EGFR-IL-6 Signaling Axis Mediated the Inhibitory Effect of Methylseleninic Acid on Esophageal Squamous Cell Carcinoma.
EGFR-IL-6 Signaling Axis Mediated the Inhibitory Effect of Methylseleninic Acid on Esophageal Squamous Cell Carcinoma.
复制标题
DOI：
10.3389/fphar.2021.719785
复制
发表时间：
2021
影响因子：
5.6
通讯作者：
Xu N
中科院分区：
文献类型：
--
作者：
Wang Y;Liu X;Hu G;Hu C;Gao Y;Huo M;Zhu H;Liu M;Xu N
流行病学和实验证据表明，硒与降低某些癌症的风险有关，包括食道癌。然而，确切的机制仍不清楚。本研究以食管鳞癌细胞株和动物模型为研究对象，探讨甲基硒酸（MSA）的抗癌作用机制。首先，MSA处理显著减弱表皮生长因子受体（EGFR）蛋白表达，但不改变ESCC细胞中的mRNA水平。相反，EGFR过表达部分取消MSA的抑制作用。通过microRNA芯片，我们发现MSA上调了直接靶向EGFR的miR-146a，而miR-146a抑制剂则拮抗了MSA诱导的EGFR蛋白的减少。我们进一步使用4-硝基喹啉-1-氧化物（4NQO）诱导的小鼠食管肿瘤模型来评价MSA的体内抑制作用。MSA治疗显著降低了肿瘤标本中的肿瘤负荷和EGFR蛋白表达。此外，MSA处理抑制EGFR通路，并随后减少癌细胞系上清液中白细胞介素-6（IL-6）的分泌。MSA诱导的IL-6抑制是EGFR依赖性的。为了进一步评价IL-6与MSA抗食管癌作用的关系，我们在IL-6敲除（IL-6 KO）小鼠中建立了4NQO诱导的食管癌模型。结果表明，IL-6缺乏对小鼠食管癌的发生无影响，但MSA对IL-6 KO小鼠食管癌的抑制作用被取消。综上所述，本研究证实MSA可上调直接靶向EGFR的miR-146 a，抑制EGFR蛋白表达和通路活性，从而降低IL-6的分泌。MSA对食管癌的抑制作用呈IL-6依赖性。结果提示，MSA可能是一种潜在的治疗食管癌的药物。
Epidemiological and experimental evidence indicate that selenium is associated with a reduced risk of some cancers, including esophageal cancer. However, the exact mechanism is still unclear. In the present study, we used esophageal squamous cell carcinoma (ESCC) cell lines and animal models to explore the anti-cancer mechanism of methylseleninic acid (MSA). Firstly, MSA treatment dramatically attenuated Epidermal Growth Factor Receptor (EGFR) protein expression but did not alter mRNA levels in ESCC cells. On the contrary, EGFR overexpression partly abolished the inhibitory effect of MSA. With a microRNA-array, we found MSA up-regulated miR-146a which directly targeted EGFR, whereas miR-146a inhibitor antagonized MSA-induced decrease of EGFR protein. We further used 4-nitroquinoline-1-oxide (4NQO)-induced esophageal tumor mice model to evaluate the inhibitory effect of MSA in vivo. MSA treatment significantly decreased the tumor burden and EGFR protein expression in tumor specimens. Furthermore, MSA treatment inhibited EGFR pathway and subsequntly reduced Interleukin-6 (IL-6) secretion in the supernatant of cancer cell lines. MSA-induced IL-6 suppression was EGFR-dependent. To further evaluate the association of IL-6 and the anti-tumor effect of MSA on esophageal cancer, we established the 4NQO-induced esophageal tumor model in IL-6 knock-out (IL-6 KO) mice. The results showed that IL-6 deficiency did not affect esophageal tumorigenesis in mice, but the inhibitory effect of MSA was abolished in IL-6 KO mice. In conclusion, our study demonstrated that MSA upregulated miR-146a which directly targeted EGFR, and inhibited EGFR protein expression and pathway activity, subsequently decreased IL-6 secretion. The inhibitory effect of MSA on esophageal cancer was IL-6 dependent. These results suggested that MSA may serve as a potential drug treating esophageal cancer.
登录
查看更多内容
影响因子：
14.9
作者：
Chen C;Ridzon DA;Broomer AJ;Zhou Z;Lee DH;Nguyen JT;Barbisin M;Xu NL;Mahuvakar VR;Andersen MR;Lao KQ;Livak KJ;Guegler KJ
通讯作者：
Guegler KJ
影响因子：
--
作者：
Chen MF;Kuan FC;Yen TC;Lu MS;Lin PY;Chung YH;Chen WC;Lee KD
通讯作者：
Lee KD
影响因子：
4.6
作者：
Hu, Chenfei;Liu, Mei;Xu, Ningzhi
通讯作者：
Xu, Ningzhi
影响因子：
11.2
作者：
Nilsson, MB;Langley, RR;Fidler, IJ
通讯作者：
Fidler, IJ
DOI：
10.1093/jnci/92.21.1753
发表时间：
2000-11-01
期刊：
JOURNAL OF THE NATIONAL CANCER INSTITUTE
影响因子：
--
作者：
Mark, SD;Qiao, YL;Taylor, PR
通讯作者：
Taylor, PR