Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
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.
ADVANCED SEARCH
Log in
Top
Journal of Translational Medicine
Published in: Journal of Translational Medicine 1/2015

Open Access 01-12-2015 | Research

HERC5 is a prognostic biomarker for post-liver transplant recurrent human hepatocellular carcinoma

Authors: Feng Xue, Brandon W. Higgs, Jiaqi Huang, Chris Morehouse, Wei Zhu, Xin Yao, Philip Brohawn, Zhan Xiao, Yinong Sebastian, Zheng Liu, Yun Xia, Dong Shen, Mike Kuziora, Zhengwei Dong, Hulin Han, Yi Gu, Jianren Gu, Qiang Xia, Yihong Yao

Published in: Journal of Translational Medicine | Issue 1/2015

Login to get access

Abstract

Background and aims

Orthotopic liver transplantation (OLT) can be an effective treatment option for certain patients with early stage hepatocellular carcinoma (HCC) meeting Milan, UCSF, or Hangzhou criteria. However, HCC recurrence rates post-OLT range from 20 to 40 %, with limited follow-up options. Elucidating genetic drivers common to primary and post-OLT recurrent tumors may further our understanding and help identify predictive biomarkers of recurrence—both to ultimately help manage clinical decisions for patients undergoing OLT.

Methods

Whole exome and RNA sequencing in matched primary and recurrent tumors, normal adjacent tissues, and blood from four Chinese HCC patients was conducted. SiRNA knockdown and both qRT-PCR and Western assays were performed on PLCPRF5, SNU449 and HEPG2 cell lines; immunohistochemistry and RNA Sequencing were conducted on the primary tumors of Chinese HCC patients who experienced tumor recurrence post-OLT (n = 9) or did not experience tumor recurrence (n = 12).

Results

In three independent HCC studies of patients undergoing transplantation (n = 21) or surgical resection (n = 242, n = 44) of primary tumors (total n = 307), HERC5 mRNA under-expression correlated with shorter: time to tumor recurrence (p = 0.007 and 0.02) and overall survival (p = 0.0063 and 0.023), even after adjustment for relevant clinical variables. HERC5 loss drives CCL20 mRNA and protein over-expression and associates with regulatory T cell infiltration as measured by FOXP3 expression. Further, matched primary and recurrent tumors from the 4 HCC patients indicated clonal selection advantage of Wnt signaling activation and CDKN2A inactivation.

