Type III transforming growth factor-beta (TGF-beta) receptor mediates apoptosis in renal cell carcinoma independent of the canonical TGF-beta signaling pathway.
Type III transforming growth factor-beta (TGF-beta) receptor mediates apoptosis in renal cell carcinoma independent of the canonical TGF-beta signaling pathway.
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III 型转化生长因子-β (TGF-β) 受体介导肾细胞癌细胞凋亡，不依赖于经典的 TGF-β 信号通路。
DOI：
10.1158/1078-0432.ccr-08-0546
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发表时间：
2008-09-15
期刊：
影响因子：
--
通讯作者：
Wood CG
中科院分区：
文献类型：
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作者：
Margulis V;Maity T;Zhang XY;Cooper SJ;Copland JA;Wood CG
转化生长因子-β（TGF-β）信号传导的改变在肾上皮细胞恶性转化的早期发生，并且与III型TGF-β受体（TβRIII）表达的丧失相关。我们使用体外细胞培养和体内肾透明细胞癌动物模型评价了TβRIII在介导细胞凋亡中的作用。采用腺病毒基因载体系统在体内外调控TβR3的表达。在感染后的不同时间点，通过Smad和丝裂原活化蛋白激酶（MAPK）途径检测细胞凋亡和信号传导的诱导。为了研究体内病毒溶瘤作用，皮下植入人肾细胞癌细胞在裸鼠的侧腹中，并通过瘤内注射腺病毒进行治疗。在体外细胞培养和体内动物模型中，恢复透明细胞肾细胞癌中TβRIII的表达可显著诱导细胞凋亡。TβRIII的胞质结构域而非胞外域的表达模拟了全长TβRIII在细胞培养中诱导的凋亡和无胸腺裸鼠中肿瘤的生长抑制。Tβ RIII相关的凋亡不依赖于经典的TGF-β/Smad信号通路，而是通过p38 MAPK介导的。这些发现提示T βRIII具有新的抗肿瘤作用机制，进一步支持其作为肾透明细胞癌重要的抑癌因子的作用。
Alterations in transforming growth factor-β (TGF-β) signaling occur early during malignant transformation of renal epithelial cells and are associated with loss of type III TGF-β receptor (TβRIII) expression. We evaluated the role of TβRIII in mediation of apoptosis using in vitro cell culture and in vivo animal models of clear cell renal cell carcinoma. TβR3 expression was manipulated with adenoviral gene vector delivery system in vitro and in vivo. Induction of apoptosis and signaling through the Smad and mitogen-activated protein kinase (MAPK) pathways were examined at various time points after infection. To study viral oncolysis in vivo, human renal cell carcinoma cells were implanted s.c. in the flanks of nude mice and treated with intratumoral injections of adenovirus. Restoring TβRIII expression in clear cell renal cell carcinoma resulted in a marked induction of apoptosis using in vitro cell culture and in vivo animal models. The expression of the cytoplasmic domain, but not the extracellular domain, of TβRIII mimicked the induction of apoptosis by full-length TβRIII in cell culture and the growth inhibition of tumors in athymic nude mice. TβRIII-associated apoptosis was not dependent on signaling through the canonical TGF-β/Smad pathway but was mediated through p38 MAPK. These findings indicate a novel mechanistic antitumor function forTβRIII and further support its role as an important tumor suppressor in clear cell renal cell carcinoma.