Boulagnon-Rombi Camille, Schneider Christophe, Leandri Chloé, Jeanne Albin, Grybek Virginie, Bressenot Aude Marchal, Barbe Coralie, Marquet Benjamin, Nasri Saviz, Coquelet Christelle, Fichel Caroline, Bouland Nicole, Bonnomet Arnaud, Kianmanesh Reza, Lebre Anne-Sophie, Bouché Olivier, Diebold Marie-Danièle, Bellon Georges, Dedieu Stéphane
Laboratoire de Biopathologie, Centre Hospitalier Universitaire et Faculté de Médecine, Reims, France.
CNRS UMR 7369, Matrice Extracellulaire et Dynamique Cellulaire, MEDyC, Reims, France.
Oncotarget. 2018 Jan 13;9(10):8849-8869. doi: 10.18632/oncotarget.24225. eCollection 2018 Feb 6.
LRP1 (low-density lipoprotein receptor-related protein 1), a multifunctional endocytic receptor, has recently been identified as a hub within a biomarker network for multi-cancer clinical outcome prediction. As its role in colon cancer has not yet been characterized, we here investigate the relationship between LRP1 and outcome.
mRNA expression was determined in colon adenocarcinoma and paired colon mucosa samples, as well as in stromal and tumor cells obtained after laser capture microdissection. Clinical potential was further investigated by immunohistochemistry in a population-based colon cancer series ( = 307). methylation, mutation and miR-205 expression were evaluated and compared with LRP1 expression levels.
mRNA levels were significantly lower in colon adenocarcinoma cells compared with colon mucosa and stromal cells obtained after laser capture microdissection. Low LRP1 immunohistochemical expression in adenocarcinomas was associated with higher age, right-sided tumor, loss of CDX2 expression, Annexin A10 expression, CIMP-H, MSI-H and V600E mutation. Low LRP1 expression correlated with poor clinical outcome, especially in stage IV patients. While LRP1 expression was downregulated by mutation, promoter was never methylated.
Loss of LRP1 expression is associated with worse colon cancer outcomes. Mechanistically, mutation modulates LRP1 expression.
低密度脂蛋白受体相关蛋白1（LRP1）是一种多功能内吞受体，最近被确定为多癌临床结局预测生物标志物网络中的一个核心。由于其在结肠癌中的作用尚未明确，我们在此研究LRP1与结局之间的关系。
在结肠腺癌及配对的结肠黏膜样本中，以及在激光捕获显微切割后获得的基质细胞和肿瘤细胞中测定mRNA表达。通过免疫组织化学在一个基于人群的结肠癌系列（n = 307）中进一步研究其临床潜力。评估了LRP1甲基化、突变和miR-205表达，并与LRP1表达水平进行比较。
与激光捕获显微切割后获得的结肠黏膜和基质细胞相比，结肠腺癌细胞中的mRNA水平显著降低。腺癌中LRP1免疫组化低表达与年龄较大、肿瘤位于右侧、CDX2表达缺失、膜联蛋白A10表达、CIMP-H、MSI-H和V600E突变有关。LRP1低表达与不良临床结局相关，尤其是在IV期患者中。虽然LRP1表达因KRAS突变而下调，但其启动子从未发生甲基化。
LRP1表达缺失与更差的结肠癌结局相关。从机制上讲，KRAS突变调节LRP1表达。