Conclusions

HERC5 plays a crucial role in HCC immune evasion and has clinical relevance as a reproducible prognostic marker for risk of tumor recurrence and survival in patients.
Appendix
Available only for authorised users
Literature
1.
El-Serag HB, Rudolph KL. Hepatocellular carcinoma: epidemiology and molecular carcinogenesis. Gastroenterology. 2007;132:2557–76.CrossRefPubMed
2.
Parkin DM. The global health burden of infection-associated cancers in the year 2002. Int J Cancer. 2006;118:3030–44.CrossRefPubMed
3.
Chang MH, You SL, Chen CJ, Liu CJ, Lee CM, Lin SM, et al. Decreased incidence of hepatocellular carcinoma in hepatitis B vaccines: a 20-year follow-up study. J Natl Cancer Inst. 2009;101:1348–55.CrossRefPubMed
4.
Zheng SS, Xu X, Wu J, Chen J, Wang WL, Zhang M, et al. Liver transplantation for hepatocellular carcinoma: Hangzhou experiences. Transplantation. 2008;85:1726–32.CrossRefPubMed
5.
Welker MW, Bechstein WO, Zeuzem S, Trojan J. Recurrent hepatocellular carcinoma after liver transplantation—an emerging clinical challenge. Transpl Int. 2013;26:109–18.CrossRefPubMed
6.
Zimmerman MA, Ghobrial RM, Tong MJ, Hiatt JR, Cameron AM, Hong J, Busuttil RW. Recurrence of hepatocellular carcinoma following liver transplantation: a review of preoperative and postoperative prognostic indicators. Arch Surg. 2008;143:182–8 (discussion 188).CrossRefPubMed
7.
Hoshida Y, Villanueva A, Kobayashi M, Peix J, Chiang DY, Camargo A, et al. Gene expression in fixed tissues and outcome in hepatocellular carcinoma. N Engl J Med. 2008;359:1995–2004.PubMedCentralCrossRefPubMed
8.
Iizuka N, Oka M, Yamada-Okabe H, Nishida M, Maeda Y, Mori N, et al. Oligonucleotide microarray for prediction of early intrahepatic recurrence of hepatocellular carcinoma after curative resection. Lancet. 2003;361:923–9.CrossRefPubMed
9.
Iizuka N, Tamesa T, Sakamoto K, Miyamoto T, Hamamoto Y, Oka M. Different molecular pathways determining extrahepatic and intrahepatic recurrences of hepatocellular carcinoma. Oncol Rep. 2006;16:1137–42.PubMed
10.
Kurokawa Y, Matoba R, Takemasa I, Nagano H, Dono K, Nakamori S, et al. Molecular-based prediction of early recurrence in hepatocellular carcinoma. J Hepatol. 2004;41:284–91.CrossRefPubMed
11.
Lee JS, Chu IS, Heo J, Calvisi DF, Sun Z, Roskams T, Durnez A, et al. Classification and prediction of survival in hepatocellular carcinoma by gene expression profiling. Hepatology. 2004;40:667–76.CrossRefPubMed
12.
Lee JS, Chu IS, Mikaelyan A, Calvisi DF, Heo J, Reddy JK, et al. Application of comparative functional genomics to identify best-fit mouse models to study human cancer. Nat Genet. 2004;36:1306–11.CrossRefPubMed
13.
Matoba K, Iizuka N, Gondo T, Ishihara T, Yamada-Okabe H, Tamesa T, et al. Tumor HLA-DR expression linked to early intrahepatic recurrence of hepatocellular carcinoma. Int J Cancer. 2005;115:231–40.CrossRefPubMed
14.
Okamoto M, Utsunomiya T, Wakiyama S, Hashimoto M, Fukuzawa K, Ezaki T, et al. Specific gene-expression profiles of noncancerous liver tissue predict the risk for multicentric occurrence of hepatocellular carcinoma in hepatitis C virus-positive patients. Ann Surg Oncol. 2006;13:947–54.CrossRefPubMed
15.
Tanaka S, Arii S, Yasen M, Mogushi K, Su NT, Zhao C, et al. Aurora kinase B is a predictive factor for the aggressive recurrence of hepatocellular carcinoma after curative hepatectomy. Br J Surg. 2008;95:611–9.CrossRefPubMed
16.
Tsuchiya M, Parker JS, Kono H, Matsuda M, Fujii H, Rusyn I. Gene expression in nontumoral liver tissue and recurrence-free survival in hepatitis C virus-positive hepatocellular carcinoma. Mol Cancer. 2010;9:74.PubMedCentralCrossRefPubMed
17.
Wang SM, Ooi LL, Hui KM. Identification and validation of a novel gene signature associated with the recurrence of human hepatocellular carcinoma. Clin Cancer Res. 2007;13:6275–83.CrossRefPubMed
18.
Woo HG, Park ES, Cheon JH, Kim JH, Lee JS, Park BJ, et al. Gene expression-based recurrence prediction of hepatitis B virus-related human hepatocellular carcinoma. Clin Cancer Res. 2008;14:2056–64.CrossRefPubMed
19.
Yokoo H, Kondo T, Okano T, Nakanishi K, Sakamoto M, Kosuge T, et al. Protein expression associated with early intrahepatic recurrence of hepatocellular carcinoma after curative surgery. Cancer Sci. 2007;98:665–73.CrossRefPubMed
