Identification of Serum Monocyte Chemoattractant Protein-1 and Prolactin as Potential Tumor Markers in Hepatocellular Carcinoma

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Abstract

Early diagnosis of hepatocellullar carcinoma (HCC) remains a challenge. The current practice of serum alpha-fetoprotein (AFP) measurement is inadequate. Here we utilized a proteomic approach to identify novel serum biomarkers for distinguishing HCC patients from non-cancer controls. We profiled the serum proteins in a group of 58 resectable HCC patients and 11 non-HCC chronic hepatitis B (HBV) carrier samples from the Singapore General Hospital (SGH) using the RayBio® L-Series 507 Antibody Array and found 113 serum markers that were significantly modulated between HCC and control groups. Selected potential biomarkers from this list were quantified using a multiplex sandwich enzyme-linked immunosorbent assay (ELISA) array in an expanded SGH cohort (126 resectable HCC patients and 115 non-HCC chronic HBV carriers (NC group)), confirming that serum prolactin and monocyte chemoattractant protein-1 (MCP-1) were significantly upregulated in HCC patients. This finding of serum MCP-1 elevation in HCC patients was validated in a separate cohort of serum samples from the Mochtar Riady Institute for Nanotechnology, Indonesia (98 resectable HCC, 101 chronic hepatitis B patients and 100 asymptomatic HBV/HCV carriers) by sandwich ELISA. MCP-1 and prolactin levels were found to correlate with AFP, while MCP-1 also correlated with disease stage. Subsequent receiver operating characteristic (ROC) analysis of AFP, prolactin and MCP-1 in the SGH cohort and comparing their area under the ROC curve (AUC) indicated that neither prolactin nor MCP-1 on their own performed better than AFP. However, the combination of AFP+MCP-1 (AUC, 0.974) had significantly superior discriminative ability than AFP alone (AUC, 0.942; p<0.001). In conclusion, prolactin and MCP-1 are overexpressed in HCC and are conveniently quantifiable in patients’ sera by ELISA. MCP-1 appears to be a promising complementary biomarker for HCC diagnosis and this MCP-1+AFP model should be further evaluated as potential biomarker on a larger scale in patients at-risk of HCC.

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Most cited references 42

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Asian Pacific Association for the Study of the Liver consensus recommendations on hepatocellular carcinoma.

Masao Omata, Laurentius Lesmana, Ryosuke Tateishi … (2010)

The Asian Pacific Association for the Study of the Liver (APASL) convened an international working party on the management of hepatocellular carcinoma (HCC) in December 2008 to develop consensus recommendations. The working party consisted of expert hepatologist, hepatobiliary surgeon, radiologist, and oncologist from Asian-Pacific region, who were requested to make drafts prior to the consensus meeting held at Bali, Indonesia on 4 December 2008. The quality of existing evidence and strength of recommendations were ranked from 1 (highest) to 5 (lowest) and from A (strongest) to D (weakest), respectively, according to the Oxford system of evidence-based approach for developing the consensus statements. Participants of the consensus meeting assessed the quality of cited studies and assigned grades to the recommendation statements. Finalized recommendations were presented at the fourth APASL single topic conference on viral-related HCC at Bali, Indonesia and approved by the participants of the conference.

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Proteomic applications for the early detection of cancer.

Julia D Wulfkuhle, Lance Liotta, Emanuel Petricoin (2003)

The ability of physicians to effectively treat and cure cancer is directly dependent on their ability to detect cancers at their earliest stages. Proteomic analyses of early-stage cancers have provided new insights into the changes that occur in the early phases of tumorigenesis and represent a new resource of candidate biomarkers for early-stage disease. Studies that profile proteomic patterns in body fluids also present new opportunities for the development of novel, highly sensitive diagnostic tools for the early detection of cancer.

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Serum DKK1 as a protein biomarker for the diagnosis of hepatocellular carcinoma: a large-scale, multicentre study.

Qiujin Shen, Jia Fan, Xin-Rong Yang … (2012)

