High leukocyte mtDNA content contributes to poor prognosis through ROS-mediated immunosuppression in hepatocellular carcinoma patients
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Xianli He1,*, Falin Qu1,2,*, Feng Zhou1, Xingchun Zhou2, Yibing Chen2, Xu Guo2, Jibin Li2, Qichao Huang2, Yefa Yang3, Zhuomin Lyu4, Hongxin Zhang4, Jinliang Xing2
1Department of General Surgery, Tangdu Hospital, The Fourth Military Medical University, Xi’an 710032, China
2State Key Laboratory of Cancer Biology and Experimental Teaching Center of Basic Medicine, The Fourth Military Medical University, Xi’an 710032, China
3Department of Radioactive Intervention, Eastern Hepatobiliary Surgery Hospital, The Second Military Medical University, Shanghai 200438, China
4Department of Pain Treatment, Tangdu Hospital, The Fourth Military Medical University, Xi’an 710032, China
*These authors have contributed equally to this work
Jinliang Xing, e-mail: [email protected]
Keywords: mitochondrial DNA content, hepatocellular carcinoma, prognosis, reactive oxygen species, immunosuppression
Received: November 10, 2015 Accepted: February 23, 2016 Published: March 14, 2016
Compelling epidemiological evidences indicate a significant association between leukocyte mitochondrial DNA (mtDNA) content and incidence risk of several malignancies, including hepatocellular carcinoma (HCC). However, whether leukocyte mtDNA content affect prognosis of HCC patients and underlying mechanism has never been explored. In our study, leukocyte mtDNA content was measured in 618 HCC patients and its prognostic value was analyzed. Moreover, we detected the immunophenotypes of peripheral blood mononuclear cells (PBMCs) and plasma concentrations of several cytokines in 40 HCC patients and assessed the modulating effects of mtDNA content on immunosuppression in cell models. Our results showed that HCC patients with high leukocyte mtDNA content exhibited a significantly worse recurrence-free survival (RFS) and overall survival (OS) than those with low leukocyte mtDNA content. Leukocyte mtDNA content and TNM stage exhibited a notable joint effect in prognosis prediction. Furthermore, we found that patients with high leukocyte mtDNA content exhibited a higher frequency of CD4+CD25+FOXP3+ regulatory T (Treg) cells and lower frequency of NK cells in PBMCs and had higher TGF-β1 and lower TNF-α and IFN-γ plasma concentration when compared with those with low leukocyte mtDNA content, which suggests an immunosuppressive status. High leukocyte mtDNA content significantly enhanced the ROS-mediated secretion of TGF-β1, which accounted for higher Treg and lower NK frequency in PBMCs. In a conclusion, our study for the first time demonstrates that leukocyte mtDNA content is an independent prognostic marker complementing TNM stage and associated with an ROS-mediated immunosuppressive phenotype in HCC patients.
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