CAR样膜蛋白（CLMP）是一种紧密连接相关蛋白，其突变与先天性短肠综合征（CSBS）相关，但其在结直肠癌（CRC）中的功能仍不清楚。在此，我们证明 CLMP 在 CRC 患者中很少发生突变，但显着下降，并且其缺陷加速了 CRC 肿瘤的发生、生长和对全反式视黄酸 (ATRA) 的耐药性。从机制上讲，CLMP 将 β-连环蛋白募集到细胞膜上，独立于钙粘蛋白。 CLMP 介导的 β-catenin 易位使 Wnt(Wingless 和 INT-1)/β-catenin 信号失活，从而抑制 ApcMin/、氧化偶氮甲烷/葡聚糖硫酸钠 (AOM/DSS) 和原位 CRC 小鼠模型中的 CRC 肿瘤发生和生长。作为 Wnt/β-连环蛋白的直接靶标，细胞色素 P450 羟化酶 A1 (CYP26A1)（一种将 ATRA 降解为生物活性较低的类视黄醇的酶）会因 CLMP 缺陷而上调，导致 ATRA 耐药性 CRC，可通过施用 CYP26A1 抑制剂来逆转。总的来说，我们的数据确定了 CLMP 的抗 CRC 作用，并表明 CYP26A1 抑制剂能够提高 ATRA 的治疗效率。版权所有 © 2023 Elsevier Inc. 保留所有权利。

CAR-like membrane protein (CLMP) is a tight junction-associated protein whose mutation is associated with congenital short bowel syndrome (CSBS), but its functions in colorectal cancer (CRC) remain unknown. Here, we demonstrate that CLMP is rarely mutated but significantly decreased in CRC patients, and its deficiency accelerates CRC tumorigenesis, growth, and resistance to all-trans retinoic acid (ATRA). Mechanistically, CLMP recruits β-catenin to cell membrane, independent of cadherin proteins. CLMP-mediated β-catenin translocation inactivates Wnt(Wingless and INT-1)/β-catenin signaling, thereby suppressing CRC tumorigenesis and growth in ApcMin/+, azoxymethane/dextran sodium sulfate (AOM/DSS), and orthotopic CRC mouse models. As a direct target of Wnt/β-catenin, cytochrome P450 hydroxylase A1 (CYP26A1)-an enzyme that degrades ATRA to a less bioactive retinoid-is upregulated by CLMP deficiency, resulting in ATRA-resistant CRC that can be reversed by administering CYP26A1 inhibitor. Collectively, our data identify the anti-CRC role of CLMP and suggest that CYP26A1 inhibitor enable to boost ATRA's therapeutic efficiency.Copyright © 2023 Elsevier Inc. All rights reserved.