MicroRNA miR-21 Regulates the Metastatic Behavior of B16 Melanoma Cells
MicroRNA miR-21 Regulates the Metastatic Behavior of B16 Melanoma Cells
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DOI：
10.1074/jbc.m111.285098
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发表时间：
2011-11-11
影响因子：
4.8
通讯作者：
Pfeffer, Lawrence M.
中科院分区：
文献类型：
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作者：
Yang, Chuan He;Yue, Junming;Pfeffer, Lawrence M.
MicroRNA-21（miR-21）在许多人类肿瘤中过表达，并与癌症中改变的各种细胞过程有关。miR-21也被许多炎症因子上调，包括IFN，考虑到炎症和癌症之间的密切关系，这是特别令人感兴趣的。由于miR-21似乎在人黑色素瘤中过表达，我们研究了miR-21在B16小鼠黑色素瘤细胞中癌症发展和转移中的作用。我们发现，miR-21是一个成员的干扰素诱导的miRNA的子集，需要STAT 3激活。为了表征miR-21在黑色素瘤行为中的作用，我们用编码miR-21基因组的慢病毒转导B16细胞，并分离miR-21敲低的B16细胞。miR-21敲除或IFN单独处理抑制体外B16细胞增殖和迁移，并且它们组合具有增强的效果。此外，miR-21敲低使B16细胞对IFN诱导的凋亡敏感。在B16细胞中，miR-21靶向肿瘤抑制蛋白（PTEN和PDCD 4）和抗增殖蛋白（BTG 2）。为了表征miR-21在体内的作用，通过尾静脉将空载体和miR-21转导的B16黑素瘤细胞注射到同基因C57 BL/6小鼠中。虽然空载体转导的B16细胞产生大的肺转移，但miR-21敲低的细胞仅形成小的肺病变。重要的是，与空载体荷瘤小鼠相比，miR-21敲低荷瘤小鼠的存活时间延长。因此，miR-21通过促进细胞增殖、存活和迁移/侵袭以及通过抑制IFN作用来调节B16黑素瘤细胞的转移行为，为miR-21在黑素瘤中的作用提供了重要的新见解。
MicroRNA-21 (miR-21) is overexpressed in many human tumors and has been linked to various cellular processes altered in cancer. miR-21 is also up-regulated by a number of inflammatory agents, including IFN, which is of particular interest considering the close relationship between inflammation and cancer. Because miR-21 appears to be overexpressed in human melanoma, we examined the role of miR-21 in cancer development and metastasis in B16 mouse melanoma cells. We found that miR-21 is a member of an IFN-induced miRNA subset that requires STAT3 activation. To characterize the role of miR-21 in melanoma behavior, we transduced B16 cells with lentivirus encoding a miR-21 antagomir and isolated miR-21 knockdown B16 cells. miR-21 knockdown or IFN treatment alone inhibited B16 cell proliferation and migration in vitro, and in combination they had an enhanced effect. Moreover, miR-21 knockdown sensitized B16 cells to IFN-induced apoptosis. In B16 cells miR-21 targeted tumor suppressor (PTEN and PDCD4) and antiproliferative (BTG2) proteins. To characterize the role of miR-21 in vivo, empty vector- and antagomiR-21-transduced B16 melanoma cells were injected via tail vein into syngeneic C57BL/6 mice. Although empty vector-transduced B16 cells produced large lung metastases, miR-21 knockdown cells only formed small lung lesions. Importantly, miR-21 knockdown tumor-bearing mice exhibited prolonged survival compared with empty vector tumor-bearing mice. Thus, miR-21 regulates the metastatic behavior of B16 melanoma cells by promoting cell proliferation, survival, and migration/invasion as well as by suppressing IFN action, providing important new insights into the role of miR-21 in melanoma.