Downregulation of dual-specificity phosphatase 4 enhances cell proliferation and invasiveness in colorectal carcinomas.
Downregulation of dual-specificity phosphatase 4 enhances cell proliferation and invasiveness in colorectal carcinomas.
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DOI：
10.1111/cas.13444
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发表时间：
2018-01
期刊：
影响因子：
5.7
通讯作者：
Moriyama M
中科院分区：
文献类型：
--
作者：
Ichimanda M;Hijiya N;Tsukamoto Y;Uchida T;Nakada C;Akagi T;Etoh T;Iha H;Inomata M;Takekawa M;Moriyama M
Wnt信号通路的异常激活是结直肠癌（CRC）发生发展的重要原因。然而，从这些前体病变进展为浸润性病变的过程中所涉及的分子机制尚未完全了解。最近，我们报道了MAPK的组成性激活伴随着双特异性磷酸酶4（DUSP4）（一种MAPK磷酸酶）的下调，有助于胰腺前驱病变的进展。在这项研究中，我们发现DUSP4的下调与CRC细胞中ERK的组成性激活有关。DUSP4的恢复导致ERK的失活，导致增殖和侵袭性的抑制，如用MEK抑制剂处理所示。此外，免疫组化显示，DUSP4表达在CRC组织的浅表区域上调，而在深部区域显著下调。与此相反，ERK在深区域显着过度激活相比，在浅表区域。这些结果表明，由DUSP4下调引起的MAPK信号通路的激活是CRC进展的原因，并且将是有希望的治疗靶点。
It is widely accepted that aberrant activation of the Wnt signaling pathway is responsible for the development of precursor lesions of colorectal cancer (CRC). However, the molecular mechanisms involved in the process of progression from these precursor lesions to invasive lesions of CRC are not fully understood. Recently, we reported that constitutive activation of MAPK accompanied by downregulation of dual‐specificity phosphatase 4 (DUSP4), a MAPK phosphatase, contributes to the progression of precursor lesions in the pancreas. In this study, we found that downregulation of DUSP4 was related to constitutive activation of ERKs in CRC cells. Restoration of DUSP4 resulted in inactivation of ERKs, leading to suppression of both proliferation and invasiveness, as shown by treatment with an MEK inhibitor. Furthermore, immunohistochemistry revealed that DUSP4 expression was upregulated in the superficial region of CRC tissue, whereas it was significantly downregulated in the deep region. In contrast, ERKs in the deep region were markedly hyperactivated compared to those in the superficial region. These results suggest that activation of the MAPK signaling pathway caused by downregulation of DUSP4 is responsible for progression of CRCs and would be a promising therapeutic target.
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作者：
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