Ji Hyeon-Geun, Piao Juan-Yu, Kim Su-Jung, Kim Do-Hee, Lee Ha-Na, Na Hye-Kyung, Surh Young-Joon
Cancer Research Institute, Seoul National University, Seoul, South Korea.
Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul, South Korea.
Mol Nutr Food Res. 2016 Jun;60(6):1448-57. doi: 10.1002/mnfr.201600009. Epub 2016 May 9.
The health beneficial effects of docosahexaenoic acid (DHA) have been attributed to its anti-inflammatory properties. However, the molecular mechanism underlying anti-inflammatory effects of DHA remains largely elusive.
In the present study, DHA was found to suppress the phosphorylation and nuclear translocation of signal transducer and activator of transcription 3 (STAT3) induced by Helicobacter pylori infection in human gastric cancer AGS cells. Notably, DHA induced expression of suppressor of cytokine signaling 3 (SOCS3), a negative regulator of STAT3. Knockdown of SOCS3 abolished the suppressive effect of DHA on STAT3(Tyr705) phosphorylation induced by H. pylori infection. DHA also induced nuclear translocation, DNA binding, and transcriptional activities of peroxisome proliferator-activated receptor gamma (PPARγ) in AGS cells. Knockdown of PPARγ inhibited the transcription of SOCS3 and attenuated the suppressive effect of DHA on phosphorylation of STAT3(Tyr705) induced by H. pylori. The PPARγ antagonist bisphenol A diglycidyl ether also mitigated the suppressive effect of DHA on H. pylori-induced phosphorylation of STAT3(Tyr705) . In addition, DHA inhibited the expression of c-Myc, which was attenuated in the AGS cells harboring SOCS3 specific siRNA. DHA also markedly decreased anchorage-independent growth of AGS cells infected by H. pylori.
DHA inhibits H. pylori-induced STAT3 phosphorylation in a PPARγ/SOCS3-dependent manner.
二十二碳六烯酸（DHA）对健康有益的作用归因于其抗炎特性。然而，DHA抗炎作用的分子机制在很大程度上仍不清楚。
在本研究中，发现DHA可抑制人胃癌AGS细胞中幽门螺杆菌感染诱导的信号转导和转录激活因子3（STAT3）的磷酸化及核转位。值得注意的是，DHA诱导细胞因子信号转导抑制因子3（SOCS3，STAT3的负调节因子）的表达。敲低SOCS3可消除DHA对幽门螺杆菌感染诱导的STAT3（Tyr705）磷酸化的抑制作用。DHA还可诱导AGS细胞中过氧化物酶体增殖物激活受体γ（PPARγ）的核转位、DNA结合及转录活性。敲低PPARγ可抑制SOCS3的转录，并减弱DHA对幽门螺杆菌诱导的STAT3（Tyr705）磷酸化的抑制作用。PPARγ拮抗剂双酚A二缩水甘油醚也可减轻DHA对幽门螺杆菌诱导的STAT3（Tyr705）磷酸化的抑制作用。此外，DHA可抑制c-Myc的表达，在携带SOCS3特异性小干扰RNA的AGS细胞中，这种抑制作用减弱。DHA还可显著降低幽门螺杆菌感染的AGS细胞的非锚定依赖性生长。
DHA以PPARγ/SOCS3依赖的方式抑制幽门螺杆菌诱导的STAT3磷酸化。
