Yang Wei, Su Jiaqi, Li Mingjing, Li Tiantian, Wang Xu, Zhao Mingdong, Hu Xuemei
Department of Imaging, Binzhou Medical University, Yantai, China.
Department of Chinese Medicine Prescription, Binzhou Medical University, Yantai, China.
Front Pharmacol. 2021 Oct 18;12:709526. doi: 10.3389/fphar.2021.709526. eCollection 2021.
Myricetin is a type of natural flavonol known for its anticancer activity. However, the molecular mechanism of myricetin in anti-hepatocellular carcinoma (HCC) is not well defined. Previous studies indicated that downregulation of membrane-associated RING-CH finger protein 1 (MARCH1) contributed to the treatment of a variety of cancers. Whether the anticancer property of myricetin is associated with MARCH1 expression remains to be investigated. This research explored the anti-HCC mechanism of myricetin. Our results indicate that myricetin induces autophagy and arrests cell cycle at the G2/M phase to suppress the proliferation of HCC cells by downregulating MARCH1. Myricetin reduces MARCH1 protein in Hep3B and HepG2 cells. Interestingly, myricetin upregulates the MARCH1 mRNA level in Hep3B cells but downregulates it in HepG2 cells. The knockdown of MARCH1 by siRNAs (small interfering RNAs) decreases the phosphorylated p38 MAPK (p-p38 MAPK) and Stat3 (p-Stat3), and inhibits HCC cell viability. Moreover, myricetin inhibits p38 MAPK and Stat3 signaling pathways by downregulating MARCH1 to repress HCC growth both and . Bafilomycin A1 (BafA1), an autophagy inhibitor, has synergetic effect with myricetin to inhibit HCC growth. Taken together, our results reveal that myricetin inhibits the proliferation of HCC cells by inhibiting MARCH1-regulated p38 MAPK and Stat3 signaling pathways. This research provides a new molecular mechanism for myricetin in anti-HCC and suggests that targeting MARCH1 could be a novel treatment strategy in developing anticancer therapeutics.
杨梅素是一种以其抗癌活性而闻名的天然黄酮醇。然而，杨梅素在抗肝细胞癌（HCC）中的分子机制尚不清楚。先前的研究表明，膜相关RING-CH指蛋白1（MARCH1）的下调有助于多种癌症的治疗。杨梅素的抗癌特性是否与MARCH1表达相关仍有待研究。本研究探讨了杨梅素的抗HCC机制。我们的结果表明，杨梅素通过下调MARCH1诱导自噬并使细胞周期停滞在G2/M期，从而抑制HCC细胞的增殖。杨梅素降低了Hep3B和HepG2细胞中的MARCH1蛋白。有趣的是，杨梅素上调了Hep3B细胞中的MARCH1 mRNA水平，但下调了HepG2细胞中的MARCH1 mRNA水平。通过小干扰RNA（siRNAs）敲低MARCH1可降低磷酸化的p38丝裂原活化蛋白激酶（p-p38 MAPK）和信号转导子和转录激活子3（p-Stat3），并抑制HCC细胞活力。此外，杨梅素通过下调MARCH1来抑制p38 MAPK和Stat3信号通路，从而在体内和体外均抑制HCC生长。自噬抑制剂巴弗洛霉素A1（BafA1）与杨梅素具有协同作用，可抑制HCC生长。综上所述，我们的结果表明，杨梅素通过抑制MARCH1调节的p38 MAPK和Stat3信号通路来抑制HCC细胞的增殖。本研究为杨梅素抗HCC提供了一种新的分子机制，并表明靶向MARCH1可能是开发抗癌治疗药物的一种新的治疗策略。
