SMURF1 silencing diminishes a CD44-high cancer stem cell-like population in head and neck squamous cell carcinoma.
SMURF1 silencing diminishes a CD44-high cancer stem cell-like population in head and neck squamous cell carcinoma.
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DOI：
10.1186/1476-4598-13-260
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发表时间：
2014-12-03
期刊：
影响因子：
37.3
通讯作者：
Dickerson EB
中科院分区：
文献类型：
--
作者：
Khammanivong A;Gopalakrishnan R;Dickerson EB
骨形态发生蛋白（BMP）信号被认为在调节癌症干细胞（CSCs）的存活和维持中发挥关键作用，这有助于许多恶性肿瘤的疾病复发和治疗失败，包括头颈部鳞状细胞癌（HNSCC）。细胞内BMP信号在细胞发育过程中受SMAD特异性E3泛素蛋白连接酶1 （SMURF1）的调控。然而，关于BMP信号在HNSCC csc中的作用和调控知之甚少。从HNSCC细胞系中富集CD44high/BMI1high和CD44high/ALDHhigh两个csc样群体，并通过qRT-PCR、流式细胞术和免疫印迹技术评估SMURF1的表达。通过免疫印迹法检测磷酸化的SMAD1/5/8 （pSMAD1/5/8）水平，确定这些群体中BMP信号的激活状态。通过RNA干扰敲低SMURF1转录本来评估SMURF1在BMP信号传导和CSC维持中的作用。SMURF1敲除后csc样表型的丧失是由cd44高水平、细胞分化和集落形成减少的变化决定的。与非csc群体相比，富集的csc样细胞群体显示pSMAD1/5/8和BMP信号靶基因ID1水平降低，而SMURF1、CD44和BMI1表达水平高。在csc样细胞中稳定敲低SMURF1的表达增加了pSMAD1/5/8蛋白水平，表明BMP信号通路的再激活。在三维培养实验中，SMURF1表达的降低也促进了成脂分化和集落形成的减少，表明其致瘤能力的丧失。SMURF1敲低细胞中cd44高表达亚群的缺失证实了SMURF1和BMP信号传导抑制在维持csc样细胞群中的作用。我们的研究结果表明，抑制BMP信号可以增强HNSCC csc的长期存活，并且这种抑制是由SMURF1介导的。靶向SMURF1并恢复BMP信号可能为促进CSC群体分化和减少从而减少耐药性和疾病复发提供新的治疗途径。本文的在线版本（doi:10.1186/1476-4598-13-260）包含补充材料，可供授权用户使用。
Bone morphogenetic protein (BMP) signaling is thought to play key roles in regulating the survival and maintenance of cancer stem cells (CSCs), which contribute to disease recurrences and treatment failures in many malignances, including head and neck squamous cell carcinoma (HNSCC). Intracellular BMP signaling is regulated by SMAD specific E3 ubiquitin protein ligase 1 (SMURF1) during cellular development. However, little is known about the role or regulation of BMP signaling in HNSCC CSCs. Two CSC-like populations, CD44high/BMI1high and CD44high/ALDHhigh, were enriched from HNSCC cell lines and evaluated for the expression of SMURF1 by qRT-PCR, flow cytometry, and immunoblotting. The activation status of BMP signaling in these populations was determined by using immunoblotting to detect phosphorylated SMAD1/5/8 (pSMAD1/5/8) levels. Knockdown of SMURF1 transcripts by RNA interference was used to assess the role of SMURF1 in BMP signaling and CSC maintenance. Loss of CSC-like phenotypes following SMURF1 knockdown was determined by changes in CD44high levels, cellular differentiation, and reduction in colony formation. Populations of enriched CSC-like cells displayed decreased levels of pSMAD1/5/8 and BMP signaling target gene ID1 while SMURF1, CD44, and BMI1 were highly expressed when compared to non-CSC populations. Stable knockdown of SMURF1 expression in CSC-like cells increased pSMAD1/5/8 protein levels, indicating the reactivation of BMP signaling pathways. Decreased expression of SMURF1 also promoted adipogenic differentiation and reduced colony formation in a three-dimensional culture assay, indicating loss of tumorigenic capacity. The role of SMURF1 and inhibition of BMP signaling in maintaining a CSC-like population was confirmed by the loss of a CD44high expressing subpopulation in SMURF1 knockdown cells. Our findings suggest that inhibition of BMP signaling potentiates the long-term survival of HNSCC CSCs, and that this inhibition is mediated by SMURF1. Targeting SMURF1 and restoring BMP signaling may offer a new therapeutic approach to promote differentiation and reduction of CSC populations leading to reduced drug resistance and disease recurrence. The online version of this article (doi:10.1186/1476-4598-13-260) contains supplementary material, which is available to authorized users.
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头颈鳞状细胞癌细胞系中顺铂敏感性和 18F 氟-2-脱氧 2 葡萄糖摄取与增殖参数和基因表达的比较。
DOI：
10.1186/1756-9966-28-17
发表时间：
2009-02-13
期刊：
Journal of experimental & clinical cancer research : CR
影响因子：
--
作者：
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DOI：
10.1002/hed.23600
发表时间：
2015-03
影响因子：
2.9
作者：
Chinn, Steven B.;Darr, Owen A.;Owen, John H.;Bellile, Emily;McHugh, Jonathan B.;Spector, Matthew E.;Papagerakis, Silvana M.;Chepeha, Douglas B.;Bradford, Carol R.;Carey, Thomas E.;Prince, Mark E. P.
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影响因子：
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作者：
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影响因子：
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作者：
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