20.
Yoshioka S, Takemasa I, Nagano H, Kittaka N, Noda T, Wada H, et al. Molecular prediction of early recurrence after resection of hepatocellular carcinoma. Eur J Cancer. 2009;45:881–9.CrossRefPubMed
21.
Lee L, Wang K, Li G, Xie Z, Wang Y, Xu J, et al. Liverome: a curated database of liver cancer-related gene signatures with self-contained context information. BMC Genomics 2011;12 Suppl 3:S3-2164-12-S3-S3.
22.
Kim JH, Sohn BH, Lee H-S, Kim S-B, Yoo JE, Park Y-Y, et al. Genomic Predictors for recurrence patterns of Hepatocellular Carcinoma: model derivation and validation. PLoS Med. 2014;11:e1001770.PubMedCentralCrossRefPubMed
23.
Zhang DY, Goossens N, Guo J, Tsai MC, Chou HI, Altunkaynak C, et al. A hepatic stellate cell gene expression signature associated with outcomes in hepatitis C cirrhosis and hepatocellular carcinoma after curative resection. Gut. 2015. doi:10.​1136/​gutjnl-2015-309655.
24.
Piras-Straub K, Khairzada K, Trippler M, Baba HA, Kaiser GM, Paul A, et al. TRAIL expression levels in human hepatocellular carcinoma have implications for tumor growth, recurrence and survival. Int J Cancer. 2015;136:E154–60. doi:10.​1002/​ijc.​29139 (Epub 2014 Aug 23).CrossRefPubMed
25.
Hashimoto R, Kanda M, Takami H, Shimizu D, Oya H, Hibino S, et al. Aberrant expression of melanoma-associated antigen-D2 serves as a prognostic indicator of hepatocellular carcinoma outcome following curative hepatectomy. Oncol Lett. 2015;9:1201–6.PubMedCentralPubMed
26.
Fujimoto A, Totoki Y, Abe T, Boroevich KA, Hosoda F, Nguyen HH, et al. Whole-genome sequencing of liver cancers identifies etiological influences on mutation patterns and recurrent mutations in chromatin regulators. Nat Genet. 2012;44:760–4.CrossRefPubMed
27.
Totoki Y, Tatsuno K, Yamamoto S, Arai Y, Hosoda F, Ishikawa S, et al. High-resolution characterization of a hepatocellular carcinoma genome. Nat Genet. 2011;43:464–9.CrossRefPubMed
28.
Kan Z, Zheng H, Liu X, Li S, Barber TD, Gong Z, et al. Whole-genome sequencing identifies recurrent mutations in hepatocellular carcinoma. Genome Res. 2013;23:1422–33.PubMedCentralCrossRefPubMed
29.
Li M, Zhao H, Zhang X, Wood LD, Anders RA, Choti MA, et al. Inactivating mutations of the chromatin remodeling gene ARID2 in hepatocellular carcinoma. Nat Genet. 2011;43:828–9.PubMedCentralCrossRefPubMed
30.
Guo G, Sun X, Chen C, Wu S, Huang P, Li Z, et al. Whole-genome and whole-exome sequencing of bladder cancer identifies frequent alterations in genes involved in sister chromatid cohesion and segregation. Nat Genet. 2013;45:1459–63.CrossRefPubMed
31.
Jiang Z, Jhunjhunwala S, Liu J, Haverty PM, Kennemer MI, Guan Y, et al. The effects of hepatitis B virus integration into the genomes of hepatocellular carcinoma patients. Genome Res. 2012;22:593–601.PubMedCentralCrossRefPubMed
32.
Kim D, Pertea G, Trapnell C, Pimentel H, Kelley R, Salzberg SL. TopHat2: accurate alignment of transcriptomes in the presence of insertions, deletions and gene fusions. Genome Biol. 2013;14(4):R36.PubMedCentralCrossRefPubMed
33.
34.
Carter SL, Cibulskis K, Helman E, McKenna A, Shen H, Zack T, et al. Absolute quantification of somatic DNA alterations in human cancer. Nat Biotechnol. 2012;30:413–21.PubMedCentralCrossRefPubMed
35.
Boyault S, Rickman DS, de Reynies A, Balabaud C, Rebouissou S, Jeannot E, et al. Transcriptome classification of HCC is related to gene alterations and to new therapeutic targets. Hepatology. 2007;45:42–52.CrossRefPubMed
36.
Roessler S, Jia HL, Budhu A, Forgues M, Ye QH, Lee JS, et al. A unique metastasis gene signature enables prediction of tumor relapse in early-stage hepatocellular carcinoma patients. Cancer Res. 2010;70:10202–12.PubMedCentralCrossRefPubMed
37.
Kim B, Woreta T, Chen PH, Limketkai B, Singer A, Dagher N, et al. Donor-transmitted malignancy in a liver transplant recipient: a case report and review of literature. Dig Dis Sci. 2013;58:1185–90.CrossRefPubMed
38.
Cankovic M, Linden MD, Zarbo RJ. Use of microsatellite analysis in detection of tumor lineage as a cause of death in a liver transplant patient. Arch Pathol Lab Med. 2006;130:529–32.PubMed
39.
