BACKGROUND CB2 (cannabinoid receptor 2) agonists have been shown to exert anti-tumor activities in different tumor types. However, there is no study exploring the role of MDA19 (a novel CB2 agonist) in tumors. In this study we aimed to investigate the effects of MDA19 treatment on HCC cell lines, Hep3B and HepG2 and determine the relevant mechanisms. RESULTS Cell proliferation analysis, including CCK8 and colony formation assays, indicated that MDA19 treatment inhibited HCC cell proliferation in a dose- and time-dependent manner. Flow cytometry suggested that MDA19 induced cell apoptosis and activation of mitochondrial apoptosis pathway. Transwell assay indicated that HCC cell migration and invasion were significantly inhibited by MDA19 treatment. Mechanism investigation suggested that MDA19 induced inactivation of AKT signaling pathway in HCC cells. In addition, we investigated the function of CB2receptor in HCC and its role in the anti-tumor activity of MDA19. By searching on Kaplan-Meier plotter ( http://kmplot.com/analysis/ ), we found that HCC patients with high CB2 expression had a better survival and CB2 expression was significantly associated with gender, clinical stages and race of HCC patients (P < 0.05). CB2 inhibited the progression of HCC cells and its knockdown could rescue the growth inhibition induced by MDA19 in HCC. Moreover, the inhibitory effect of MDA19 on AKT signaling pathway was also reversed by CB2 knockdown. CONCLUSION Our data suggest that MDA-19 exerts an anti-tumor activity at least partly through inactivation of AKT signaling pathway in HCC. CB2 functions as a tumor suppressor gene in HCC, and MDA19-induced growth inhibition of HCC cells depends on its binding to CB2 to activate it. MDA-19 treatment may be a promising strategy for HCC therapy. REVIEWER This article was reviewed by Tito Cali, Mohamed Naguib and Bo Chen.

中文翻译：

---

MDA19 是一种新型 CB2 激动剂，部分通过 AKT 信号通路失活来抑制肝细胞癌。


背景 CB2（大麻素受体 2）激动剂已被证明在不同肿瘤类型中发挥抗肿瘤活性。然而，目前还没有研究探讨 MDA19（一种新型 CB2 激动剂）在肿瘤中的作用。在本研究中，我们旨在研究 MDA19 治疗对 HCC 细胞系 Hep3B 和 HepG2 的影响并确定相关机制。结果细胞增殖分析，包括 CCK8 和集落形成测定，表明 MDA19 治疗以剂量和时间依赖性方式抑制 HCC 细胞增殖。流式细胞术表明MDA19诱导细胞凋亡并激活线粒体凋亡途径。 Transwell实验表明MDA19处理显着抑制HCC细胞迁移和侵袭。机制研究表明MDA19诱导HCC细胞中AKT信号通路失活。此外，我们还研究了CB2受体在HCC中的功能及其在MDA19抗肿瘤活性中的作用。通过Kaplan-Meier绘图仪（http://kmplot.com/analysis/）搜索，我们发现CB2高表达的HCC患者具有更好的生存率，并且CB2表达与HCC患者的性别、临床分期和种族显着相关（ P< 0.05）。 CB2 抑制 HCC 细胞的进展，其敲低可以挽救 MDA19 在 HCC 中诱导的生长抑制。此外，MDA19对AKT信号通路的抑制作用也被CB2敲低所逆转。结论 我们的数据表明，MDA-19 至少部分通过 HCC 中 AKT 信号通路的失活发挥抗肿瘤活性。 CB2在HCC中充当抑癌基因，MDA19诱导的HCC细胞生长抑制依赖于其与CB2的结合以激活它。 MDA-19 治疗可能是 HCC 治疗的一种有前途的策略。审稿人 本文由 Tito Cali、Mohamed Naguib 和 Bo Chen 审阅。