Zhou Wei, Liu Meiyue, Li Xia, Zhang Peng, Li Jiong, Zhao Yue, Sun Guogui, Mao Weimin
Cancer Hospital of University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institute of Cancer and Basic Medicine of Chinese Academy of Sciences, Hangzhou, 310022, China.
School of Public Health, North China University of Science and Technology Affiliated People's Hospital, North China University of Science and Technology, Tangshan, 063001, China.
Cell Biosci. 2020 Dec 22;10(1):146. doi: 10.1186/s13578-020-00508-x.
Increased reactive oxygen species (ROS) production by arsenic treatment in solid tumors showed to be effective to sensitize cancer cells to chemotherapies. Arsenic nano compounds are known to increase the ROS production in solid tumors.
In this study we developed arsenic-ferrosoferric oxide conjugated Nano Complex (AsS-FeO AFCNC) to further promote the ROS induction ability of arsenic reagent in solid tumors. We screen for the molecular pathways that are affect by arsenic treatment in ESCC cancer cells. And explored the underlying molecular mechanism for the arsenic mediated degradations of the key transcription factor we identified in the gene microarray screen. Mouse xenograft model were used to further verify the synthetic effects of AFCNC with chemo and radiation therapies, and the molecular target of arsenic treatment is verified with IHC analysis.
With gene expression microarray analysis we found Hippo signaling pathway is specifically affected by arsenic treatment, and induced ubiquitination mediated degradation of YAP in KYSE-450 esophageal squamous cell carcinoma (ESCC) cells. Mechanistically we proved PML physically interacted with YAP, and arsenic induced degradation PML mediated the degradation of YAP in ESCC cells. As a cancer stem cell related transcription factor, YAP 5SA over expressions in cancer cells are correlated with resistance to chemo and radiation therapies. We found AFCNC treatment inhibited the increased invasion and migration ability of YAP 5SA overexpressing KYSE-450 cells. AFCNC treatment also effectively reversed protective effects of YAP 5SA overexpression against cisplatin induced apoptosis in KYSE-450 cells. Lastly, with ESCC mouse xenograft model we found AFCNC combined with cisplatin treatment or radiation therapy significantly reduced the tumor volumes in vivo in the xenograft ESCC tumors.
Together, these findings suggested besides ROS, YAP is a potential target for arsenic based therapy in ESCC, which should play an important role in the synthetic effects of arsenic nano complex with chemo and radiation therapy.
在实体瘤中，砷处理可增加活性氧（ROS）的产生，这已被证明能有效使癌细胞对化疗敏感。已知砷纳米化合物可增加实体瘤中ROS的产生。
在本研究中，我们开发了砷 - 四氧化三铁共轭纳米复合物（AsS - FeO AFCNC），以进一步提高砷试剂在实体瘤中诱导ROS的能力。我们筛选了在食管鳞状细胞癌（ESCC）细胞中受砷处理影响的分子途径。并探索了砷介导的我们在基因微阵列筛选中鉴定的关键转录因子降解的潜在分子机制。使用小鼠异种移植模型进一步验证AFCNC与化疗和放疗的联合效果，并用免疫组化分析验证砷治疗的分子靶点。
通过基因表达微阵列分析，我们发现Hippo信号通路特别受砷处理影响，并诱导KYSE - 450食管鳞状细胞癌（ESCC）细胞中YAP的泛素化介导降解。从机制上我们证明PML与YAP发生物理相互作用，并且砷诱导的PML降解介导了ESCC细胞中YAP的降解。作为一种癌症干细胞相关转录因子，癌细胞中YAP 5SA的过表达与对化疗和放疗的抗性相关。我们发现AFCNC处理抑制了YAP 5SA过表达的KYSE - 450细胞侵袭和迁移能力的增加。AFCNC处理还有效逆转了YAP 5SA过表达对KYSE - 450细胞中顺铂诱导凋亡的保护作用。最后，在ESCC小鼠异种移植模型中，我们发现AFCNC与顺铂治疗或放疗联合使用可显著减小异种移植ESCC肿瘤的体内肿瘤体积。
总之，这些发现表明除了ROS外，YAP是ESCC中基于砷的治疗的潜在靶点，这在砷纳米复合物与化疗和放疗的联合效果中应发挥重要作用。