Chen YJ, Yeh SH, Chen JT, et al. Chromosomal changes and clonality relationship between primary and recurrent hepatocellular carcinoma. Gastroenterology. 2000;119(2):431–40.CrossRefPubMed
40.
Myron KH, McBride MA, Cherikh WS, Spain PC, Marks WH, Roza AM. Transplant tumor registry: donor related malignancies. Transplantation. 2002;74:358–62.CrossRef
41.
Hoshida Y, Villanueva A, Sangiovanni A, Sole M, Hur C, Andersson KL, et al. Prognostic gene expression signature for patients with hepatitis C-related early-stage cirrhosis. Gastroenterology. 2013;144:1024–30.PubMedCentralCrossRefPubMed
42.
Zhang H, Ma H, Wang Q, Chen M, Weng D, Wang H, et al. Analysis of loss of heterozygosity on chromosome 4q in hepatocellular carcinoma using high-throughput SNP array. Oncol Rep. 2010;23:445–55.CrossRefPubMed
43.
Danner BC, Gerdes JS, Jung K, Sander B, Enders C, Liersch T, et al. Comparison of chromosomal aberrations in primary colorectal carcinomas to their pulmonary metastases. Cancer Genet. 2011;204:122–8.CrossRefPubMed
44.
Wrage M, Ruosaari S, Eijk PP, Kaifi JT, Hollmén J, Yekebas EF, et al. Genomic profiles associated with early micrometastasis in lung cancer: relevance of 4q deletion. Clin Cancer Res. 2009;15:1566–74.CrossRefPubMed
45.
Luebke AM, Baudis M, Matthaei H, Vashist YK, Verde PE, Hosch SB, et al. Losses at chromosome 4q are associated with poor survival in operable ductal pancreatic adenocarcinoma. Pancreatology. 2012;12:16–22.CrossRefPubMed
46.
Wrage M, Hagmann W, Kemming D, Uzunoglu FG, Riethdorf S, Effenberger K, et al. Identification of HERC5 and its potential role in NSCLC progression. Int J Cancer. 2015;136:2264–72.CrossRefPubMed
47.
Uzunoglu FG, Dethlefsen E, Hanssen A, Wrage M, Deutsch L, Harms-Effenberger K, et al. Loss of 4q21.23-22.1 is a prognostic marker for disease free and overall survival in non-small cell lung cancer. PLoS One. 2014;9:e113315.PubMedCentralCrossRefPubMed
48.
Yang L, Pang Y, Moses HL. TGF-beta and immune cells: an important regulatory axis in the tumor microenvironment and progression. Trends Immunol. 2010;31:220–7.PubMedCentralCrossRefPubMed
49.
Shields JD, Kourtis IC, Tomei AA, Roberts JM, Swartz MA. Induction of lymphoidlike stroma and immune escape by tumors that express the chemokine CCL21. Science. 2010;328:749–52.CrossRefPubMed
50.
Rubie C, Frick VO, Wagner M, Rau B, Weber C, Kruse B, et al. Enhanced expression and clinical significance of CC-chemokine MIP-3 alpha in hepatocellular carcinoma. Scand J Immunol. 2006;63:468–77.CrossRefPubMed
51.
52.
Ding X, Wang K, Wang H, Zhang G, Liu Y, Yang Q, et al. High expression of CCL20 is associated with poor prognosis in patients with hepatocellular carcinoma after curative resection. J Gastrointest Surg. 2012;16:828–36.CrossRefPubMed
53.
Wu J, Du J, Liu L, Li Q, Rong W, Wang L, et al. Elevated pretherapy serum IL17 in primary hepatocellular carcinoma patients correlate to increased risk of early recurrence after curative hepatectomy. PLoS One. 2012;7:e50035.PubMedCentralCrossRefPubMed
54.
Punt S, Houwing JJ, Schulkens IA, Thijssen VL, Osse EM, de Kroon CD, et al. A high IL6/IL17 ratio combined with low IL5 expression is correlated with poor survival in squamous cervical cancer. J Immunotherap Cancer. 2014;2:P232. doi:10.​1186/​2051-1426-2-S3-P232.CrossRef
55.
Wong JJ, Pung YF, Sze NS, Chin KC. HERC5 is an IFN-induced HECT-type E3 protein ligase that mediates type I IFN-induced ISGylation of protein targets. Proc Natl Acad Sci USA. 2006;103:10735–40.PubMedCentralCrossRefPubMed
56.
Guichard C, Amaddeo G, Imbeaud S, Ladeiro Y, Pelletier L, Maad IB, et al. Integrated analysis of somatic mutations and focal copy-number changes identifies key genes and pathways in hepatocellular carcinoma. Nat Genet. 2012;44:694–8.PubMedCentralCrossRefPubMed
Metadata
Title
HERC5 is a prognostic biomarker for post-liver transplant recurrent human hepatocellular carcinoma
Authors
Feng Xue
Brandon W. Higgs
Jiaqi Huang
Chris Morehouse
Wei Zhu
Xin Yao
Philip Brohawn
Zhan Xiao
Yinong Sebastian
Zheng Liu
Yun Xia
Dong Shen
Mike Kuziora
Zhengwei Dong
Hulin Han
Yi Gu
Jianren Gu
Qiang Xia
Yihong Yao
Publication date
01-12-2015
Publisher
BioMed Central
Published in
Journal of Translational Medicine / Issue 1/2015
Electronic ISSN: 1479-5876
DOI
https://doi.org/10.1186/s12967-015-0743-2

