Shishido Akemi, Miyo Masaaki, Oishi Kazuki, Nishiyama Natsumi, Wu Meiqiao, Yamamoto Hiroyuki, Kouda Shihori, Wu Xin, Shibata Satoshi, Yokoyama Yuhki, Yamamoto Hirofumi
Department of Molecular Pathology, Division of Health Sciences, Graduate School of Medicine, Osaka University, Yamadaoka 1-7, Suita City 565-0871, Japan.
Department of Surgery, Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Yamadaoka 2-2, Suita City 565-0871, Japan.
Life (Basel). 2023 Feb 23;13(3):615. doi: 10.3390/life13030615.
High expression of low-density lipoprotein receptor-related protein 6 (LRP6), a key component of the Wnt/β-catenin signaling pathway, is reported to be associated with malignant potential in some solid tumors including breast cancer and hepatocellular carcinoma. Few reports, however, have examined its function and clinical significance in colorectal cancers (CRC) demonstrating constitutive activation of Wnt signaling. Here, we compared the expression level and function of LRP6 in CRC with that of esophageal squamous cell carcinoma (ESCC) bearing few Wnt/β-catenin pathway mutations. On immunohistochemical staining, high LRP6 expression was noted in three of 68 cases (4.4%), and high β-catenin in 38 of 67 cases (56.7%) of CRC. High LRP6 expression was found in 21 of 82 cases (25.6%), and high β-catenin expression in 29 of 73 cases (39.7%) of ESCC. In our in vitro studies, LRP6 knockdown hardly changed Wnt signaling activity in CRC cell lines with mutations in Wnt signaling downstream genes. In contrast, in ESCC cell lines without Wnt signaling-related mutations, LRP6 knockdown significantly decreased Wnt signaling activity. LRP6 function may depend on constitutive activation of Wnt signaling.
低密度脂蛋白受体相关蛋白6（LRP6）是Wnt/β-连环蛋白信号通路的关键组成部分，据报道，其高表达与包括乳腺癌和肝细胞癌在内的一些实体瘤的恶性潜能相关。然而，很少有报道研究其在显示Wnt信号通路组成性激活的结直肠癌（CRC）中的功能和临床意义。在这里，我们比较了CRC中LRP6与几乎没有Wnt/β-连环蛋白通路突变的食管鳞状细胞癌（ESCC）中LRP6的表达水平和功能。免疫组织化学染色显示，68例CRC中有3例（4.4%）LRP6高表达，67例中有38例（56.7%）β-连环蛋白高表达。82例ESCC中有21例（25.6%）LRP6高表达，73例中有29例（39.7%）β-连环蛋白高表达。在我们的体外研究中，在Wnt信号下游基因突变的CRC细胞系中，LRP6敲低几乎不会改变Wnt信号活性。相反，在没有Wnt信号相关突变的ESCC细胞系中，LRP6敲低显著降低了Wnt信号活性。LRP6的功能可能依赖于Wnt信号的组成性激活。
