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Hepatology. 2017 Jan;65(1):134-151. doi: 10.1002/hep.28889. Epub 2016 Nov 25.

Erythrocytosis in hepatocellular carcinoma portends poor prognosis by respiratory dysfunction secondary to mitochondrial DNA mutations.

Ke S1, Chen S2,3, Dong Z2,3, Hong CS4,5, Zhang Q4, Tang L2,3, Yang P6, Zhai J7, Yan H2,3, Shen F6, Zhuang Z4, Wen W2,3, Wang H1,2,3,8.

Author information

1
State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
2
National Center for Liver Cancer, Second Military Medical University, Shanghai, China.
3
International Cooperation Laboratory on Signal Transduction of Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China.
4
Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD.
5
Department of Neurosurgery, Yale School of Medicine, New Haven, CT.
6
Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China.
7
Department of Interventional Radiology, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China.
8
Ministry of Education (MOE) Key Laboratory on Signaling Regulation and Targeting Therapy of Liver Cancer, Second Military Medical University, Shanghai, China.

Abstract

Erythrocytosis is a common paraneoplastic syndrome associated with hepatocellular carcinoma. Although increased erythropoietin (EPO) is found in these patients, the clinical significance and molecular mechanisms underlying this observation are unclear. We demonstrate an inverse relationship between EPO production and overall prognosis in our cohort of 664 patients as well as in data from The Cancer Genome Atlas. In the subset of hepatocellular carcinoma patients with erythrocytosis, we identified somatic mutations of mitochondrial DNA, resulting in impairment of respiratory metabolism, which sequentially led to depletion of α-ketoglutarate, stabilization of hypoxia inducible factor-α, and expression of target genes such as EPO. Cell lines and patient-derived xenograft models were used to demonstrate that EPO promoted cancer stem cell self-renewal and expansion in an autocrine/paracrine manner through enhanced Janus kinase/signal transducer and activator of transcription signaling both in vitro and in vivo. Furthermore, to explore the therapeutic targeting of EPO-induced tumor changes, we found that blocking EPO signaling with soluble EPO receptor extracellular domain Fc fusion protein could inhibit tumor growth both in vitro and in vivo.

CONCLUSION:

These findings suggest clinical and therapeutic implications for erythrocytosis in hepatocellular carcinoma. There is an underlying link between mitochondrial function and hypoxia inducible factor alpha signaling, revealing a mechanism of erythrocytosis in a subset of hepatocellular carcinoma patients who may benefit from treatment involving EPO signaling interference. (Hepatology 2017;65:134-151).

PMID:
27774607
DOI:
10.1002/hep.28889
[Indexed for MEDLINE]
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