Proinvasive activity of BMP-7 through SMAD4/src-independent and ERK/Rac JNK-dependent signaling pathways in colon cancer cells
Proinvasive activity of BMP-7 through SMAD4/src-independent and ERK/Rac JNK-dependent signaling pathways in colon cancer cells
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DOI：
10.1016/j.cellsig.2007.03.008
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发表时间：
2007-08-01
影响因子：
4.8
通讯作者：
Gespach, Christian
中科院分区：
文献类型：
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作者：
Grijelmo, Clara;Rodrigue, Christelle;Gespach, Christian
最近的数据表明，骨形态发生蛋白BMP-7表现出对大鼠实验性结肠炎的粘膜保护作用，表明这种细胞因子在炎症性肠病和其他结肠癌前病变期间对肠上皮细胞发挥直接作用。在这项研究中，我们研究了BMP-7及其受体在正常人结肠隐窝，异常隐窝病灶（ACF）在乙状结肠炎和结直肠肿瘤，及其衍生的癌细胞系的功能表达。在几种癌前病变和癌细胞系中通过RT-PCR清楚地检测到编码BMP-7受体II型（BMPRII、ActRII、ActRIIB）和I型（ALK-2）的转录物。免疫组化检测正常结肠粘膜、乙状结肠炎、散发性高度异型增生腺瘤和9/16例结肠癌中ACF的表面上皮细胞和隐窝中细胞因子的表达。此外，从培养物中的腺瘤PC/AA/C1和癌HCT 8/S11和SW 48细胞系收集的条件培养基含有显著水平的BMP-7，范围为0.17至0.38 ng/ml。我们发现，BMP-7诱导散射和proinvasive反应（EC 50 = 1 ng/ml）在肾脏和结肠癌细胞系通过SMAD 4和src的独立途径和信号级联使用FAK磷酸化在Y 925和激活ERK 1/2，Rac 1和JNK。Y 925上FAK的这种磷酸化也由促侵袭剂EGF诱导。综上所述，我们的研究结果表明，BMP-7在结肠粘膜中发挥不同的作用，一种是对抗短暂的炎症情况，另一种是与慢性溃疡性疾病和肿瘤性结肠炎期间的贬义功能有关。
Recent data indicate that the Bone Morphogenetic Protein BMP-7 exhibits mucosal protection against experimental colitis in rats, suggesting that this cytokine exerts direct actions in intestinal epithelial cells during inflammatory bowel diseases and other precancerous lesions of the colon. In this study, we investigated the functional expression of BMP-7 and its receptors in normal human colon crypts, aberrant crypt foci (ACF) in sigmoiditis and colorectal tumors, and their derived cancer cell lines. Transcripts encoding BMP-7 receptors type II (BMPRII, ActRII, ActRIIB) and type I (ALK-2) were clearly detected by RT-PCR in several premalignant and carcinoma cell lines. The cytokine was identified by immunohistochemistry in surface epithelial cells and crypts in the normal colon mucosa, ACF in sigmoiditis, sporadic high grade dysplastic adenoma, and in 9 of 16 colon carcinomas (56.2%). In addition, the conditioned medium collected from the adenoma PC/AA/C1 and carcinoma HCT8/S11 and SW48 cell lines in culture contained significant levels of BMP-7 ranging from 0.17 to 0.38 ng/ml. We found that BMP-7 induced scattering and proinvasive responses (EC50= 1 ng/ml) in kidney and colon cancer cell lines through SMAD4 and src-independent pathways and signaling cascades using FAK phosphorylation at Y925 and activation of ERK1/2, Rac1 and JNK. This phosphorylation of FAK on Y925 was also induced by the proinvasive agent EGF. Taken together, our findings suggest that BMP-7 exerts divergent effects in the colon mucosa, one counteracting transient inflammatory situations and the other linked to pejorative functions during chronic ulcerative diseases and the neoplastic