mbc.5.5.565 pmid:7522656
38 Mi Z, Oliver T, Guo H, Gao C, Kuo PC. Thrombin-cleaved COOH(–) terminal osteopontin peptide binds with cyclophilin C to CD147 in murine breast cancer cells. Cancer Res 2007; 67(9): 4088-4097
doi: 10.1158/0008-5472.CAN-06-4066 pmid:17483319
39 Nierodzik ML, Karpatkin S. Thrombin induces tumor growth, metastasis, and angiogenesis: evidence for a thrombin-regulated dormant tumor phenotype. Cancer Cell 2006; 10(5): 355-362
doi: 10.1016/j.ccr.2006.10.002 pmid:17097558
40 Hu L, Lee M, Campbell W, Perez-Soler R, Karpatkin S. Role of endogenous thrombin in tumor implantation, seeding, and spontaneous metastasis. Blood 2004; 104(9): 2746-2751
doi: 10.1182/blood-2004-03-1047 pmid:15265791
41 Singhal H, Bautista DS, Tonkin KS, O’Malley FP, Tuck AB, Chambers AF, Harris JF. Elevated plasma osteopontin in metastatic breast cancer associated with increased tumor burden and decreased survival. Clin Cancer Res 1997; 3(4): 605-611
pmid:9815727
42 Blasberg JD, Pass HI, Goparaju CM, Flores RM, Lee S, Donington JS. Reduction of elevated plasma osteopontin levels with resection of non-small-cell lung cancer. J Clin Oncol 2010; 28(6): 936-941
doi: 10.1200/JCO.2009.25.5711 pmid:20085934
43 Zhao J, Dong L, Lu B, Wu G, Xu D, Chen J, Li K, Tong X, Dai J, Yao S, Wu M, Guo Y. Down-regulation of osteopontin suppresses growth and metastasis of hepatocellular carcinoma via induction of apoptosis. Gastroenterology 2008; 135(3): 956-968
doi: 10.1053/j.gastro.2008.05.025 pmid:18555021
44 Smith LL, Cheung HK, Ling LE, Chen J, Sheppard D, Pytela R, Giachelli CM. Osteopontin N-terminal domain contains a cryptic adhesive sequence recognized by α9β1 integrin. J Biol Chem 1996; 271(45): 28485-28491
doi: 10.1074/jbc.271.45.28485 pmid:8910476
45 Senger DR, Perruzzi CA. Cell migration promoted by a potent GRGDS-containing thrombin-cleavage fragment of osteopontin. Biochim Biophys Acta 1996; 1314(1-2): 13-24
doi: 10.1016/S0167-4889(96)00067-5 pmid:8972713
46 Hasegawa M, Nakoshi Y, Iino T, Sudo A, Segawa T, Maeda M, Yoshida T, Uchida A. Thrombin-cleaved osteopontin in synovial fluid of subjects with rheumatoid arthritis. J Rheumatol 2009; 36(2): 240-245
doi: 10.3899/jrheum.080753 pmid:19208558
47 Radjabi AR, Sawada K, Jagadeeswaran S, Eichbichler A, Kenny HA, Montag A, Bruno K, Lengyel E. Thrombin induces tumor invasion through the induction and association of matrix metalloproteinase-9 andβ1-integrin on the cell surface. J Biol Chem 2008; 283(5): 2822-2834
doi: 10.1074/jbc.M704855200 pmid:18048360
48 Young MF, Kerr JM, Termine JD, Wewer UM, Wang MG, McBride OW, Fisher LW. cDNA cloning, mRNA distribution and heterogeneity, chromosomal location, and RFLP analysis of human osteopontin (OPN). Genomics 1990; 7(4): 491-502
doi: 10.1016/0888-7543(90)90191-V pmid:1974876
49 Naito M, Matsui A, Inao M, Nagoshi S, Nagano M, Ito N, Egashira T, Hashimoto M, Mishiro S, Mochida S, Fujiwara K. SNPs in the promoter region of the osteopontin gene as a marker predicting the efficacy of interferon-based therapies in patients with chronic hepatitis C. J Gastroenterol 2005; 40(4): 381-388
doi: 10.1007/s00535-005-1558-3 pmid:15868370
50 Giacopelli F, Marciano R, Pistorio A, Catarsi P, Canini S, Karsenty G, Ravazzolo R. Polymorphisms in the osteopontin promoter affect its transcriptional activity. Physiol Genomics 2004; 20(1): 87-96
doi: 10.1152/physiolgenomics.00138.2004 pmid:15479859
