Combined CSL and p53 downregulation promotes cancer-associated fibroblast activation.
Combined CSL and p53 downregulation promotes cancer-associated fibroblast activation.
复制标题
DOI：
10.1038/ncb3228
复制
发表时间：
2015-09
影响因子：
21.3
通讯作者：
Dotto GP
中科院分区：
文献类型：
--
作者：
Procopio MG;Laszlo C;Al Labban D;Kim DE;Bordignon P;Jo SH;Goruppi S;Menietti E;Ostano P;Ala U;Provero P;Hoetzenecker W;Neel V;Kilarski WW;Swartz MA;Brisken C;Lefort K;Dotto GP
间质成纤维细胞衰老与衰老相关的癌症风险有关。然而，肿瘤相关成纤维细胞(CAF)的密度和增殖经常增加。在真皮成纤维细胞中，Notch效应分子Csl/RBP-Jκ的缺失或下调足以导致CAF激活和随后的角质形成细胞来源的肿瘤。我们报道CSL沉默诱导真皮、口腔粘膜、乳腺和肺的原代成纤维细胞衰老。CSL在这些细胞中作为多个衰老效应基因和CAF效应基因的直接抑制因子发挥作用。它还与p53在物理上相互作用，抑制其活性。CSL在癌前皮肤光化性角化病和鳞状细胞癌的间质成纤维细胞中表达下调，而p53的表达和功能仅在后者中下调，旁分泌的成纤维细胞生长因子信号可能是罪魁祸首。随之而来的CSL和P53的丢失克服了成纤维细胞的衰老，增强了CAF效应分子的表达，促进了间质和癌细胞的扩张。这一发现支持CSL/P53趋同控制下的CAF激活/基质协同进化模型。
Stromal fibroblast senescence has been linked to aging-associated cancer risk. However, density and proliferation of cancer-associated fibroblasts (CAF) are frequently increased. Loss or down-modulation of the Notch effector CSL/RBP-Jκ in dermal fibroblasts is sufficient for CAF activation and ensuing keratinocyte-derived tumors. We report that CSL silencing induces senescence of primary fibroblasts from dermis, oral mucosa, breast and lung. CSL functions in these cells as direct repressor of multiple senescence- and CAF-effector genes. It also physically interacts with p53, repressing its activity. CSL is down-modulated in stromal fibroblasts of premalignant skin actinic keratosis lesions and squamous cell carcinomas (SCC), while p53 expression and function is down-modulated only in the latter, with paracrine FGF signaling as likely culprit. Concomitant loss of CSL and p53 overcomes fibroblast senescence, enhances expression of CAF effectors and promotes stromal and cancer cell expansion. The findings support a CAF activation/stromal co-evolution model under convergent CSL/p53 control.