Hypoxia-induced ANGPTL4 sustains tumour growth and anoikis resistance through different mechanisms in scirrhous gastric cancer cell lines.
Hypoxia-induced ANGPTL4 sustains tumour growth and anoikis resistance through different mechanisms in scirrhous gastric cancer cell lines.
复制标题
DOI：
10.1038/s41598-017-11769-x
复制
发表时间：
2017-09-11
影响因子：
4.6
通讯作者：
Noshiro H
中科院分区：
文献类型：
--
作者：
Baba K;Kitajima Y;Miyake S;Nakamura J;Wakiyama K;Sato H;Okuyama K;Kitagawa H;Tanaka T;Hiraki M;Yanagihara K;Noshiro H
硬化性胃癌(SGC)患者常发生腹膜播散，预后不良。低氧诱导的血管生成素样蛋白4(ANGPTL4)在肿瘤的发生、发展过程中发挥多种作用。本研究旨在探讨ANGPTL4在低氧条件下对SGC细胞的生物学功能。在低氧条件下，SGC细胞中ANGPTL4的水平高于其他类型的胃癌细胞。缺氧诱导因子-1α(HIF-1α)对缺氧诱导的ANGPTL4mRNA表达有调节作用。在低氧条件下，与对照58As9-SC细胞相比，ANGPTL4基因敲除(KD)58As9-SGC(58As9-KD)细胞通过下调c-Myc和上调p27，使细胞周期停滞于G1期。此外，58As9-KD移植瘤在裸鼠体内形成肿瘤的能力受到强烈抑制。当58As9-KD细胞悬浮培养时，低氧通过抑制FAK/Src/PI3K-Akt/ERK促生存通路，继而激活凋亡因子caspase-3、-8和-9，从而显著增加其对失巢凋亡的敏感性。与58As9-SC细胞相比，58As9-KD细胞的腹膜转移完全被抑制。综上所述，ANGPTL4在培养的SGC细胞中被低氧诱导，并且通过不同的机制对肿瘤的生长和对失巢凋亡的抵抗起着至关重要的作用。
Patients with scirrhous gastric cancer (SGC) frequently develop peritoneal dissemination, which leads to poor prognosis. The secreted protein angiopoietin-like-4 (ANGPTL4), which is induced by hypoxia, exerts diverse effects on cancer progression. Here, we aimed to determine the biological function of ANGPTL4 in SGC cells under hypoxia. ANGPTL4 levels were higher in SGC cells under hypoxia than in other types of gastric cancer cells. Hypoxia-induced ANGPTL4 mRNA expression was regulated by hypoxia-inducible factor-1α (HIF-1α). Under hypoxic conditions, monolayer cultures of ANGPTL4 knockdown (KD) 58As9 SGC (58As9-KD) cells were arrested in the G1 phase of the cell cycle through downregulation of c-Myc and upregulation of p27, in contrast to control 58As9-SC cells. Moreover, the ability of 58As9-KD xenografts to form tumours in nude mice was strongly suppressed. When 58As9-KD cells were cultured in suspension, hypoxia strongly increased their susceptibility to anoikis through suppression of the FAK/Src/PI3K-Akt/ERK pro-survival pathway, followed by activation of the apoptotic factors caspases-3, -8 and -9. The development of peritoneal dissemination by 58As9-KD cells was completely inhibited compared with that by 58As9-SC cells. In conclusion, ANGPTL4 is uniquely induced by hypoxia in cultured SGC cells and is essential for tumour growth and resistance to anoikis through different mechanisms.
登录
查看更多内容
影响因子：
8
作者：
Semenza, G. L.
通讯作者：
Semenza, G. L.
影响因子：
37.3
作者：
Hua KT;Wang MY;Chen MW;Wei LH;Chen CK;Ko CH;Jeng YM;Sung PL;Jan YH;Hsiao M;Kuo ML;Yen ML
通讯作者：
Yen ML
影响因子：
13.8
作者：
Semenza GL
通讯作者：
Semenza GL
影响因子：
10.3
作者：
Stoeltzing, O;McCarty, MF;Ellis, LM
通讯作者：
Ellis, LM
影响因子：
4.2
作者：
Nakayama, Toshyuki;Hirakawa, Hiroshi;Taguchi, Takashi
通讯作者：
Taguchi, Takashi