Department of Pathology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China.
State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong, China.
Nat Commun. 2022 Feb 17;13(1):954. doi: 10.1038/s41467-022-28618-9.
Hepatocellular carcinoma (HCC) invariably exhibits inadequate O (hypoxia) and nutrient supply. Hypoxia-inducible factor (HIF) mediates cascades of molecular events that enable cancer cells to adapt and propagate. Macropinocytosis is an endocytic process initiated by membrane ruffling, causing the engulfment of extracellular fluids (proteins), protein digestion and subsequent incorporation into the biomass. We show that macropinocytosis occurs universally in HCC under hypoxia. HIF-1 activates the transcription of a membrane ruffling protein, EH domain-containing protein 2 (EHD2), to initiate macropinocytosis. Knockout of HIF-1 or EHD2 represses hypoxia-induced macropinocytosis and prevents hypoxic HCC cells from scavenging protein that support cell growth. Germline or somatic deletion of Ehd2 suppresses macropinocytosis and HCC development in mice. Intriguingly, EHD2 is overexpressed in HCC. Consistently, HIF-1 or macropinocytosis inhibitor suppresses macropinocytosis and HCC development. Thus, we show that hypoxia induces macropinocytosis through the HIF/EHD2 pathway in HCC cells, harnessing extracellular protein as a nutrient to survive.
肝细胞癌 (HCC) 通常表现出供氧不足 (缺氧) 和营养供应不足。缺氧诱导因子 (HIF) 介导了一系列分子事件，使癌细胞能够适应和增殖。巨胞饮作用是由细胞膜皱襞引发的内吞过程，导致细胞外液 (蛋白质) 的吞噬、蛋白质消化和随后纳入生物质。我们发现，在缺氧条件下 HCC 中普遍存在巨胞饮作用。HIF-1 激活细胞膜皱褶蛋白 EH 结构域蛋白 2 (EHD2) 的转录，启动巨胞饮作用。敲除 HIF-1 或 EHD2 可抑制缺氧诱导的巨胞饮作用，并防止缺氧 HCC 细胞从支持细胞生长的蛋白质中摄取营养。Ehd2 的种系或体细胞缺失可抑制巨胞饮作用和小鼠 HCC 的发展。有趣的是，EHD2 在 HCC 中过度表达。一致地，HIF-1 或巨胞饮抑制剂抑制巨胞饮作用和 HCC 的发展。因此，我们表明缺氧通过 HCC 细胞中的 HIF/EHD2 途径诱导巨胞饮作用，利用细胞外蛋白质作为营养物质来存活。
