Purpose: Hepatocellular carcinoma (HCC) lacks effective curative therapy. Hypoxia is commonly found in HCC. Hypoxia elicits a series of pro-tumorigenic responses through hypoxia-inducible factor-1 (HIF-1). Better understanding of the metabolic adaptations of HCC cells during hypoxia is essential to the design of new therapeutic regimen. Experimental Design: Expressions of genes involved in the electron transport chain (ETC) in HCC cell lines (20% and 1% O2) and human HCC samples were analyzed by transcriptome sequencing. Expression of NDUFA4L2, a less active subunit in complex I of the ETC, in 100 pairs of HCC and non-tumorous liver tissues were analyzed by qRT-PCR. Student's t test and Kaplan-Meier analysis were used for clinicopathological correlation and survival studies. Orthotopic HCC implantation model was used to evaluate the efficiency of HIF inhibitor. Results: NDUFA4L2 was drastically over-expressed in human HCC and induced by hypoxia. NDUFA4L2 over-expression was closely associated with tumor microsatellite formation, absence of tumor encapsulation, and poor overall survival in HCC patients. We confirmed that NDUFA4L2 was HIF-1-regulated in HCC cells. Inactivation of HIF-1/NDUFA4L2 increased mitochondrial activity and oxygen consumption, resulting in ROS accumulation and apoptosis. Knockdown of NDUFA4L2 markedly suppressed HCC growth and metastasis in vivo. HIF inhibitor, digoxin, significantly suppressed growth of tumors that expressed high level of NDUFA4L2. Conclusions: Our study has provided the first clinical relevance of NDUFA4L2 in human cancer and suggested that HCC patients with NDUFA4L2 over-expression may be suitable candidates for HIF inhibitor treatment.
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