Hepatocellular carcinoma (HCC) is prevalent worldwide and improvements in timely and effective diagnosis are needed. We assessed whether measurement of Dickkopf-1 (DKK1) in serum could improve diagnostic accuracy for HCC. We analysed data for patients with HCC, chronic hepatitis B virus (HBV) infection, liver cirrhosis, and healthy controls, recruited from two Chinese centres between December, 2008, and July, 2009. A validation cohort matched for age and sex was recruited from another centre in China between July, 2010, and June, 2011. DKK1 was measured in serum by ELISA by independent researchers who had no access to patients' clinical information. We used receiver operating characteristics (ROC) to calculate diagnostic accuracy. We assessed serum DKK1 in 831 participants: 424 with HCC, 98 with chronic HBV infection, 96 with cirrhosis, and 213 healthy controls. The validation cohort comprised 453 participants: 209 with HCC, 73 with chronic HBV infection, 72 with cirrhosis, and 99 healthy controls. Levels of DKK1 in serum were significantly higher in patients with HCC than in all controls. ROC curves showed the optimum diagnostic cutoff was 2·153 ng/mL (area under curve [AUC] 0·848 [95% CI 0·820-0·875], sensitivity 69·1%, and specificity 90·6% in the test cohort; 0·862 [0·825-0·899], 71·3%, and 87·2% in the validation cohort). Similar results were noted for early-stage HCC (0·865 [0·835-0·895], 70·9%, and 90·5% in the test cohort; 0·896 [0·846-0·947], 73·8%, and 87·2% in the validation cohort). Furthermore, DKK1 maintained diagnostic accuracy for patients with HCC who were α-fetoprotein (AFP) negative (0·841 [0·801-0·882], 70·4%, and 90·0% in the test cohort; 0·869 [0·815-0·923], 66·7%, and 87·2% in the validation cohort), including for patients with early-stage HCC (0·870 [0·829-0·911], 73·1%, and 90·0% in the test cohort; 0·893 [0·804-0·983], 72·2%, and 87·2% in the validation cohort), compared with all controls. Raised concentrations of DKK1 in serum could differentiate HCC from chronic HBV infection and cirrhosis (0·834 [0·798-0·871], 69·1%, and 84·7% in the test cohort; 0·873 [0·832-0·913], 71·3%, and 90·6% in the validation cohort). Moreover, measurement of DKK1 and AFP together improved diagnostic accuracy for HCC versus all controls compared with either test alone (0·889 [0·866-0·913], 73·3%, and 93·4% in the test cohort; 0·888 [0·856-0·920], 78·5%, and 87·2% in the validation cohort). DKK1 could complement measurement of AFP in the diagnosis of HCC and improve identification of patients with AFP-negative HCC and distinguish HCC from non-malignant chronic liver diseases. National Key Basic Research Programme of China, National Key Sci-Tech Special Projects of Infectious Diseases, National Natural Science Foundation of China, Research Fund for the Doctoral Programme of Higher Education of China. Copyright © 2012 Elsevier Ltd. All rights reserved.

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Author and article information

Contributors

Nikki Pui-yue Lee: Role: Editor

Journal

Journal ID (nlm-ta): PLoS One

Journal ID (iso-abbrev): PLoS ONE

Journal ID (publisher-id): plos

Journal ID (pmc): plosone

Title: PLoS ONE

Publisher: Public Library of Science (San Francisco, USA )

ISSN (Electronic): 1932-6203

Publication date Collection: 2013

Publication date (Electronic): 18 July 2013

Volume: 8

Issue: 7

Electronic Location Identifier: e68904

Affiliations

[1 ]Department of Medical Oncology, National Cancer Centre Singapore, Singapore, Singapore

[2 ]Department of Gastroenterology & Hepatology, Singapore General Hospital, Singapore, Singapore

[3 ]Duke-NUS Graduate Medical School, Singapore, Singapore

[4 ]Mochtar Riady Institute for Nanotechnology, Jakarta, Indonesia

[5 ]Department of Clinical Research, Singapore General Hospital, Singapore, Singapore

[6 ]Department of Clinical Trials and Epidemiological Sciences, National Cancer Centre Singapore, Singapore, Singapore

The University of Hong Kong, Hong Kong

Author notes

* E-mail: hanchongtoh@ 123456gmail.com

Competing Interests: The authors have declared that no competing interests exist.

Conceived and designed the experiments: WWW SFA SPC HCT. Performed the experiments: WWW CH AU NPT. Analyzed the data: SFA RK HL SHT DP. Contributed reagents/materials/analysis tools: WCC CKT. Wrote the paper: WWW SFA HCT.

Article

Publisher ID: PONE-D-12-39995

DOI: 10.1371/journal.pone.0068904

PMC ID: 3715515

PubMed ID: 23874805

SO-VID: f382e8e9-4227-42ac-a742-92e7dbcd313f

License:

This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

History

Date received : 17 December 2012

Date accepted : 31 May 2013

Page count

Pages: 10

Funding

Study of the SGH cohort in this research was supported by grants awarded by the National Medical Research Council (NMRC), Ministry of Health, Republic of Singapore (NMRC/1191/2008 and NMRC/IBG/NCC/2009; http://www.nmrc.gov.sg/content/nmrc_internet/home.html). Study of the MRIN cohort was supported by the institutional funding of MRIN ( http://www.mrinstitute.org/). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Identification of Serum Monocyte Chemoattractant Protein-1 and Prolactin as Potential Tumor Markers in Hepatocellular Carcinoma

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Most cited references 42

Asian Pacific Association for the Study of the Liver consensus recommendations on hepatocellular carcinoma.

Proteomic applications for the early detection of cancer.

Serum DKK1 as a protein biomarker for the diagnosis of hepatocellular carcinoma: a large-scale, multicentre study.

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