ING4 suppresses hepatocellular carcinoma via a NF-κB/miR-155/FOXO3a signaling axis
ING4 suppresses hepatocellular carcinoma via a NF-κB/miR-155/FOXO3a signaling axis
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ING4 通过 NF-kappa B/miR-155/FOXO3a 信号轴抑制肝细胞癌
DOI：
10.7150/ijbs.28422
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发表时间：
2019-01-01
影响因子：
9.2
通讯作者：
Xie, Yufeng
中科院分区：
文献类型：
--
作者：
Qian, Fuliang;Hu, Qingqing;Xie, Yufeng
肿瘤抑制因子ING 4已显示在人HCC中减少。ING 4的改变有助于HCC的进展。然而，其在HCC中的作用及其潜在机制在很大程度上尚不清楚。在此，我们发现ING 4在HCC肿瘤组织中的下调与癌症分期、肿瘤大小和血管浸润密切相关。慢病毒介导的ING 4过表达明显抑制MHCC 97 H人肝癌细胞的增殖、迁移和侵袭，并诱导细胞周期G1期阻滞和细胞凋亡。此外，ING 4的过表达显著抑制了裸鼠体内MHCC 97 H肿瘤细胞的生长和肺转移。机制研究表明，ING 4的过表达显著增加FOXO 3a在mRNA和蛋白水平的表达，以及增强核水平和转录活性的FOXO 3a在MHCC 97 H肿瘤细胞。此外，ING 4抑制NF-κ B B的转录活性和靶向FOXO 3 a的miR-155的表达。ING 4的敲低在MHCC 97 L人HCC细胞中表现出相反的作用。有趣的是，FOXO 3a的敲低不仅减弱了ING 4引起的肿瘤抑制，而且减弱了ING 4介导的对FOXO 3a下游靶点的调节作用，证实FOXO 3a参与了HCC中ING 4介导的肿瘤抑制作用。miR-155的过表达减弱了ING 4诱导的FOXO 3a上调，而miR-155的抑制减弱了ING 4敲减诱导的FOXO 3a减少。此外，NF-κ B的抑制显著削弱了ING 4敲除诱导的miR-155上调和FOXO 3 a下调。综上所述，我们的研究提供了第一个令人信服的证据，即ING 4可以通过NF-κ B/miR-155/FOXO 3 a途径在很大程度上抑制人HCC的生长和转移。
The tumor suppressor ING4 has been shown to be reduced in human HCC. The alteration of ING4 contributes to HCC progression. However, its effect in HCC and the potential mechanism is largely unclear. Herein, we found that downregulation of ING4 in HCC tumor tissues was closely associated with cancer staging, tumor size and vascular invasion. Lentivirus-mediated ING4 overexpression significantly inhibited proliferation, migration and invasion, and induced cell cycle G1 phase arrest and apoptosis in MHCC97H human HCC cells. Moreover, overexpression of ING4 dramatically suppressed MHCC97H tumor cell growth and metastasis to lung in vivo in athymic BALB/c nude mice. Mechanistic studies revealed that overexpression of ING4 markedly increased expression of FOXO3a both at the mRNA and protein level as well as enhanced nuclear level and transcriptional activity of FOXO3a in MHCC97H tumor cells. In addition, ING4 repressed transcriptional activity of NF-kappa B and expression of miR-155 targeting FOXO3a. Knockdown of ING4 exhibited opposing effects in MHCC97L human HCC cells. Interestingly, knockdown of FOXO3a attenuated not only ING4-elicited tumor suppression but also ING4-mediated regulatory effect on FOXO3a downstream targets, confirming that FOXO3a is involved in ING4-directed tumor-inhibitory effect in HCC. Overexpression of miR-155 attenuated ING4-induced upregulation of FOXO3a, whereas inhibition of miR-155 blunted ING4 knockdown-induced reduction of FOXO3a. Furthermore, inhibition of NF-kappa B markedly impaired ING4 knockdown-induced upregulation of miR-155 and downregulation of FOXO3a. Taken together, our study provided the first compelling evidence that ING4 can suppress human HCC growth and metastasis to a great extent via a NF-kappa B/miR-155/FOXO3a pathway.