51 Hendig D, Arndt M, Szliska C, Kleesiek K, G?tting C. SPP1 promoter polymorphisms: identification of the first modifier gene for pseudoxanthoma elasticum. Clin Chem 2007; 53(5): 829-836
doi: 10.1373/clinchem.2006.083675 pmid:17384004
52 Liu CC, Huang SP, Tsai LY, Wu WJ, Juo SH, Chou YH, Huang CH, Wu MT. The impact of osteopontin promoter polymorphisms on the risk of calcium urolithiasis. Clin Chim Acta 2010; 411(9-10): 739-743
doi: 10.1016/j.cca.2010.02.007 pmid:20144595
53 D’Alfonso S, Barizzone N, Giordano M, Chiocchetti A, Magnani C, Castelli L, Indelicato M, Giacopelli F, Marchini M, Scorza R, Danieli MG, Cappelli M, Migliaresi S, Bigliardo B, Sabbadini MG, Baldissera E, Galeazzi M, Sebastiani GD, Minisola G, Ravazzolo R, Dianzani U, Momigliano-Richiardi P. Two single-nucleotide polymorphisms in the 5′ and 3′ ends of the osteopontin gene contribute to susceptibility to systemic lupus erythematosus. Arthritis Rheum 2005; 52(2): 539-547
doi: 10.1002/art.20808 pmid:15692970
54 Chiu YW, Tu HF, Wang IK, Wu CH, Chang KW, Liu TY, Kao SY. The implication of osteopontin (OPN) expression and genetic polymorphisms of OPN promoter in oral carcinogenesis. Oral Oncol 2010; 46(4): 302-306
doi: 10.1016/j.oraloncology.2010.01.018 pmid:20219412
55 El-Tanani MK, Campbell FC, Kurisetty V, Jin D, McCann M, Rudland PS. The regulation and role of osteopontin in malignant transformation and cancer. Cytokine Growth Factor Rev 2006; 17(6): 463-474
doi: 10.1016/j.cytogfr.2006.09.010 pmid:17113338
56 Mochida S, Hashimoto M, Matsui A, Naito M, Inao M, Nagoshi S, Nagano M, Egashira T, Mishiro S, Fujiwara K. Genetic polymorphims in promoter region of osteopontin gene may be a marker reflecting hepatitis activity in chronic hepatitis C patients. Biochem Biophys Res Commun 2004; 313(4): 1079-1085
doi: 10.1016/j.bbrc.2003.12.045 pmid:14706653
57 Sakaki M, Makino R, Hiroishi K, Ueda K, Eguchi J, Hiraide A, Doi H, Omori R, Imawari M. Cyclooxygenase-2 gene promoter polymorphisms affect susceptibility to hepatitis C virus infection and disease progression. Hepatol Res 2010; 40(12): 1219-1226
doi: 10.1111/j.1872-034X.2010.00727.x pmid:20880066
58 Shaker OG, Sadik NA, El-Dessouki A. Single-nucleotide polymorphism in the promoter region of the osteopontin gene at nucleotide –443 as a marker predicting the efficacy of pegylated interferon/ribavirin-therapy in Egyptians patients with chronic hepatitis C. Hum Immunol 2012; 73(10): 1039-1045
doi: 10.1016/j.humimm.2012.07.329 pmid:22836041
59 Yamamoto S, Hijiya N, Setoguchi M, Matsuura K, Ishida T, Higuchi Y, Akizuki S. Structure of the osteopontin gene and its promoter. Ann N Y Acad Sci 1995; 760(1 Osteopontin): 44-58
doi: 10.1111/j.1749-6632.1995.tb44619.x pmid:7785924
60 Schultz J, Lorenz P, Ibrahim SM, Kundt G, Gross G, Kunz M. The functional –443T/C osteopontin promoter polymorphism influences osteopontin gene expression in melanoma cells via binding of c-Myb transcription factor. Mol Carcinog 2009; 48(1): 14-23
doi: 10.1002/mc.20452 pmid:18459127
61 Shang S, Plymoth A, Ge S, Feng Z, Rosen HR, Sangrajrang S, Hainaut P, Marrero JA, Beretta L. Identification of osteopontin as a novel marker for early hepatocellular carcinoma. Hepatology 2012; 55(2): 483-490
doi: 10.1002/hep.24703 pmid:21953299
[1] Xinsen Xu,Yanyan Zhou,Runchen Miao,Wei Chen,Kai Qu,Qing Pang,Chang Liu. Transcriptional modules related to hepatocellular carcinoma survival: coexpression network analysis[J]. Front. Med., 2016, 10(2): 183-190.
