Collagen triple helix repeat containing 1 (CTHRC1) acts via ERK-dependent induction of MMP9 to promote invasion of colorectal cancer cells.
Collagen triple helix repeat containing 1 (CTHRC1) acts via ERK-dependent induction of MMP9 to promote invasion of colorectal cancer cells.
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DOI：
10.18632/oncotarget.1714
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发表时间：
2014-01-30
期刊：
影响因子：
--
通讯作者：
Lee HG
中科院分区：
文献类型：
--
作者：
Kim HC;Kim YS;Oh HW;Kim K;Oh SS;Kim JT;Kim BY;Lee SJ;Choe YK;Kim DH;Kim SH;Chae SW;Kim KD;Lee HG
已知胶原蛋白三螺旋重复序列1（CTHRC 1）在大多数人类实体瘤中异常上调，尽管CTHRC 1在结直肠癌中的功能作用尚不清楚。在这项研究中，我们研究了CTHRC 1上调的发生及其在体内和体外的作用。通过逆转录-聚合酶链反应和免疫组化分析，在正常和肿瘤患者样本中检测CTHRC 1的表达谱和临床意义。CTHRC 1在正常组织中可检测到，但在肿瘤标本中也高度表达。CTHRC 1上调与结肠癌细胞系和肿瘤组织中CTHRC 1启动子的去甲基化显著相关。临床病理分析显示，淋巴结状态和CTHRC 1表达（95%CI 0.999-3.984，p=0.05）是无病生存的重要预后因素。通过亚硫酸氢盐测序和焦磷酸测序分析测量启动子CpG甲基化和超甲基化状态。此外，我们发现CTHRC 1在SW 480和HT-29细胞系中的过表达增加了侵袭性，这是由细胞外信号调节激酶（ERK）依赖的基质金属蛋白酶9（MMP 9）上调介导的。与此一致，我们发现CTHRC 1的敲低减弱了ERK激活和癌细胞侵袭力。这些结果表明，CTHRC 1表达在人结肠癌细胞系和临床标本中升高，并通过ERK依赖性诱导MMP 9表达促进癌细胞侵袭力。我们的研究结果进一步表明，高水平的CTHRC 1表达与不良的临床结局相关。
Collagen triple helix repeat-containing 1 (CTHRC1) is known to be aberrantly upregulated in most human solid tumors, although the functional roles of CTHRC1 in colorectal cancer remain unclear. In this study, we investigated the occurrence of CTHRC1 upregulation and its role in vivo and in vitro. The expression profile and clinical importance of CTHRC1 were examined by reverse transcription-polymerase chain reaction and immunohistochemical analyses in normal and tumor patient samples. CTHRC1 was detectable in normal tissues, but also was highly expressed in tumor specimens. CTHRC1 upregulation was significantly associated with demethylation of the CTHRC1 promoter in colon cancer cell lines and tumor tissues. Clinicopathologic analyses showed that nodal status and expression of CTHRC1 (95% CI 0.999–3.984, p=0.05) were significant prognostic factors for disease-free survival. Promoter CpG methylation and hypermethylation status were measured by bisulfite sequencing and pyrosequencing analysis. Furthermore, we showed that overexpression of CTHRC1 in the SW480 and HT-29 cell lines increased invasiveness, an effect mediated by extracellular signal-regulated kinase (ERK)-dependent upregulation of matrix metalloproteinase 9 (MMP9). Consistent with this, we found that knockdown of CTHRC1 attenuated ERK activation and cancer cell invasivity. These results demonstrate that CTHRC1 expression is elevated in human colon cancer cell lines and clinical specimens, and promotes cancer cell invasivity through ERK-dependent induction of MMP9 expression. Our results further suggest that high levels of CTHRC1 expression are associated with poor clinical outcomes.
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