PDF(Pubmed)
Abstract：
In this study, we explored the oncogenic mechanism of cleavage and polyadenylation-specific factor 6 (CPSF6) in hepatocellular carcinoma (HCC). CPSF6 was overexpressed in HCC tissues with poor survival rates compared to normal tissues. Hence, CPSF6 depletion suppressed cell viability and colony formation, induced apoptosis via PARP cleavage, and increased the sub-G1 population of Hep3B and Huh7 cells. In addition, CPSF6 enhanced the stability of c-Myc via their binding through nuclear co-localization by binding to c-Myc at the site of 258-360. Furthermore, c-Myc degradation by CPSF6 depletion was disturbed by FBW7 depletion or treatment with the proteasomal inhibitor MG132. Additionally, CPSF6 depletion suppressed the Warburg effect by inhibiting glucose, HK2, PKM2, LDH, and lactate; showed a synergistic effect with Sorafenib in Hep3B cells; and inhibited angiogenesis by tube formation and CAM assays, along with decreased expression and production of vascular endothelial growth factor (VEGF). Notably, CPSF6 depletion attenuated PD-L1 expression and increased Granzyme B levels, along with an increase in the percentage of CD4/CD8 cells in the splenocytes of BALB/c nude mice bearing Hep3B cells. Consistently, immunohistochemistry showed that CPSF6 depletion reduced the growth of Hep3B cells in BALB/c mice in orthotopic and xenograft tumor models by inhibiting tumor microenvironment-associated proteins. Overall, these findings suggest that CPSF6 enhances the Warburg effect for immune escape and angiogenesis, leading to cancer progression via c-Myc, mediated by the HK, PD-L1, and VEGF networks, with synergistic potential with sorafenib as a molecular target for liver cancer therapy.
摘要：
在这项研究中,我们探讨了肝细胞癌（HCC）中裂解和多聚腺苷酸化特异性因子6（CPSF6）的致癌机制。与正常组织相比，CPSF6在HCC组织中过表达，存活率低。因此，CPSF6耗竭抑制细胞活力和集落形成，通过PARP裂解诱导细胞凋亡，并增加了Hep3B和Huh7细胞的sub-G1群体。此外,CPSF6通过在258-360位点与c-Myc结合，通过核共定位，通过它们的结合增强了c-Myc的稳定性。此外，由CPSF6消耗引起的c-Myc降解受到FBW7消耗或用蛋白酶体抑制剂MG132处理的干扰。此外,CPSF6消耗通过抑制葡萄糖抑制Warburg效应，HK2,PKM2,LDH,和乳酸；在Hep3B细胞中显示与索拉非尼的协同作用；并通过管形成和CAM测定抑制血管生成，随着血管内皮生长因子（VEGF）的表达和产生减少。值得注意的是,CPSF6消耗减弱PD-L1表达并增加颗粒酶B水平，随着携带Hep3B细胞的BALB/c裸鼠脾细胞中CD4/CD8细胞百分比的增加。始终如一，免疫组织化学显示，CPSF6耗竭通过抑制肿瘤微环境相关蛋白降低了BALB/c小鼠原位和异种移植肿瘤模型中Hep3B细胞的生长。总的来说,这些发现表明，CPSF6增强了Warburg对免疫逃逸和血管生成的作用，通过c-Myc导致癌症进展，由香港调解，PD-L1和VEGF网络，与索拉非尼作为肝癌治疗的分子靶标具有协同潜力。
