Shinohara Shogo, Rothstein Jay L
Department of Microbiology/Immunology, Kimmel Cancer Institute, Thomas Jefferson University, Philadelphia, PA 19107, USA.
Oncogene. 2004 Sep 30;23(45):7571-9. doi: 10.1038/sj.onc.1207964.
Thyroid cancers, like hematological malignancies, are commonly associated with chromosomal translocations leading to the formation of fusion proteins. Through altered signaling by fusion proteins, cell death and survival pathways are disrupted and the physiological balance of cell-cell communication may be lost. A consequence of this disruption is the release of factors by stressed cells that alert the host. One type of host response is leukocytic infiltration that may develop into chronic inflammation or autoimmune disease. Although inflammation can be associated with neoplastic tissue, the mechanism driving this process is largely unknown. Therefore, to address the mechanism of cancer inflammation we investigated the effects of an oncogene in a murine model system. A comprehensive genetic analysis revealed several soluble factors that were induced by RET/papillary thyroid carcinoma (PTC)3 gene expression including several proinflammatory cytokines, chemokines and immunologically relevant costimulatory molecules. Following a large genetic screen using RP3-expressing thyroid cells, we identified a highly abundant transcript and later identified it as interleukin 24 (Il24), a cytokine with diverse tumor suppressor and inflammatory activities. We show that RET/PTC3 induces Il24 expression in rat thyrocytes and that this expression is dependent on the signaling properties of its tyrosine kinase. Likewise, RET/PTC3 induces large amounts of Il24 following expression in murine thyrocytes, but its expression is dramatically reduced in poorly differentiated carcinomas, a finding that parallels the loss of RET/PTC3 expression. Consistent with its behavior as a tumor suppressor, the loss of Il24 coincided with the loss of RET/PTC3 in poorly differentiated mouse tumors. A functional role of Il24 in the autocrine growth/survival of RET/PTC3-expressing thyroid cells was identified helping to support its role in cellular transformation. These data suggest that the induction of Il24 by oncogenes may support tumor growth at the early stages of cancer.
甲状腺癌与血液系统恶性肿瘤一样，通常与导致融合蛋白形成的染色体易位有关。通过融合蛋白改变信号传导，细胞死亡和存活途径被破坏，细胞间通讯的生理平衡可能丧失。这种破坏的一个后果是应激细胞释放警报宿主的因子。宿主反应的一种类型是白细胞浸润，其可能发展为慢性炎症或自身免疫性疾病。虽然炎症可能与肿瘤组织相关，但驱动这一过程的机制在很大程度上尚不清楚。因此，为了探讨癌症炎症的机制，我们在小鼠模型系统中研究了一种癌基因的作用。全面的基因分析揭示了几种由RET/甲状腺乳头状癌（PTC）3基因表达诱导的可溶性因子，包括几种促炎细胞因子、趋化因子和免疫相关的共刺激分子。在用表达RP3的甲状腺细胞进行大规模基因筛选后，我们鉴定出一种高度丰富的转录本，后来将其鉴定为白细胞介素24（Il24），一种具有多种肿瘤抑制和炎症活性的细胞因子。我们表明RET/PTC3在大鼠甲状腺细胞中诱导Il24表达，并且这种表达依赖于其酪氨酸激酶的信号特性。同样，RET/PTC3在小鼠甲状腺细胞中表达后诱导大量Il24，但在低分化癌中其表达显著降低，这一发现与RET/PTC3表达的丧失相平行。与其作为肿瘤抑制因子的行为一致，在低分化小鼠肿瘤中Il24的丧失与RET/PTC3的丧失同时发生。确定了Il24在表达RET/PTC3的甲状腺细胞的自分泌生长/存活中的功能作用有助于支持其在细胞转化中的作用。这些数据表明癌基因诱导Il24可能在癌症早期支持肿瘤生长。
