Protein-arginine deiminase 2 suppresses proliferation of colon cancer cells through protein citrullination.
Protein-arginine deiminase 2 suppresses proliferation of colon cancer cells through protein citrullination.
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DOI：
10.1111/cas.13179
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发表时间：
2017-04
期刊：
影响因子：
5.7
通讯作者：
Nakayama K
中科院分区：
文献类型：
--
作者：
Funayama R;Taniguchi H;Mizuma M;Fujishima F;Kobayashi M;Ohnuma S;Unno M;Nakayama K
蛋白质精氨酸脱亚胺酶2（PADI 2）基因的表达已被证明在结肠癌中下调，这种下调表明患有这种疾病的个体预后不良。我们现在已经检测了PADI2在匹配的结肠癌和正常结肠组织标本以及结肠癌细胞系中的表达。我们发现PADI 2的亚型1是结肠组织中的主要亚型，并且在结肠癌发生过程中下调。免疫组织化学分析显示PADI 2在正常结肠上皮细胞中表达。PADI 2亚型1的过表达抑制了体外结肠癌细胞的增殖，与瓜氨酸蛋白的增加有关。PADI2或PADI2亚型2的催化失活突变体（C647A）的表达没有诱导这种效应，表明PADI2的蛋白质瓜氨酸酶活性是抑制细胞生长所必需的。PADI 2诱导的生长缺陷不是由于细胞凋亡增加，而是伴随着G1期细胞周期进程的停滞。最后，我们通过免疫印迹分析检测了正常结肠组织中的瓜氨酸化蛋白。因此，我们的数据表明，PADI2抑制结肠上皮细胞的增殖，通过催化蛋白质瓜氨酸，PADI2的表达下调，因此可能有助于结肠癌的发生。
Expression of the gene for protein‐arginine deiminase 2 (PADI2) has been shown to be downregulated in colon cancer, with such downregulation being indicative of a poor prognosis in individuals with this disease. We have now examined the expression of PADI2 in matched colon cancer and normal colon tissue specimens as well as in colon cancer cell lines. We found that isoform 1 of PADI2 is the predominant isoform in colon tissue and is downregulated during colon carcinogenesis. Immunohistochemical analysis showed that PADI2 is expressed in normal colonic epithelial cells. Overexpression of PADI2 isoform 1 suppressed the proliferation of colon cancer cells in vitro in association with increased protein citrullination. Expression of a catalytically inactive mutant (C647A) of PADI2 or of PADI2 isoform 2 did not induce such effects, indicating that the protein citrullination activity of PADI2 is required for inhibition of cell growth. The growth defect induced by PADI2 was not attributable to increased apoptosis but rather was accompanied by arrest of cell cycle progression in G1 phase. Finally, we detected citrullinated proteins in normal colon tissue by immunoblot analysis. Our data thus suggest that PADI2 suppresses the proliferation of colonic epithelial cells through catalysis of protein citrullination, and that downregulation of PADI2 expression might therefore contribute to colon carcinogenesis.