Cleaved CD44 intracellular domain supports activation of stemness factors and promotes tumorigenesis of breast cancer.
Cleaved CD44 intracellular domain supports activation of stemness factors and promotes tumorigenesis of breast cancer.
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DOI：
10.18632/oncotarget.3325
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发表时间：
2015-04-20
期刊：
影响因子：
--
通讯作者：
Chun KH
中科院分区：
文献类型：
--
作者：
Cho Y;Lee HW;Kang HG;Kim HY;Kim SJ;Chun KH
CD 44在肿瘤的进展中起作用，并在癌症干细胞（CSC）中表达。然而，CSC维持中CD 44与干性基因的串扰的潜在机制仍不清楚。在这项研究中，我们证明了CD 44的裂解细胞内结构域（CD 44 ICD）如何激活干性因子，如Nanog，Sox 2和Oct 4，并有助于乳腺癌的肿瘤发生。我们已经发现，CD 44 ICD的过表达增加了乳腺癌细胞中乳腺球的形成。γ-分泌酶抑制剂（GSI）可阻断CD 44 ICD的裂解，干扰乳腺球的形成。有趣的是，CD 44 ICD降低了干细胞因子的表达水平和核定位，但CD 44 ICD过表达逆转了这些作用。此外，我们发现，核定位的CD 44 ICD是重要的转录激活的干因子。此外，在小鼠模型中，CD 44 ICD过表达的细胞表现出较强的致瘤性和比对照细胞或CD 44耗尽的细胞更大的转移潜力。综上所述，推测CD 44通过其胞内结构域和干细胞因子的相互作用和核转位促进肿瘤发生。我们认为，阻止CD 44 ICD的裂解和核转位是治疗乳腺癌的一个潜在靶点。
CD44 plays a role in the progression of tumors and is expressed in cancer stem cells (CSCs). However, the mechanisms underlying the crosstalk of CD44 with stemness genes in CSC maintenance remains unclear. In this study, we demonstrated how the cleaved intracellular domain of CD44 (CD44ICD) activates stemness factors such as Nanog, Sox2 and Oct4, and contributes to the tumorigenesis of breast cancer. We have found that the overexpression of CD44ICD increased mammosphere formation in breast cancer cells. Treatment with a γ-secretase inhibitor (GSI), which blocks the cleavage of CD44ICD, interfered with mammosphere formation. Interestingly, CD44ICD decreased the expression levels and nuclear localization of stemness factors, but overexpression of CD44ICD reversed these effects. In addition, we showed that nuclear localization of CD44ICD is important for transcriptional activation of the stemness factors. Furthermore, CD44ICD-overexpressed cells exhibited strong tumorigenecity and greater metastatic potential than did the control cells or CD44-depleted cells in vivo in mice models. Taken together, it was supposed that CD44 promotes tumorigenesis through the interaction and nuclear-translocation of its intracellular domain and stemness factors. We suggest that the prevention of cleavage and nuclear-translocation of CD44ICD is a potential target in treating breast cancer.
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DOI：
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发表时间：
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期刊：
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影响因子：
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