Department of General Surgery, Qilu Hospital, Cheeloo College of Medicine, Shandong University, 107 Wenhuaxi Road, Jinan, 250012, Shandong, China.
Department of General Surgery, Shandong Second Provincial General Hospital, Shandong Provincial ENT Hospital, Jinan, China.
J Exp Clin Cancer Res. 2021 Mar 1;40(1):86. doi: 10.1186/s13046-021-01890-1.
Cholangiocarcinoma is a highly malignant cancer with very dismal prognosis. Perihilar cholangiocarcinoma(pCCA) accounts for more than 50% of all cholangiocarcinoma and is well-characterized for its low rate of radical resection. Effects of radiotherapy and chemotherapy of pCCA are very limited.
Here we screened potential biomarkers of pCCA with transcriptome sequencing and evaluated the prognostic significance of HMGA1 in a large cohort pCCA consisting of 106 patients. With bioinformatics and in vitro/vivo experiments, we showed that HMGA1 induced tumor cell stemness and epithelial-mesenchymal-transition (EMT), and thus facilitated proliferation, migration and invasion by promoting TRIP13 transcription. Moreover, TRIP13 was also an unfavorable prognostic biomarker of pCCA, and double high expression of HMGA1/TRIP13 could predict prognosis more sensitively. TRIP13 promoted pCCA progression by suppressing FBXW7 transcription and stabilizing c-Myc. c-Myc in turn induced the transcription and expression of both HMGA1 and TRIP13, indicating that HMGA-TRIP13 axis facilitated pCCA stemness and EMT in a positive feedback pathway.
HMGA1 and TRIP13 were unfavorable prognostic biomarkers of pCCA. HMGA1 enhanced pCCA proliferation, migration, invasion, stemness and EMT, by inducing TRIP13 expression, suppressing FBXW7 expression and stabilizing c-Myc. Moreover, c-Myc can induce the transcription of HMGA1 and TRIP13, suggesting that HMGA-TRIP13 axis promoted EMT and stemness in a positive feedback pathway dependent on c-Myc.
胆管癌是一种恶性程度很高的癌症，预后极差。肝门部胆管癌（pCCA）占所有胆管癌的 50%以上，其根治性切除率较低。pCCA 的放化疗效果非常有限。
我们采用转录组测序筛选 pCCA 的潜在生物标志物，并在包含 106 例患者的大型 pCCA 队列中评估 HMGA1 的预后意义。通过生物信息学和体外/体内实验，我们发现 HMGA1 通过促进 TRIP13 转录，诱导肿瘤细胞干性和上皮-间充质转化（EMT），从而促进增殖、迁移和侵袭。此外，TRIP13 也是 pCCA 的不利预后生物标志物，HMGA1/TRIP13 双高表达可更敏感地预测预后。TRIP13 通过抑制 FBXW7 转录和稳定 c-Myc 来促进 pCCA 的进展。c-Myc 反过来又诱导 HMGA1 和 TRIP13 的转录和表达，表明 HMGA-TRIP13 轴通过正向反馈通路促进 pCCA 的干性和 EMT。
HMGA1 和 TRIP13 是 pCCA 的不利预后生物标志物。HMGA1 通过诱导 TRIP13 表达、抑制 FBXW7 表达和稳定 c-Myc 增强 pCCA 的增殖、迁移、侵袭、干性和 EMT。此外，c-Myc 可以诱导 HMGA1 和 TRIP13 的转录，表明 HMGA-TRIP13 轴依赖于 c-Myc 以正向反馈通路促进 EMT 和干性。
