Department of General Surgery, Qilu Hospital, Cheeloo College of Medicine, Shandong University, 107 Wenhuaxi Road, Jinan, 250012, Shandong, China.
Department of Hepatobiliary Surgery, Shandong Provincial Third Hospital, Cheeloo College of Medicine, Shandong University, 11 Wuyingshan Middle Road, Jinan, 250031, Shandong, China.
Cell Mol Life Sci. 2022 Aug 6;79(9):469. doi: 10.1007/s00018-022-04500-1.
Cholangiocarcinoma (CCA) is a class of malignant tumors originating from bile duct epithelial cells. Due to difficult early diagnosis and limited treatment, the prognosis of CCA is extremely poor. BMI1 is dysregulated in many human malignancies. However, the prognostic significance and oncogenic role of BMI1 in cholangiocarcinoma (CCA) are not well elucidated.
In the present study, we investigated its clinical importance and the potential mechanisms in the progression of CCA. We detected BMI1 expression in a large CCA cohort. We demonstrated that BMI1 was substantially upregulated in CCA tissues and was identified as an independent prognostic biomarker of CCA. Moreover, overexpression of BMI1 promoted CCA proliferation, migration, and invasion. And BMI1 knockdown could inhibit proliferation and metastases of CCA in vitro and in vitro/vivo validation. Interestingly, we found that CCA-derived exosomes contain BMI1 proteins, which can transfer BMI1 between CCA cells. The unique BMI1-containing exosomes promote CCA proliferation and metastasis through autocrine/paracrine mechanisms. In addition, we demonstrated that BMI1 inhibits CD8T cell-recruiting chemokines by promoting repressive H2A ubiquitination in CCA cells.
BMI1 is an unfavorable prognostic biomarker of CCA. Our data depict a novel function of BMI1 in CCA tumorigenesis and metastasis mediated by exosomes. Besides, BMI1 inhibition may augment immune checkpoint blockade to inhibit tumor progression by activating cell-intrinsic immunity of CCA.
胆管癌（CCA）是一类起源于胆管上皮细胞的恶性肿瘤。由于早期诊断困难和治疗手段有限，CCA 的预后极差。BMI1 在许多人类恶性肿瘤中失调。然而，BMI1 在胆管癌（CCA）中的预后意义和致癌作用尚不清楚。
在本研究中，我们研究了其在 CCA 进展中的临床重要性和潜在机制。我们检测了大 CCA 队列中的 BMI1 表达。结果表明，BMI1 在 CCA 组织中大量上调，并且被鉴定为 CCA 的独立预后生物标志物。此外，BMI1 的过表达促进了 CCA 的增殖、迁移和侵袭。并且 BMI1 的敲低可抑制 CCA 在体外和体内/体外的增殖和转移。有趣的是，我们发现 CCA 衍生的外体含有 BMI1 蛋白，可在 CCA 细胞之间转移 BMI1。独特的含有 BMI1 的外体通过自分泌/旁分泌机制促进 CCA 的增殖和转移。此外，我们证明 BMI1 通过促进 CCA 细胞中抑制性 H2A 泛素化来抑制 CD8T 细胞募集趋化因子。
BMI1 是 CCA 的不利预后生物标志物。我们的数据描绘了 BMI1 在 CCA 肿瘤发生和转移中的新功能，外体介导。此外，通过激活 CCA 的细胞内在免疫，BMI1 抑制可能增强免疫检查点阻断以抑制肿瘤进展。
