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裂解的CD44细胞内结构域支持干性因子的激活并促进乳腺癌的肿瘤发生。

Cleaved CD44 intracellular domain supports activation of stemness factors and promotes tumorigenesis of breast cancer.

作者信息

Cho Yunhee, Lee Hyun-Woo, Kang Hyeok-Gu, Kim Hye-Young, Kim Seok-Jun, Chun Kyung-Hee

机构信息

Department of Biochemistry & Molecular Biology, Yonsei University College of Medicine, Seodaemun-gu, Seoul 120-752, Korea.

Brain Korea 21 Plus Project for Medical Science, Yonsei University, Seodaemun-gu, Seoul 120-752, Korea.

出版信息

Oncotarget. 2015 Apr 20;6(11):8709-21. doi: 10.18632/oncotarget.3325.

DOI:10.18632/oncotarget.3325
PMID:25909162
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC4496178/
Abstract

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.

摘要

CD44在肿瘤进展中发挥作用，并在癌症干细胞（CSC）中表达。然而，CD44与CSC维持中的干性基因相互作用的潜在机制仍不清楚。在本研究中，我们证明了CD44的裂解细胞内结构域（CD44ICD）如何激活如Nanog、Sox2和Oct4等干性因子，并促进乳腺癌的肿瘤发生。我们发现CD44ICD的过表达增加了乳腺癌细胞中乳腺球的形成。用γ-分泌酶抑制剂（GSI）处理可阻断CD44ICD的裂解，从而干扰乳腺球的形成。有趣的是，CD44ICD降低了干性因子的表达水平和核定位，但CD44ICD的过表达逆转了这些效应。此外，我们表明CD44ICD的核定位对于干性因子的转录激活很重要。此外，在小鼠模型体内，与对照细胞或CD44缺失的细胞相比，过表达CD44ICD的细胞表现出更强的肿瘤发生能力和更大的转移潜能。综上所述，推测CD44通过其细胞内结构域与干性因子的相互作用和核转位促进肿瘤发生。我们认为，防止CD44ICD的裂解和核转位是治疗乳腺癌的一个潜在靶点。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/21e2/4496178/ce7e11d5ad52/oncotarget-06-8709-g007.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/21e2/4496178/7fa0910f8c0c/oncotarget-06-8709-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/21e2/4496178/ff56005791a0/oncotarget-06-8709-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/21e2/4496178/ce7e11d5ad52/oncotarget-06-8709-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/21e2/4496178/d983ea4eda2e/oncotarget-06-8709-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/21e2/4496178/fafe6961564e/oncotarget-06-8709-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/21e2/4496178/c73c618c422e/oncotarget-06-8709-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/21e2/4496178/aa367cbd84c5/oncotarget-06-8709-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/21e2/4496178/7fa0910f8c0c/oncotarget-06-8709-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/21e2/4496178/ff56005791a0/oncotarget-06-8709-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/21e2/4496178/ce7e11d5ad52/oncotarget-06-8709-g007.jpg

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