Epigenetic inactivation of the extracellular matrix metallopeptidase ADAMTS19 gene and the metastatic spread in colorectal cancer.
Epigenetic inactivation of the extracellular matrix metallopeptidase ADAMTS19 gene and the metastatic spread in colorectal cancer.
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DOI：
10.1186/s13148-015-0158-1
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发表时间：
2015
影响因子：
5.7
通讯作者：
Perucho M
中科院分区：
文献类型：
--
作者：
Alonso S;González B;Ruiz-Larroya T;Durán Domínguez M;Kato T;Matsunaga A;Suzuki K;Strongin AY;Gimènez-Bonafé P;Perucho M
ADAMTS19编码ADAMTS（一种具有凝血反应蛋白基序的崩解素和金属蛋白酶结构域）蛋白家族的一个成员，该蛋白家族在癌症发生和转移中起着新的作用。ADAMTS共享几个不同的蛋白质模块，包括前肽区域，金属蛋白酶结构域，崩解素样结构域和1型血栓反应蛋白（TS）基序。在之前的研究中，我们发现ADAMTS19在结直肠癌（CRC）中经常高甲基化。我们探讨了甲基化与肿瘤基因型和表型的关系。在252例结直肠癌、65例胰腺癌、33例乳腺癌和169例卵巢原发肿瘤、70例结直肠癌转移瘤和10例结直肠癌细胞系中检测了ADAMTS19启动子CpG岛的甲基化状态。肿瘤特异性ADAMTS19甲基化在胃肠道肿瘤中的发生率明显高于妇科肿瘤(优势比(OR) = 2.9，置信区间（CI) = (1.9-4.7), p = 5.2 × 10−7），且与结直肠癌中邻近位点的甲基化无关。高甲基化与BRAF癌基因突变的结直肠癌相关（OR = 10.1, CI = (3.1-42.9), p = 6.3 × 10−6），与结直肠癌（OR = 2.1, CI = (1.1-4.1), p = 0.023）和卵巢癌（OR = 60, CI = (16 - 346), p = 4 × 10−16）的粘液表型相关。在转移到卵巢和网膜的结直肠癌中，甲基化明显高于转移到肝和肺的结直肠癌（OR = 6.1, CI = (1.8-22.2), p = 0.001）。区分局部和远处转移性扩散，甲基化与肿瘤进展呈负相关（p = 0.031），但与浸润深度呈正相关（p = 0.030）。CRC细胞系中与转录抑制相关的高甲基化，以及用5 ' -AZA-2 ' -脱氧胞苷处理导致mRNA表达的再激活。shrna介导的ADAMTS19沉默对结直肠癌细胞的体外增殖率没有影响，但显著降低了它们的集体迁移速度（56%,p = 3.3 × 10−4）和在I型胶原中的迁移潜力（64%,p = 4.3 × 10−10）。我们的研究结果强调了ADAMTS19表观遗传沉默在结直肠癌和黏液性卵巢癌中的频繁参与。转移扩散靶器官的机制偏好可能导致CRC诊断生物标志物的发展。与黏液表型的关联也可能对卵巢癌有诊断应用。本文的在线版本（doi:10.1186/s13148-015-0158-1）包含补充材料，可供授权用户使用。
ADAMTS19 encodes a member of the ADAMTS (a disintegrin and metalloproteinase domain with thrombospondin motifs) protein family with emerging roles in carcinogenesis and metastasis. ADAMTS shares several distinct protein modules including a propeptide region, a metalloproteinase domain, a disintegrin-like domain, and a thrombospondin type 1 (TS) motif. In a previous work, we found ADAMTS19 frequently hypermethylated in colorectal cancer (CRC). We explored the association of methylation with tumor genotype and phenotype. The methylation status of the CpG island in the promoter of ADAMTS19 was determined in 252 colorectal, 65 pancreatic, 33 breast and 169 ovarian primary tumors, 70 CRC metastases, and 10 CRC cell lines. Tumor-specific methylation of ADAMTS19 was significantly more frequent in gastrointestinal than in gynecological cancers (odds ratio (OR) = 2.9, confidence interval (CI) = (1.9–4.7), p = 5.2 × 10−7) and was independent of the methylation of adjacent loci in CRC. Hypermethylation associated with CRC with mutated BRAF oncogene (OR = 10.1, CI = (3.1–42.9), p = 6.3 × 10−6) and with the mucinous phenotype in CRC (OR = 2.1, CI = (1.1–4.1), p = 0.023) and ovarian cancer (OR = 60, CI = (16–346), p = 4 × 10−16). Methylation was significantly more frequent in CRC metastases homing to the ovary and omentum than in those homing to the liver and lung (OR = 6.1, CI = (1.8–22.2), p = 0.001). Differentiating local from distant metastatic spread, methylation negatively associated with tumor progression (p = 0.031) but positively with depth of invasion (p = 0.030). Hypermethylation associated with transcriptional repression in CRC cell lines, and treatment with 5′-AZA-2′-deoxycytidine led to reactivation of mRNA expression. shRNA-mediated silencing of ADAMTS19 had no effect on the in vitro proliferation rate of CRC cells but significantly diminished their collective migration speed (56 %, p = 3.3 × 10−4) and potential to migrate in collagen I (64 %, p = 4.3 × 10−10). Our results highlight the frequent involvement of ADAMTS19 epigenetic silencing in CRC and mucinous ovarian cancer. The mechanistic preferences for the target organ of metastatic spread may lead to the development of diagnostic CRC biomarkers. The association with the mucinous phenotype also may have diagnostic applications for ovarian cancer. The online version of this article (doi:10.1186/s13148-015-0158-1) contains supplementary material, which is available to authorized users.