The oncoprotein HBXIP upregulates Lin28B via activating TF II D to promote proliferation of breast cancer cells
The oncoprotein HBXIP upregulates Lin28B via activating TF II D to promote proliferation of breast cancer cells
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癌蛋白 HBXIP 通过激活 TF II D 上调 Lin28B 促进乳腺癌细胞增殖
DOI：
10.1002/ijc.28154
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发表时间：
2013-09-15
影响因子：
6.4
通讯作者：
Ye, Lihong
中科院分区：
文献类型：
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作者：
Liu, Qian;Bai, Xiao;Ye, Lihong
B型肝炎病毒X相互作用蛋白（HBXIP）是一种新的癌蛋白，在乳腺癌的发生发展中起着关键作用。然而，其作用机制知之甚少。Lin 28 B在多种人类癌症中作为癌基因发挥作用。在我们的研究中，我们报告了HBXIP与其伴侣Lin 28 B一起作用，以促进致癌作用。我们的数据显示，HBXIP和Lin 28 B在临床乳腺癌组织中的表达水平显著正相关。然后，我们发现HBXIP能够上调乳腺癌MCF-7细胞中的Lin 28 B。染色质免疫沉淀法（ChIP）和电泳迁移率变动法（EMSA）分析表明HBXIP位于Lin 28 B启动子区（-1199/-1073 nt）。重要的是，免疫共沉淀（Co-IP）和GST下拉试验验证了HBXIP直接结合TATA结合蛋白（TBP），转录因子TF II D复合物的基础亚基。此外，我们发现Lin 28 B可以通过抑制细胞中直接靶向HBXIP mRNA的miR-520 b来阻断HBXIP的下调。在功能上，我们证明HBXIP通过Lin 28 B在体外和体内增强乳腺癌细胞的增殖。结论：癌蛋白HBXIP作为TF II D的共激活因子，通过与TBP直接结合，反式激活Lin 28 B启动子，上调Lin 28 B的表达，促进乳腺癌细胞增殖，其中Lin 28 B通过反馈抑制miR-520 b，维持HBXIP的高水平。在治疗上，HBXIP可以作为乳腺癌的靶点。一种能刺激乳腺癌的蛋白质是B型肝炎X相互作用蛋白，或HBXIP。在这篇论文中，作者报告说，HBXIP促进了另一种蛋白质Lin 28 B的表达，这也有助于推动癌症进展。Lin 28 B通过抑制microRNA，miR-520 b，从而抑制HBXIP表达来回报。因此，Lin 28 B有助于保持HBXIP水平高，HBXIP通过上调Lin 28 B促进致癌作用，表明HBXIP可以成为治疗乳腺癌的良好治疗靶点。
Hepatitis B X-interacting protein (HBXIP) is a novel oncoprotein and plays a key role in the development of breast cancer. However, its mechanisms of action are poorly understood. Lin28B functions as an oncogene in a variety of human cancers. In our study, we report that HBXIP acts with its partner Lin28B to contribute to carcinogenesis. Our data showed that the expression levels of HBXIP were significantly positively correlated with those of Lin28B in clinical breast cancer tissues. Then, we found that HBXIP was able to upregulate Lin28B in breast cancer MCF-7 cells. Chromatin immunoprecipitation assay (ChIP) and electrophoretic mobility shift assay (EMSA) revealed that HBXIP occupied the promoter region (-1199/-1073 nt) of Lin28B. Importantly, co-immunoprecipitation (Co-IP) and GST pull-down assay validated that HBXIP directly bound to the TATA-binding protein (TBP), a basal subunit of transcription factor TF II D complex. In addition, we discovered that Lin28B could block the downregulation of HBXIP via suppressing miR-520b which directly targeted HBXIP mRNA in the cells. In function, we demonstrated that HBXIP enhanced the proliferation of breast cancer cells through Lin28B in vitro and in vivo. Thus, we conclude that the oncoprotein HBXIP as a co-activator of TF II D transactivates Lin28B promoter via directly binding to TBP to upregulate the expression of Lin28B in promotion of proliferation of breast cancer cells, in which Lin28B maintains the high level of HBXIP through suppressing miR-520b in a feedback manner. Therapeutically, HBXIP may serve as a target of breast cancer.What's new?One protein that can spur on breast cancer is hepatitis B X-interacting protein, or HBXIP. In this paper, the authors report that HBXIP boosts expression of another protein, Lin28B, which also helps drive cancer progression. Lin28B returns the favor by suppressing a microRNA, miR-520b, which inhibits HBXIP expression. Thus Lin28B helps keep HBXIP levels high, and HBXIP promotes carcinogenesis by upregulating Lin28B, suggesting HBXIP could make a good therapeutic target for treating breast cancer.