文章：

激肽释放酶相关肽酶6在由突变腺瘤性息肉病基因驱动的小鼠肠道肿瘤发生中的作用

Kallikrein-Related Peptidase 6 Contributes to Murine Intestinal Tumorigenesis Driven by a MutantAdenomatous polyposis coliGene

原文发布日期：15 November 2024

DOI: 10.3390/cancers16223842

类型: Article

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英文摘要：

Background/Objectives: The objective of this study was to assess the role of a secreted serine protease, kallikrein-related peptidase 6 (KLK6), during colorectal tumorigenesis driven by a mutantAdenomatous polyposis coli (APC)tumor suppressor gene. A first analysis of KLK6 expression in the intestinal tract ofApc-mutant multiple intestinal neoplasia (ApcMin/+) mice revealed up to four-fold induction ofKlk6mRNA levels in adenomas relative to its level in the adjacent mucosa. Methods and Results: The presence of KLK6 protein in the adenomatous areas was confirmed by immunohistochemistry and optical coherence tomography/laser-induced fluorescence (OCT/LIF) imaging. To assess the contribution of the KLK6 expression on theApc-mutant intestinal and colon tumorigenesis, we engineered a mouse with floxed alleles of theKlk6gene (Klk6lox/lox) and crossed it with a mouse expressing the truncated APC protein under control of the intestinal tract-specific humanCDX2P9.5-NLS Cretransgene (CPC;Apcfl/fl;Klk6+/+). We found thatCPC;Apcfl/flmice with disruptedKlk6gene expression (CPC;Apcfl/fl;Klk6fl/fl) had a significantly smaller average size of the small intestinal and colon crypts (p< 0.001 andp= 0.04, respectively) and developed a significantly fewer adenomas (p= 0.01). Moreover, a decrease in high-grade adenomas (p= 0.03) and adenomas with a diameter above 2 mm (p< 0.0001) was noted inCPC;Apcfl/fl;Klk6fl/flmice. Further molecular analysis showed thatKlk6gene inactivation in the small intestine and colon tissues ofCPC;Apcfl/fl;Klk6fl/flmice resulted in a significant suppression of transforming growth factor β2 (TGF-β2) protein (p≤ 0.02) and mitogen-activated protein kinase (MAPK) phosphorylation (p≤ 0.01). Conclusions: These findings demonstrate the oncogenic role of KLK6 in the mutantApc-mediated intestinal tumorigenesis and suggest the utility of KLK6 for early diagnosis of colorectal tumors.

摘要翻译： 

背景/目的：本研究旨在评估分泌型丝氨酸蛋白酶——激肽释放酶相关肽酶6（KLK6）在腺瘤性结肠息肉病（APC）抑癌基因突变驱动的结直肠肿瘤发生中的作用。对Apc突变多发性肠肿瘤（ApcMin/+）小鼠肠道中KLK6表达的初步分析显示，腺瘤中Klk6 mRNA水平相较于邻近黏膜升高达四倍。方法与结果：通过免疫组织化学及光学相干断层扫描/激光诱导荧光（OCT/LIF）成像技术，证实了KLK6蛋白在腺瘤区域的存在。为评估KLK6表达对Apc突变型肠道及结肠肿瘤发生的影响，我们构建了携带Klk6基因条件性等位基因（Klk6lox/lox）的小鼠模型，并将其与在肠道特异性人CDX2P9.5-NLS Cre转基因（CPC;Apcfl/fl;Klk6+/+）控制下表达截短型APC蛋白的小鼠进行杂交。研究发现，Klk6基因表达被破坏的CPC;Apcfl/fl小鼠（CPC;Apcfl/fl;Klk6fl/fl）其小肠与结肠隐窝平均尺寸显著减小（分别为p<0.001和p=0.04），且形成的腺瘤数量显著减少（p=0.01）。此外，在CPC;Apcfl/fl;Klk6fl/fl小鼠中，高级别腺瘤（p=0.03）及直径超过2毫米的腺瘤（p<0.0001）数量均有所下降。进一步的分子分析表明，CPC;Apcfl/fl;Klk6fl/fl小鼠小肠及结肠组织中Klk6基因失活可显著抑制转化生长因子β2（TGF-β2）蛋白表达（p≤0.02）及丝裂原活化蛋白激酶（MAPK）磷酸化水平（p≤0.01）。结论：这些发现证实了KLK6在Apc突变介导的肠道肿瘤发生中的促癌作用，并提示KLK6在结直肠肿瘤早期诊断中具有潜在应用价值。

原文链接：

Kallikrein-Related Peptidase 6 Contributes to Murine Intestinal Tumorigenesis Driven by a MutantAdenomatous polyposis coliGene