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Detection of promoter methylation status of suppressor of cytokine signaling 3 (SOCS3) in tissue and plasma from Chinese patients with different hepatic diseases

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Abstract

SOCS3 as an important negative regulator of IL6/JAK/STAT3 signaling pathway may be early critical determinants of carcinogenesis. This study aimed to explore the aberrant promoter methylation of SOCS3 gene in circulating DNA as a noninvasive biomarker for screening hepatocellular carcinoma (HCC) high-risk individuals and for prognosis of HCC patients after partial hepatectomy. We detected its methylation status in 116 liver tissues and 326 plasma specimens of different hepatic diseases and healthy subjects, and its mRNA and protein expression in tissues. Higher methylation rate was remarkably detected in HCC (47.92%), compared with corresponding non-tumor (25.0%), liver cirrhosis (LC) (10.0%), benign liver diseases (0%) and normal liver tissues (0%) (all P < 0.05). SOCS3 mRNA level was significantly lower in methylated HCC tissues (P < 0.05). The expressions of SOCS3 and pSTAT3 were affected by methylation status. Correlation and consistency of SOCS3 methylation were found between cancer tissue and corresponding plasma (P < 0.001, κ = 0.747). The detection rate of plasma for HCC reached 73.91%, with no false positive error. SOCS3 methylation status both in tissue and plasma was significantly associated with AFP400, tumor size, tumor differentiation, LC, metastasis and recurrence (all P < 0.05). Patients with SOCS3 methylation were followed up a markedly poorer prognosis than those unmethylated for disease-free survival (P < 0.05). These data indicate that methylation status of SOCS3 in plasma cell-free DNA can correctly reflect that in tissue DNA and be used as a noninvasive potential biomarker for chronic liver disease monitoring, predicting the degree of malignancy and poor prognosis of HCC.

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Acknowledgements

This work was supported by a Grant No. 2013SZ0048 from Sichuan Province Science and Technology Support Plan to Yuquan Wei.

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Author notes

  1. Jing Zhang

    Present address: Department of Clinical Laboratory, West China Fourth Hospital, Sichuan University, Chengdu, China

  2. Ling Wei and Yuan Huang have contributed equally to this work.

Authors and Affiliations

  1. Department of Biochemistry and Molecular Biology, West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, No. 17, Section 3, South Renmin Road, Chengdu, 610041, Sichuan Province, China

    Ling Wei, Yuan Huang, Qiuying Liu, Jingyang He, Xiaoqin Yu, Zhongjian Liu & Yang Qin

  2. Department of Surgery Division of Liver Transplantation, West China Hospital, Sichuan University, 37 Guo Xue Rd., Chengdu, 610041, Sichuan Province, China

    Rongce Zhao & Bo Li

  3. West China College of Public Health, Sichuan University, No. 18, Section 3, South Renmin Road, Chengdu, 610041, Sichuan Province, China

    Jing Zhang & Chengjun Sun

  4. Analytical & Testing Center, Sichuan University, Chengdu, 610041, Sichuan Province, China

    Xueqin Ding, Bo Gao & Aimin Sun

  5. Department of Forensic Genetics, West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, Chengdu, 610041, Sichuan Province, China

    Weibo Liang

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  1. Ling Wei
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Correspondence to Aimin Sun or Yang Qin.

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All procedures performed in studies involving human participants were got approval from the institutional research committee according the 1964 Helsinki Declaration and its latter amendments or comparable ethical standards.

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Figure S1

MSP detecting the methylation status on the promoter of SOCS3 gene of specimens. (a) Typical results of agarose gel electrophoresis of MSP product. Marker, 20bp DNA ladder; U, unmethylaion; M, methylation; case, patient with HCC. (b) Sequencing diagram of MSP reaction purified product. The arrow in the figure refers to the CpG site which is invariant (methylation, M) and changed (unmethylation, U) after bisulfite modification. (TIFF 1296 kb)

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Wei, L., Huang, Y., Zhao, R. et al. Detection of promoter methylation status of suppressor of cytokine signaling 3 (SOCS3) in tissue and plasma from Chinese patients with different hepatic diseases. Clin Exp Med 18, 79–87 (2018). https://doi.org/10.1007/s10238-017-0473-2

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