Inhibitor of DNA Binding 4 (ID4) is highly expressed in human melanoma tissues and may function to restrict normal differentiation of melanoma cells.
Inhibitor of DNA Binding 4 (ID4) is highly expressed in human melanoma tissues and may function to restrict normal differentiation of melanoma cells.
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DOI：
10.1371/journal.pone.0116839
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Katz RA
中科院分区：
文献类型：
--
作者：
Peretz Y;Wu H;Patel S;Bellacosa A;Katz RA
黑色素瘤组织和细胞系是异质的，并且包括具有侵袭性、增殖性、干细胞样和分化性质的细胞。这种异质性可能导致疾病的侵袭性和对治疗的抗性。一种模型表明，异质性来自产生不同癌细胞谱系的罕见癌症干细胞（CSC）。另一个模型表明，异质性是通过可逆的细胞可塑性或表型转换产生的。最近的研究表明，表型转换可能包括癌细胞去分化为干细胞样状态的能力。我们着手研究黑色素瘤细胞的表型转换能力，并使用无偏的方法来识别可能控制这种转换的基因。我们开发了一个系统，以可逆地同步黑色素瘤细胞之间的二维单层和三维干细胞样生长状态。保持在干细胞样状态的黑色素瘤细胞显示出与发育和神经干细胞生物学相关的基因集的显著上调，所述基因集包括SRY盒2（SOX 2）和DNA结合抑制剂4（ID4）。与癌细胞运动性和侵袭性相关的基因组伴随下调。在人黑色素瘤组织样品中检测到强烈和普遍的ID4蛋白表达，表明该蛋白与疾病相关。ID4的SiRNA敲低抑制了从单层到3D干细胞样生长的转换，而是促进了向高度分化的神经元样形态的转换。我们认为，ID4在黑色素瘤中上调，作为促进进一步适应性可塑性的干细胞样程序的一部分。ID4可能通过阻止干细胞样黑色素瘤细胞进展到正常分化状态而导致疾病。这种解释是由ID4在正常发育过程中作为分化抑制剂的已知作用指导的。黑色素瘤干细胞样状态可能受到诸如ID4的因子的保护，从而潜在地鉴定新的治疗脆弱性以驱动分化为正常细胞表型。
Melanoma tissues and cell lines are heterogeneous, and include cells with invasive, proliferative, stem cell-like, and differentiated properties. Such heterogeneity likely contributes to the aggressiveness of the disease and resistance to therapy. One model suggests that heterogeneity arises from rare cancer stem cells (CSCs) that produce distinct cancer cell lineages. Another model suggests that heterogeneity arises through reversible cellular plasticity, or phenotype-switching. Recent work indicates that phenotype-switching may include the ability of cancer cells to dedifferentiate to a stem cell-like state. We set out to investigate the phenotype-switching capabilities of melanoma cells, and used unbiased methods to identify genes that may control such switching. We developed a system to reversibly synchronize melanoma cells between 2D-monolayer and 3D-stem cell-like growth states. Melanoma cells maintained in the stem cell-like state showed a striking upregulation of a gene set related to development and neural stem cell biology, which included SRY-box 2 (SOX2) and Inhibitor of DNA Binding 4 (ID4). A gene set related to cancer cell motility and invasiveness was concomitantly downregulated. Intense and pervasive ID4 protein expression was detected in human melanoma tissue samples, suggesting disease relevance for this protein. SiRNA knockdown of ID4 inhibited switching from monolayer to 3D-stem cell-like growth, and instead promoted switching to a highly differentiated, neuronal-like morphology. We suggest that ID4 is upregulated in melanoma as part of a stem cell-like program that facilitates further adaptive plasticity. ID4 may contribute to disease by preventing stem cell-like melanoma cells from progressing to a normal differentiated state. This interpretation is guided by the known role of ID4 as a differentiation inhibitor during normal development. The melanoma stem cell-like state may be protected by factors such as ID4, thereby potentially identifying a new therapeutic vulnerability to drive differentiation to the normal cell phenotype.
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影响因子：
4.7
作者：
Hong, Sunghoi;Kang, Un Jung;Kim, Kwang-Soo
通讯作者：
Kim, Kwang-Soo
影响因子：
6.5
作者：
Flammiger, Anna;Besch, Robert;Berking, Carola
通讯作者：
Berking, Carola
影响因子：
4.3
作者：
Bailey, Caleb M.;Morrison, Jason A.;Kulesa, Paul M.
通讯作者：
Kulesa, Paul M.
影响因子：
64.8
作者：
通讯作者：
--
DOI：
10.1073/pnas.73.9.3278
发表时间：
1976-01-01
影响因子：
11.1
作者：
CAREY, TE;TAKAHASHI, T;OLD, LJ
通讯作者：
OLD, LJ