Department of General Surgery, Xinhua Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, 200092, China.
Department of Colorectal Surgery, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, 510655, China.
Cell Death Dis. 2020 Oct 16;11(10):871. doi: 10.1038/s41419-020-03080-x.
Gallbladder cancer (GBC) accounts for 85-90% malignancies of the biliary tree worldwide. Considerable evidence has demonstrated that dysregulation of lncRNAs is involved in the progression of cancer. LncRNA PVT1 has been reported to play important roles in various cancers, but its role in gallbladder cancer remains unknown. In the present study, we found that PVT1 was upregulated in GBC tissues and cells, and its upregulation was related with poor prognosis in GBC patients. PVT1 promoted GBC cells proliferation in vitro and in vivo. Mechanistically, PVT1 recruited DNMT1 via EZH2 to the miR-18b-5p DNA promoter and suppressed the transcription of miR-18b-5p through DNA methylation. Moreover, HIF1A was proved to be the downstream target gene of miR-18b-5p and PVT1 regulated GBC cells proliferation via HIF1A. In conclusion, our studies clarified the PVT1/miR-18b-5p/HIF1A regulation axis and indicated that PVT1 could be a potential therapeutic target for GBC.
胆囊癌（GBC）占全球胆道系统恶性肿瘤的 85-90%。大量证据表明，lncRNAs 的失调参与了癌症的进展。已有研究报道，lncRNA PVT1 在多种癌症中发挥重要作用，但它在胆囊癌中的作用尚不清楚。本研究发现，PVT1 在 GBC 组织和细胞中上调，其上调与 GBC 患者的预后不良相关。PVT1 促进 GBC 细胞在体外和体内的增殖。机制上，PVT1 通过 EZH2 将 DNMT1 募集到 miR-18b-5p 的 DNA 启动子，通过 DNA 甲基化抑制 miR-18b-5p 的转录。此外，HIF1A 被证实是 miR-18b-5p 的下游靶基因，PVT1 通过 HIF1A 调节 GBC 细胞的增殖。总之，本研究阐明了 PVT1/miR-18b-5p/HIF1A 调控轴，并表明 PVT1 可能是 GBC 的潜在治疗靶点。
