Oncogenic effects of urotensin-II in cells lacking tuberous sclerosis complex-2.
Oncogenic effects of urotensin-II in cells lacking tuberous sclerosis complex-2.
复制标题
DOI：
10.18632/oncotarget.10748
复制
发表时间：
2016-09-20
期刊：
影响因子：
--
通讯作者：
Kristof AS
中科院分区：
文献类型：
--
作者：
Goldberg AA;Joung KB;Mansuri A;Kang Y;Echavarria R;Nikolajev L;Sun Y;Yu JJ;Laporte SA;Schwertani A;Kristof AS
淋巴管肌瘤病(LAM)是一种破坏性的肺部疾病，可以零星发生，也可以发生在患有肿瘤综合征结节性硬化症(TSC)的成年人身上。肺间质的微小肿瘤(‘LAM结节’)是由淋巴管的侵袭和转移引起的。这些细胞由平滑肌样细胞(LAM细胞)组成，这些细胞表现出神经脊分化的标志和肿瘤抑制蛋白结节硬化症复合体-2(TSC2)的丢失。与神经表型一致，在LAM结节中检测到神经肽Urotensin-II及其受体的表达。我们假设TSC2的缺失使细胞对尾加压素-II的致癌作用敏感。将TSC2基因缺失的Eker大鼠子宫肌瘤ELT3细胞稳定地转染空载体或表达TSC2的质粒。尾加压素-II促进TSC2缺陷细胞的细胞活力和增殖，但不能促进TSC2重组细胞。当暴露于尾加压素-II时，TSC2缺陷细胞表现出更大的迁移、不依赖锚定的细胞生长和基质侵袭。尾加压素-II对TSC2缺陷细胞的作用可被尾加压素受体拮抗剂SB657510阻断，并伴随ERK丝裂原活化蛋白激酶和粘着斑激酶的激活。尾加压素-II诱导的增殖和迁移在TSC2缺陷的人血管平滑肌脂肪瘤细胞中复制，但在那些稳定表达TSC2的细胞中不复制。在小鼠异种移植模型中，SB657510阻断了已建立的ELT3肿瘤的生长，减少了循环中的肿瘤细胞数量，并减弱了LAM的临床生物标志物--血管内皮生长因子-D的产生。尾加压素受体拮抗剂可能是治疗LAM或其他以TSC2缺失或尾加压素受体表达增加为特征的神经脊源性肿瘤的选择性治疗药物。
Lymphangioleiomyomatosis (LAM) is a destructive lung disease that can arise sporadically or in adults suffering from the tumor syndrome tuberous sclerosis complex (TSC). Microscopic tumors (‘LAM nodules’) in the lung interstitium arise from lymphatic invasion and metastasis. These consist of smooth muscle-like cells (LAM cells) that exhibit markers of neural crest differentiation and loss of the tumor suppressor protein ‘tuberous sclerosis complex-2’ (TSC2). Consistent with a neural phenotype, expression of the neuropeptide urotensin-II and its receptor was detected in LAM nodules. We hypothesized that loss of TSC2 sensitizes cells to the oncogenic effects of urotensin-II. TSC2-deficient Eker rat uterine leiomyoma ELT3 cells were stably transfected with empty vector or plasmid for the expression of TSC2. Urotensin-II increased cell viability and proliferation in TSC2-deficient cells, but not in TSC2-reconstituted cells. When exposed to urotensin-II, TSC2-deficient cells exhibited greater migration, anchorage-independent cell growth, and matrix invasion. The effects of urotensin-II on TSC2-deficient cells were blocked by the urotensin receptor antagonist SB657510, and accompanied by activation of Erk mitogen-activated protein kinase and focal adhesion kinase. Urotensin-II-induced proliferation and migration were reproduced in TSC2-deficient human angiomyolipoma cells, but not in those stably expressing TSC2. In a mouse xenograft model, SB657510 blocked the growth of established ELT3 tumors, reduced the number of circulating tumor cells, and attenuated the production of VEGF-D, a clinical biomarker of LAM. Urotensin receptor antagonists may be selective therapeutic agents for the treatment of LAM or other neural crest-derived neoplasms featuring loss of TSC2 or increased expression of the urotensin receptor.