Background: Tumor metastasis and poor drug efficacy are two of the most common causes of therapeutic failure in cancer patients. The underlying molecular mechanism requires further exploration, and novel effective curative strategies are urgently needed. Nature is a rich source of novel drugs, andLycorine hydrochloride(Lyc.HCL) is a natural alkaloid with tremendous therapeutic potential. However, the molecular mechanisms of its antitumor activity are still unknown. In the current study, we investigated the effects and mechanisms ofLyc.HCLagainst esophageal squamous cell carcinomas (ESCCs), which pose serious threats to human life. Methods: An MTS assay and a clone formation assay were used to assess the viability of ESCC cell lines afterLyc.HCLtreatment in vitro. Apoptosis and cell cycle regulation were analyzed using flow cytometry. Wound healing and Transwell assays were used to analyze cell migration, while invasion was analyzed using the Matrigel Transwell assay. We detected the expression of tripartite motif-containing 22 (TRIM22) through immunohistochemistry and Western blotting. A docking experiment was performed to explore the targets ofLyc.HCL. The expression levels of Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) and phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/extracellular signal-regulated kinase (Erk) pathway components were detected through Western blotting. A rescue experiment was performed to determine the potential role of TRIM22. In addition, we explored the in vivo anti-ESCC effects and mechanism ofLyc.HCLby using it to treat tumor-bearing mice. Results: TheLyc.HCLtreatment was found to inhibit esophageal squamous cell carcinoma cell proliferation both in vitro and in vivo by blocking the cell cycle at the G2 phase, inhibiting cell migration and invasion. We found that the TRIM22 protein was highly expressed in ESCCs but not in normal esophageal tissue.Lyc.HCLdirectly targeted TRIM22, decreasing the expression of TRIM22 and the JAK2/STAT3 and Erk signaling pathways, both in vitro and in vivo. Using animal experiments, we observed that the depletion of TRIM22 delayed tumor growth, but this effect was significantly reversed upon TRIM22 overexpression. Conclusions: Taken together, these findings demonstrate thatLyc.HCLcan effectively suppress ESCC both in vitro and in vivo by targeting TRIM22 and regulating the JAK2/STAT3 and Erk pathways. These results suggest thatLyc.HCLmay serve as a potential novel therapeutic for ESCC, with TRIM22 emerging as a promising target for treatment.
背景：肿瘤转移和药物疗效不佳是导致癌症患者治疗失败的两种最常见原因。其潜在的分子机制有待进一步探索，亟需开发新型有效的治疗策略。自然界是新型药物的重要来源，盐酸石蒜碱是一种具有巨大治疗潜力的天然生物碱。然而，其抗肿瘤活性的分子机制尚不明确。本研究探讨了盐酸石蒜碱对严重威胁人类生命的食管鳞状细胞癌的作用及其机制。 方法：采用MTS法和克隆形成实验评估体外盐酸石蒜碱处理后ESCC细胞系的活力。通过流式细胞术分析细胞凋亡和细胞周期调控。采用划痕实验和Transwell实验分析细胞迁移能力，并通过基质胶Transwell实验分析细胞侵袭能力。通过免疫组织化学和Western blotting检测三结构域蛋白22的表达。通过分子对接实验探索盐酸石蒜碱的作用靶点。采用Western blotting检测Janus激酶2/信号转导与转录激活因子3通路以及磷酸肌醇3-激酶/蛋白激酶B/细胞外信号调节激酶通路相关蛋白的表达水平。通过挽救实验验证TRIM22的潜在作用。此外，我们通过荷瘤小鼠模型探讨了盐酸石蒜碱在体内的抗ESCC作用及其机制。 结果：研究发现盐酸石蒜碱处理可通过将细胞周期阻滞于G2期、抑制细胞迁移和侵袭，在体外和体内抑制食管鳞状细胞癌细胞的增殖。我们发现TRIM22蛋白在ESCC组织中高表达，而在正常食管组织中不表达。盐酸石蒜碱可直接靶向TRIM22，在体外和体内均能降低TRIM22及JAK2/STAT3和Erk信号通路的表达。通过动物实验，我们观察到TRIM22的缺失可延缓肿瘤生长，但该效应在TRIM22过表达时被显著逆转。 结论：综上所述，这些研究结果表明盐酸石蒜碱可通过靶向TRIM22并调控JAK2/STAT3和Erk通路，在体外和体内有效抑制ESCC。这些结果提示盐酸石蒜碱可能成为ESCC的潜在新型治疗药物，而TRIM22则有望成为治疗的新靶点。
肿瘤(癌症)患者之家