Institute of Infectious Diseases of Chinese PLA, Southwest Hospital, Third Military Medical University (Army Medical University)ChongqingP.R. China.
Department of Laboratory, The Fourth Medical Center of PLA General HospitalBeijingP.R. China.
Oncol Res. 2020 Sep 1;28(4):371-383. doi: 10.3727/096504020X15853075736554. Epub 2020 Mar 27.
Chemotherapy is critical for the treatment of hepatocellular carcinoma (HCC). Despite the proapoptotic effects of corosolic acid (CA) treatment, its underlying mechanism is not completely clear. The aim of this study was to determine the molecular mechanism of CA in HCC treatment. MTT assay was used to determine the IC of CA. Immunoprecipitation and immunofluorescence were used to detect the interaction and subcellular localization of Yes-associated protein (YAP) and mouse double minute 2 (MDM2). In addition, in vivo xenotransplantation was performed to assess the effects of CA, YAP, and MDM2 on tumorigenesis. The IC of CA was about 40 M in different HCC cell lines, and CA decreased YAP expression by reducing its stability and increasing its ubiquitination. CA treatment and MDM2 overexpression significantly decreased the crosstalk between YAP and cAMP-responsive element-binding protein (CREB), TEA domain transcription factor (TEAD), and Runt-related transcription factor 2 (Runx2). CA stimulation promoted the translocation of YAP and MDM2 from the nucleus to the cytoplasm and increased their binding. In addition, CA treatment obviously reduced tumorigenesis, whereas this effect was abolished when cells were transfected with sh-MDM2 or Vector-YAP. The present study uncovered that CA induced cancer progress repression through translocating YAP from the nucleus in HCC, which might provide a new therapeutic target for HCC.
化疗对于肝细胞癌 (HCC) 的治疗至关重要。尽管熊果酸 (CA) 治疗具有促凋亡作用，但其潜在机制尚不完全清楚。本研究旨在确定 CA 在 HCC 治疗中的分子机制。MTT 测定法用于确定 CA 的 IC。免疫沉淀和免疫荧光用于检测 Yes 相关蛋白 (YAP) 和双微体 2 (MDM2) 的相互作用和亚细胞定位。此外，进行体内异种移植以评估 CA、YAP 和 MDM2 对肿瘤发生的影响。CA 在不同的 HCC 细胞系中的 IC 约为 40 μM，CA 通过降低其稳定性和增加其泛素化来降低 YAP 表达。CA 处理和 MDM2 过表达显着降低了 YAP 和 cAMP 反应元件结合蛋白 (CREB)、TEA 结构域转录因子 (TEAD) 和 Runt 相关转录因子 2 (Runx2) 之间的串扰。CA 刺激促进 YAP 和 MDM2 从核易位到细胞质，并增加它们的结合。此外，CA 处理明显降低了肿瘤发生，而当用 sh-MDM2 或 Vector-YAP 转染细胞时，这种作用被消除。本研究揭示了 CA 通过将 YAP 从 HCC 的核中转位来诱导癌症进展抑制，这可能为 HCC 提供新的治疗靶点。
