Notch Signaling Suppresses Melanoma Tumor Development in BRAF/Pten Mice.
Notch Signaling Suppresses Melanoma Tumor Development in BRAF/Pten Mice.
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Notch信号抑制BRAF/Pten小鼠黑色素瘤的发展。
作者：
现在人们普遍认识到，皮肤黑色素瘤的发生需要致癌基因和抑癌基因的改变。尽管Notch信号传导与黑色素瘤生物学的许多方面有关，但Notch基因在黑色素瘤发生中的确切作用尚不完全清楚。我们利用 BRAFCA/Pten-/- 小鼠（一种广泛使用的黑色素瘤遗传小鼠模型）着手研究 Notch 基因在黑色素瘤发生中的作用。此外，通过对临床注释的人原发性黑色素瘤组织微阵列进行定量免疫组织化学分析，我们询问肿瘤中存在的 NOTCH 蛋白的量是否与通过患者转移性疾病的发展来测量的肿瘤侵袭性相关。我们的数据表明，与 Pten 不同，Notch1 和 Notch2 基因不具有抑癌基因的功能。即，Notch1 或 Notch 2 或两者的缺失不能在 BRAFCA 小鼠中诱发黑色素瘤。然而，Notch1 或 Notch2 的缺失加速了黑色素瘤的生成。一旦黑色素瘤开始形成，人类黑色素瘤中表达的 NOTCH 蛋白量似乎并不能可靠地预测黑色素瘤的侵袭性。因此，识别和靶向Notch调节的信号通路可能是预防黑色素瘤的有效策略。黑色素瘤中的 Notch 信号传导既具有致癌作用，又具有抑癌作用。在临床试验中，Notch抑制剂被证明对黑色素瘤治疗无效。 Notch信号传导也与黑色素瘤转分化有关，这是原发性黑色素瘤的预后特征。在本研究中，我们通过将 BRAFCA/+/Pten+/+/Tyr-CreER+ (B) 和 BRAFCA/+/Pten-/-/Tyr-CreER + (BP) 小鼠与 Notch1 或 Notch2 floxed 等位基因小鼠杂交，利用小鼠黑色素瘤遗传模型研究了 Notch 信号在黑色素瘤肿瘤发生和生长中的作用。局部应用他莫昔芬可在 BP 小鼠中诱导肿瘤，但在缺失或未缺失 Notch1 或 Notch2 的 B 小鼠中不会诱导肿瘤。这些数据表明，Notch1 或 Notch2 的缺失可以替代 Pten 在 BRAFV600E 诱导的黑色素瘤发生中的肿瘤抑制功能。然而，在 Pten 缺失的背景下，Notch1 或 Notch2 的缺失似乎会加速 BRAFV600E 诱导的肿瘤发展，表明 Notch1 和 Notch2 在 BRAFV600E/Pten 缺失驱动的黑色素瘤发生中具有肿瘤抑制作用。对由超过 100 个具有完整临床病史的原发性肿瘤组成的人皮肤黑色素瘤组织微阵列进行的定量免疫化学分析显示，NOTCH 蛋白水平与临床和病理参数之间存在弱至中度相关性。我们的数据表明，Notch 信号传导参与黑色素瘤发生过程，并表明识别 Notch 下游的基因和信号传导途径有助于制定黑色素瘤预防策略。
It is now well recognized that alterations in both oncogenic and tumor suppressor genes are required for cutaneous melanoma tumorigenesis. Although Notch signaling has been implicated in many aspects of melanoma biology, the exact role Notch genes play in melanomagenesis is not completely understood. Employing BRAFCA/Pten-/- mice, a widely used genetic mouse model of melanoma, we set out to investigate the role of Notch genes in melanomagenesis. Furthermore, using a quantitative immunohistochemical analysis of a clinically annotated human primary melanoma tissue microarray, we asked whether the amount of NOTCH proteins present in the tumor correlate with the aggressiveness of the tumor as measured by the development of metastatic disease in patients. Our data show that Notch1 and Notch2 genes do not function as tumor suppressor genes, unlike Pten, i. e., the loss of Notch1 or Notch 2 or both fail to induce melanoma in BRAFCA mice. However, the loss of Notch1 or Notch2 accelerated melanomagenesis. Once the melanoma tumor is initiated, the amount of NOTCH protein expressed in human melanoma does not appear to reliably predict melanoma aggressiveness. Therefore, identifying and targeting signaling pathways regulated by Notch may be a useful strategy for melanoma prevention. Both oncogenic and tumor suppressor roles have been assigned to Notch signaling in melanoma. In clinical trials, Notch inhibitors proved to be ineffective for melanoma treatment. Notch signaling has also been implicated in melanoma transdifferentiation, a prognostic feature in primary melanoma. In this study, we investigated the role of Notch signaling in melanoma tumor development and growth using the genetic model of mouse melanoma by crossing BRAFCA/+/Pten+/+/Tyr-CreER+ (B) and BRAFCA/+/Pten-/-/Tyr-CreER + (BP) mice with Notch1 or Notch2 floxed allele mice. The topical application of tamoxifen induced tumors in BP mice but not in B mice with or without the deletion of either Notch1 or Notch2. These data show that the loss of either Notch1 nor Notch2 can substitute the tumor suppressor function of Pten in BRAFV600E-induced melanomagenesis. However, in Pten-null background, the loss of either Notch1 or Notch2 appeared to accelerate BRAFV600E-induced tumor development, suggesting a tumor suppressor role for Notch1 and Notch2 in BRAFV600E/Pten-null driven melanomagenesis. Quantitative immunochemical analysis of a human cutaneous melanoma tissue microarray that consists of >100 primary tumors with complete clinical history showed a weak to moderate correlation between NOTCH protein levels and clinical and pathological parameters. Our data show that Notch signaling is involved during melanomagenesis and suggest that the identification of genes and signaling pathways downstream of Notch could help devise strategies for melanoma prevention.
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Notch配体Delta-like 1通过增强肿瘤粘附促进黑色素瘤转移
DOI：
10.1590/1414-431x20143368
发表时间：
2014-04
期刊：
Brazilian journal of medical and biological research = Revista brasileira de pesquisas medicas e biologicas
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11.2
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15.9
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