Other articles of this Issue 1/2015

Journal of Translational Medicine 1/2015 Go to the issue

Research

Value of the prognostic nutritional index and weight loss in predicting metastasis and long-term mortality in nasopharyngeal carcinoma

Research

Loss of tapasin correlates with diminished CD8+ T-cell immunity and prognosis in colorectal cancer

Research

CD4+CD25−Foxp3+ T cells play a role in tuberculous hydrothorax rather than malignant hydrothorax

Research

Differential urinary glycoproteome analysis of type 2 diabetic nephropathy using 2D-LC–MS/MS and iTRAQ quantification

Research

In vitro migration and proliferation (“wound healing”) potential of mesenchymal stromal cells generated from human CD271+ bone marrow mononuclear cells

Research

Assessment of the effector function of CMV-specific CTLs isolated using MHC-multimers from granulocyte-colony stimulating factor mobilized peripheral blood
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

Read more

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

Highlights from the ACC 2024 Congress

Year in Review: Pediatric cardiology

Pediatric Cardiology Video

Watch Dr. Anne Marie Valente present the last year's highlights in pediatric and congenital heart disease in the official ACC.24 Year in Review session.

Year in Review: Pulmonary vascular disease

Cardiopulmonary Comorbidity Video

The last year's highlights in pulmonary vascular disease are presented by Dr. Jane Leopold in this official video from ACC.24.

Year in Review: Valvular heart disease

Valvular Heart Disease Video

Watch Prof. William Zoghbi present the last year's highlights in valvular heart disease from the official ACC.24 Year in Review session.

Year in Review: Heart failure and cardiomyopathies

Heart Failure Video

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Heart Failure Video

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.

Watch now

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

16-04-2024 Type 2 Diabetes News

Incentivised to exercise

11-04-2024 Lifestyle Modifications News

New intervention for STEMI-related cardiogenic shock

10-04-2024 Myocardial Infarction News

» View more highlights on the ACC 2024 congress hub page

Image Credits