ADAM17-mediated CD44 cleavage promotes orasphere formation or stemness and tumorigenesis in HNSCC.
ADAM17-mediated CD44 cleavage promotes orasphere formation or stemness and tumorigenesis in HNSCC.
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DOI：
10.1002/cam4.147
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发表时间：
2013-12
期刊：
影响因子：
4
通讯作者：
Kapila, Yvonne L.
中科院分区：
文献类型：
--
作者：
Kamarajan, Pachiyappan;Shin, Jae M.;Qian, Xu;Matte, Bibiana;Zhu, Joey Yizhou;Kapila, Yvonne L.
CD44是一种细胞外基质（ECM）受体，已被描述为多种癌症（包括头颈部鳞状细胞癌（HNSCC））中的癌症干细胞标志物。HNSCC orasphere形成或干性的特征在于CD44的切割，因此我们假设这种蛋白水解加工可能对干性和肿瘤发生至关重要。我们通过检查在体外和体内调节这一过程的机制，并通过探索其在人体标本中的临床相关性来验证这一假设。球体试验已用于体外评价干性。使用由HNSCC细胞组成的球体或orpheres和口腔癌小鼠模型，使用稳定的抑制和抑制方法来检查CD44切割的意义。这些机制也在HNSCC标本中进行了研究。与其粘附对应物相比，Oraspheres表现出增加的CD44切割水平。考虑到去整合素和金属蛋白酶结构域蛋白17（ADAM17）是已知切割CD44的主要基质金属蛋白酶，我们化学抑制并稳定抑制HNSCC细胞中的ADAM17表达，发现这些治疗阻断了CD44切割并消除了orasphere形成。此外，HNSCC细胞中的ADAM 17的稳定抑制也减少了口腔癌小鼠模型中的肿瘤发生。一致地，稳定抑制HNSCC细胞中的CD44废除orasphere形成并抑制体内肿瘤发生。在匹配的原发性和转移性人HNSCC标本中证实了这些发现的临床相关性，与对照组相比，这些标本显示出ADAM 17表达水平升高和伴随的CD 44裂解。ADAM17对CD44的切割对角膜球形成或干性和HNSCC肿瘤发生至关重要。
CD44, an extracellular matrix (ECM) receptor, has been described as a cancer stem cell marker in multiple cancers, including head and neck squamous cell carcinoma (HNSCC). HNSCC orasphere formation or stemness was characterized by cleavage of CD44, and thus we hypothesized that this proteolytic processing may be critical to stemness and tumorigenesis. We tested this hypothesis by examining the mechanisms that regulate this process in vitro and in vivo, and by exploring its clinical relevance in human specimens. Sphere assays have been used to evaluate stemness in vitro. Spheres comprised of HNSCC cells or oraspheres and an oral cancer mouse model were used to examine the significance of CD44 cleavage using stable suppression and inhibition approaches. These mechanisms were also examined in HNSCC specimens. Oraspheres exhibited increased levels of CD44 cleavage compared to their adherent counterparts. Given that disintegrin and metalloproteinase domain-containing protein 17 (ADAM17) is a major matrix metalloproteinase known to cleave CD44, we chemically inhibited and stably suppressed ADAM17 expression in HNSCC cells and found that these treatments blocked CD44 cleavage and abrogated orasphere formation. Furthermore, stable suppression of ADAM17 in HNSCC cells also diminished tumorigenesis in an oral cancer mouse model. Consistently, stable suppression of CD44 in HNSCC cells abrogated orasphere formation and inhibited tumorigenesis in vivo. The clinical relevance of these findings was confirmed in matched primary and metastatic human HNSCC specimens, which exhibited increased levels of ADAM17 expression and concomitant CD44 cleavage compared to controls. CD44 cleavage by ADAM17 is critical to orasphere formation or stemness and HNSCC tumorigenesis.
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影响因子：
3.8
作者：
Harper LJ;Costea DE;Gammon L;Fazil B;Biddle A;Mackenzie IC
通讯作者：
Mackenzie IC
DOI：
10.1186/1758-3284-1-27
发表时间：
2009-07-14
期刊：
Head & neck oncology
影响因子：
--
作者：
Han J;Kioi M;Chu WS;Kasperbauer JL;Strome SE;Puri RK
通讯作者：
Puri RK
DOI：
10.1186/bcr2106
发表时间：
2008
期刊：
Breast cancer research : BCR
影响因子：
--
作者：
Grimshaw MJ;Cooper L;Papazisis K;Coleman JA;Bohnenkamp HR;Chiapero-Stanke L;Taylor-Papadimitriou J;Burchell JM
通讯作者：
Burchell JM
影响因子：
11.2
作者：
Biddle, Adrian;Liang, Xiao;Mackenzie, Ian C.
通讯作者：
Mackenzie, Ian C.
影响因子：
5.2
作者：
Klingbeil, Pamela;Marhaba, Rachid;Zoeller, Margot
通讯作者：
Zoeller, Margot