Hypoxia-induced macropinocytosis represents a metabolic route for liver cancer.
Hypoxia-induced macropinocytosis represents a metabolic route for liver cancer.
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DOI：
10.1038/s41467-022-28618-9
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发表时间：
2022-02-17
影响因子：
16.6
通讯作者：
Wong CC
中科院分区：
文献类型：
--
作者：
Zhang MS;Cui JD;Lee D;Yuen VW;Chiu DK;Goh CC;Cheu JW;Tse AP;Bao MH;Wong BPY;Chen CY;Wong CM;Ng IO;Wong CC
肝细胞癌（HCC）总是表现出氧气（缺氧）和营养供应不足。缺氧诱导因子（HIF）介导的级联分子事件，使癌细胞适应和繁殖。巨胞饮作用是由膜皱褶引发的内吞过程，引起细胞外液（蛋白质）的吞噬、蛋白质消化和随后掺入生物质中。我们发现，巨胞饮普遍发生在肝癌缺氧。HIF-1激活膜皱褶蛋白EH结构域蛋白2（EHD 2）的转录，以启动巨胞饮。敲除HIF-1或EHD 2可抑制低氧诱导的巨胞饮作用，并阻止低氧HCC细胞清除支持细胞生长的蛋白质。Ehd 2的胚系或体细胞缺失抑制小鼠中的巨胞饮和HCC发展。有趣的是，EHD 2在HCC中过表达。因此，HIF-1或巨胞饮抑制剂抑制巨胞饮和HCC的发展。因此，我们表明，缺氧诱导巨胞饮通过HIF/EHD 2途径在肝癌细胞，利用细胞外蛋白作为营养生存。癌细胞依赖于巨胞饮作用来吸收细胞外蛋白以进行生长。在这里，作者表明，巨胞饮支持缺氧肝细胞癌细胞的存活，这依赖于HIF-1，HIF-1反过来激活膜皱褶蛋白（EH结构域蛋白2）的转录。
Hepatocellular carcinoma (HCC) invariably exhibits inadequate O2 (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. Cancer cells rely on macropinocytosis to scavenge extracellular proteins for growth. Here the authors show that macropinocytosis supports the survival of hypoxic hepatocellular carcinoma cells and this is dependent on HIF-1, which in turns activates the transcription of a membrane ruffling protein, EH domain-containing protein 2.
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影响因子：
14.8
作者：
通讯作者：
--
影响因子：
82.9
作者：
Davidson SM;Jonas O;Keibler MA;Hou HW;Luengo A;Mayers JR;Wyckoff J;Del Rosario AM;Whitman M;Chin CR;Condon KJ;Lammers A;Kellersberger KA;Stall BK;Stephanopoulos G;Bar-Sagi D;Han J;Rabinowitz JD;Cima MJ;Langer R;Vander Heiden MG
通讯作者：
Vander Heiden MG
DOI：
10.1152/ajprenal.00532.2013
发表时间：
2014-05-01
影响因子：
4.2
作者：
Dobrinskikh, Evgenia;Okamura, Kayo;Blaine, Judith
通讯作者：
Blaine, Judith
影响因子：
29.4
作者：
Chiu, David Kung-Chun;Yuen, Vincent Wai-Hin;Wong, Carmen Chak-Lui
通讯作者：
Wong, Carmen Chak-Lui
DOI：
10.1073/pnas.1307237110
发表时间：
2013-05-28
影响因子：
11.1
作者：
Kamphorst, Jurre J.;Cross, Justin R.;Rabinowitz, Joshua D.
通讯作者：
Rabinowitz, Joshua D.