title: Erythrocytosis in hepatocellular carcinoma portends poor prognosis by respiratory dysfunction secondary to mitochondrial DNA mutations.
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.
  
  
  
  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).
authors: State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors: Shizhong
authors: S
authors: Ke
authors: National Center for Liver Cancer, Second Military Medical University, Shanghai, China.|International Cooperation Laboratory on Signal Transduction of Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China.
authors: Shuzhen
authors: S
authors: Chen
authors: National Center for Liver Cancer, Second Military Medical University, Shanghai, China.|International Cooperation Laboratory on Signal Transduction of Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China.
authors: Zihui
authors: Z
authors: Dong
authors: Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD.|Department of Neurosurgery, Yale School of Medicine, New Haven, CT.
authors: Christopher S
authors: CS
authors: Hong
authors: Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD.
authors: Qi
authors: Q
authors: Zhang
authors: National Center for Liver Cancer, Second Military Medical University, Shanghai, China.|International Cooperation Laboratory on Signal Transduction of Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China.
authors: Liang
authors: L
authors: Tang
authors: Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China.
authors: Pinghua
authors: P
authors: Yang
authors: Department of Interventional Radiology, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China.
authors: Jian
authors: J
authors: Zhai
authors: National Center for Liver Cancer, Second Military Medical University, Shanghai, China.|International Cooperation Laboratory on Signal Transduction of Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China.
authors: Hexin
authors: H
authors: Yan
authors: Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China.
authors: Feng
authors: F
authors: Shen
authors: Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD.
authors: Zhengping
authors: Z
authors: Zhuang
authors: National Center for Liver Cancer, Second Military Medical University, Shanghai, China.|International Cooperation Laboratory on Signal Transduction of Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China.
authors: Wen
authors: W
authors: Wen
authors: State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.|National Center for Liver Cancer, Second Military Medical University, Shanghai, China.|International Cooperation Laboratory on Signal Transduction of Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China.|Ministry of Education (MOE) Key Laboratory on Signaling Regulation and Targeting Therapy of Liver Cancer, Second Military Medical University, Shanghai, China.
authors: Hongyang
authors: H
authors: Wang
mesh_terms: D006528:Carcinoma, Hepatocellular / Q000150:complications* / Q000235:genetics* / Q000503:physiopathology; D015687:Cell Hypoxia; D004272:DNA, Mitochondrial / Q000235:genetics*; D005260:Female; D006801:Humans; D008113:Liver Neoplasms / Q000150:complications* / Q000235:genetics* / Q000503:physiopathology; D008297:Male; D028361:Mitochondrial Diseases / Q000235:genetics; D009154:Mutation; D010257:Paraneoplastic Syndromes / Q000209:etiology*; D011086:Polycythemia / Q000209:etiology* / Q000503:physiopathology; D011379:Prognosis
chemical_list: D004272:DNA, Mitochondrial