Department of General Surgery, The Fourth Affiliated Hospital of China Medical University, 4 Chongshan East Street, Shenyang, Liaoning, 110032, People's Republic of China.
Department of Oncology, Tumour Angiogenesis and Microenvironment Laboratory (TAML), The First Affiliated Hospital of Jinzhou Medical College, Jinzhou, China.
J Exp Clin Cancer Res. 2018 Sep 4;37(1):216. doi: 10.1186/s13046-018-0892-2.
Hypoxia-inducible factor 1α (HIF-1α) is essential in hepatocellular carcinoma (HCC) glycolysis and progression. Yes-associated protein (YAP) is a powerful regulator and is overexpressed in many cancers, including HCC. The regulatory mechanism of YAP and HIF-1α in HCC glycolysis is unknown.
We detected YAP expression in 54 matched HCC tissues and the adjacent noncancerous tissues. The relationship between YAP mRNA expression and that of HIF-1α was analyzed using The Cancer Genome Atlas HCC tissue data. We cultured HepG2 and Huh7 HCC cells under normoxic (20% O) and hypoxic (1% O) conditions, and measured the lactate and glucose levels, migration and invasive capability, and the molecular mechanism of HCC cell glycolysis and progression.
In this study, we detected YAP expression in 54 matched HCC tissues and the adjacent noncancerous tissues. We observed that hypoxia-induced YAP activation is crucial for accelerating HCC cell glycolysis. Hypoxia inhibited the Hippo signaling pathway and promoted YAP nuclear localization, and decreased phosphorylated YAP expression in HCC cells. YAP knockdown inhibited HCC cell glycolysis under hypoxic. Mechanistically, hypoxic stress in the HCC cells promoted YAP binding to HIF-1α in the nucleus and sustained HIF-1α protein stability to bind to PKM2 gene and directly activates PKM2 transcription to accelerate glycolysis.
Our findings describe a new regulatory mechanism of hypoxia-mediated HCC metabolism, and YAP might be a promising therapeutic target in HCC.
缺氧诱导因子 1α（HIF-1α）在肝细胞癌（HCC）的糖酵解和进展中至关重要。Yes 相关蛋白（YAP）是一种强大的调节剂，在许多癌症中过度表达，包括 HCC。YAP 和 HIF-1α 在 HCC 糖酵解中的调节机制尚不清楚。
我们检测了 54 对配对的 HCC 组织和相邻非癌组织中的 YAP 表达。使用癌症基因组图谱 HCC 组织数据分析了 YAP mRNA 表达与 HIF-1α 表达之间的关系。我们在常氧（20% O）和低氧（1% O）条件下培养 HepG2 和 Huh7 HCC 细胞，测量了乳酸和葡萄糖水平、迁移和侵袭能力，以及 HCC 细胞糖酵解和进展的分子机制。
在这项研究中，我们检测了 54 对配对的 HCC 组织和相邻非癌组织中的 YAP 表达。我们观察到缺氧诱导的 YAP 激活对于加速 HCC 细胞糖酵解至关重要。低氧抑制 Hippo 信号通路，促进 YAP 核定位，并降低 HCC 细胞中磷酸化 YAP 的表达。在低氧条件下，YAP 敲低抑制 HCC 细胞糖酵解。机制上，HCC 细胞中的缺氧应激促进了 YAP 与核内 HIF-1α 的结合，并维持了 HIF-1α 蛋白的稳定性，以结合 PKM2 基因并直接激活 PKM2 转录以加速糖酵解。
我们的研究结果描述了一种新的缺氧介导的 HCC 代谢调节机制，YAP 可能是 HCC 有前途的治疗靶点。
