Oncogenic Smad3 Signaling Induced by Chronic Inflammation Is an Early Event in Ulcerative Colitis-associated Carcinogenesis
Oncogenic Smad3 Signaling Induced by Chronic Inflammation Is an Early Event in Ulcerative Colitis-associated Carcinogenesis
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DOI：
10.1002/ibd.21395
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发表时间：
2011-03-01
影响因子：
4.9
通讯作者：
Okazaki, Kazuichi
中科院分区：
文献类型：
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作者：
Kawamata, Seiji;Matsuzaki, Koichi;Okazaki, Kazuichi
背景资料：慢性炎症和体细胞突变都可能导致溃疡性结肠炎（UC）相关的异型增生和癌症的发病机制。另一方面，肿瘤抑制和肿瘤发生都可以由转化生长因子（TGF）-β信号传导引起。TGF-β I型受体（T β R1）和Ras相关激酶差异磷酸化介体Smad 3，成为C-末端磷酸化Smad 3（pSmad 3C）、接头磷酸化Smad 3（pSmad 3L）和C-末端和接头磷酸化Smad 3（pSmad 3L/C）。pSmad 3C/p2 i（WAF 1）途径传递细胞抑制性TGF-β信号，而pSmad 3L和pSmad 3L/C通过上调c-Myc癌蛋白促进细胞增殖。本研究的目的是澄清改变Smad 3信号在UC相关carcinogenesization.Methods：通过免疫染色和免疫荧光，我们比较了pSmad 3C，pSmad 3L，和pSmad 3L/C介导的信号在结肠直肠标本代表结肠炎，异型增生，或癌症从8例UC患者在正常结肠隐窝的信号。我们还研究了p53表达和p53和K-ras基因突变。结果：随着肠上皮细胞向肠腔方向的迁移，细胞生长抑制因子pSmad 3C/p21（WAP 1）呈上升趋势，而前体细胞表达的pSmad 3L/c-Myc呈下降趋势。结肠炎标本显示，在整个隐窝的所有肠上皮细胞核中，由TGF-β和肿瘤坏死因子（TNF）-α介导的pSmad 3L/C/c-Myc显著表达。在从异型增生到癌症的进展过程中，与p53和K-ras突变的频率增加成比例，致癌pSmad 3L/c-Myc通路成为占主导地位的pSmad 3C/p21（WAN 1）pathway.Conclusions：致癌Smad 3信号，改变慢性炎症和最终体细胞突变，促进UC相关的肿瘤进展，通过上调生长相关蛋白。
Background: Both chronic inflammation and somatic mutations likely contribute to the pathogenesis of ulcerative colitis (UC)-associated dysplasia and cancer. On the other hand, both tumor suppression and oncogenesis can result from transforming growth factor (TGF)-beta signaling. TGF-beta type I receptor (T beta R1) and Ras-associated kinases differentially phosphorylate a mediator, Smad3, to become C-terminally phosphorylated Smad3 (pSmad3C), linker phosphorylated Smad3 (pSmad3L), and both C-terminally and linker phosphorylated Smad3 (pSmad3L/C). The pSmad3C/p2i(WAF1) pathway transmits a cytostatic TGF-beta signal, while pSmad3L and pSmad3L/C promote cell proliferation by upregulating c-Myc oncoprotein. The purpose of this study was to clarify the alteration of Smad3 signaling during UC-associated carcinogenesis.Methods: By immunostaining and immunofluorescence, we compared pSmad3C-, pSmad3L-, and pSmad3L/C-mediated signaling in colorectal specimens representing colitis, dysplasia, or cancer from eight UC patients with signaling in normal colonic crypts. We also investigated p53 expression and mutations of p53 and K-ras genes. We further sought functional meaning of the phosphorylated Smad3-mediated signaling in vitro.Results: As enterocytes in normal crypts migrated upward toward the lumen, cytostatic pSmad3C/p21(WAP1) tended to increase, while pSmad3L/c-Myc shown by progenitor cells gradually decreased. Colitis specimens showed prominence of pSmad3L/C/c-Myc, mediated by TGF-beta and tumor necrosis factor (TNF)-alpha, in all enterocyte nuclei throughout entire crypts. In proportion with increases in frequency of p53 and K-ras mutations during progression from dysplasia to cancer, the oncogenic pSmad3L/c-Myc pathway came to be dominant with suppression of the pSmad3C/p21(WAN1) pathway.Conclusions: Oncogenic Smad3 signaling, altered by chronic inflammation and eventually somatic mutations, promotes UC-associated neoplastic progression by upregulating growth-related protein.