[2] Chunxiao Li,Haijuan Wang,Feng Lin,Hui Li,Tao Wen,Haili Qian,Qimin Zhan. Bioinformatic exploration of MTA1-regulated gene networks in colon cancer[J]. Front. Med., 2016, 10(2): 178-182.
[3] Jiangnan Liu,Bin Yi,Zhe Zhang,Yi Cao. CD176 single-chain variable antibody fragment inhibits the adhesion of cancer cells to endothelial cells and hepatocytes[J]. Front. Med., 2016, 10(2): 204-211.
[4] Zhi Xu,Chunxiang Cao,Haiyan Xia,Shujing Shi,Lingzhi Hong,Xiaowei Wei,Dongying Gu,Jianmin Bian,Zijun Liu,Wenbin Huang,Yixin Zhang,Song He,Nikki Pui-Yue Lee,Jinfei Chen. Protein phosphatase magnesium-dependent 1δ is a novel tumor marker and target in hepatocellular carcinoma[J]. Front. Med., 2016, 10(1): 52-60.
[5] Aixiu Qiao,Feng Gu,Xiaojing Guo,Xinmin Zhang,Li Fu. Breast cancer-associated fibroblasts: their roles in tumor initiation, progression and clinical applications[J]. Front. Med., 2016, 10(1): 33-40.
[6] Jing Zhang,Shan Gao,Zhongping Duan,Ke-Qin Hu. Overview on acute-on-chronic liver failure[J]. Front. Med., 2016, 10(1): 1-17.
[7] Yi Cao. Environmental pollution and DNA methylation: carcinogenesis, clinical significance, and practical applications[J]. Front. Med., 2015, 9(3): 261-274.
[8] Felice Ho-Ching Tsang,Sandy Leung-Kuen Au,Lai Wei,Dorothy Ngo-Yin Fan,Joyce Man-Fong Lee,Carmen Chak-Lui Wong,Irene Oi-Lin Ng,Chun-Ming Wong. MicroRNA-142-3p and microRNA-142-5p are downregulated in hepatocellular carcinoma and exhibit synergistic effects on cell motility[J]. Front. Med., 2015, 9(3): 331-343.
[9] Farhad Sahebjam,John M. Vierling. Autoimmune hepatitis[J]. Front. Med., 2015, 9(2): 187-219.
[10] Guanghua Rong,Wenlin Bai,Zheng Dong,Chunping Wang,Yinying Lu,Zhen Zeng,Jianhui Qu,Min Lou,Hong Wang,Xudong Gao,Xiujuan Chang,Linjing An,Yan Chen,Yongping Yang. Cryotherapy for cirrhosis-based hepatocellular carcinoma: a single center experience from 1595 treated cases[J]. Front. Med., 2015, 9(1): 63-71.
[11] Feng Wang,Chen Chen,Daowen Wang. Circulating microRNAs in cardiovascular diseases: from biomarkers to therapeutic targets[J]. Front. Med., 2014, 8(4): 404-418.
[12] Marielle Reataza,David K. Imagawa. Advances in managing hepatocellular carcinoma[J]. Front. Med., 2014, 8(2): 175-189.
[13] Kai Qu,Ting Lin,Zhixin Wang,Sinan Liu,Hulin Chang,Xinsen Xu,Fandi Meng,Lei Zhou,Jichao Wei,Minghui Tai,Yafeng Dong,Chang Liu. Reactive oxygen species generation is essential for cisplatin-induced accelerated senescence in hepatocellular carcinoma[J]. Front. Med., 2014, 8(2): 227-235.
[14] Du Yan, Han Xue, Pu Rui, Xie Jiaxin, Zhang Yuwei, Cao Guangwen. Association of miRNA-122-binding site polymorphism at the interleukin-1 α gene and its interaction with hepatitis B virus mutations with hepatocellular carcinoma risk[J]. Front. Med., 2014, 8(2): 217-226.
[15] Xiao Liu, Hui Ren, Daizhi Peng. Sepsis biomarkers: an omics perspective[J]. Front Med, 2014, 8(1): 58-67.
Viewed
Full text


Abstract

Cited

  Shared   
  Discussed