Chronic Disease Programme (UFIEC), Instituto de Salud Carlos III, Majadahonda, E-28220, Madrid, Spain.
Molecular Imaging and Photonics Division, Chemistry Department, Faculty of Sciences, KU Leuven, Celestijnenlaan 200F, 3001 Heverlee, Leuven, Belgium.
Br J Cancer. 2022 Jun;126(11):1604-1615. doi: 10.1038/s41416-022-01762-1. Epub 2022 Mar 28.
Liver metastasis is the primary cause of colorectal cancer (CRC)-associated death. Aryl-hydrocarbon receptor-interacting protein (AIP), a putative positive intermediary in aryl-hydrocarbon receptor-mediated signalling, is overexpressed in highly metastatic human KM12SM CRC cells and other highly metastatic CRC cells.
Meta-analysis and immunohistochemistry were used to assess the relevance of AIP. Cellular functions and signalling mechanisms mediated by AIP were assessed by gain-of-function experiments and in vitro and in vivo experiments.
A significant association of high AIP expression with poor CRC patients' survival was observed. Gain-of-function and quantitative proteomics experiments demonstrated that AIP increased tumorigenic and metastatic properties of isogenic KM12C (poorly metastatic) and KM12SM (highly metastatic to the liver) CRC cells. AIP overexpression dysregulated epithelial-to-mesenchymal (EMT) markers and induced several transcription factors and Cadherin-17 activation. The former induced the signalling activation of AKT, SRC and JNK kinases to increase adhesion, migration and invasion of CRC cells. In vivo, AIP expressing KM12 cells induced tumour growth and liver metastasis. Furthermore, KM12C (poorly metastatic) cells ectopically expressing AIP became metastatic to the liver.
Our data reveal new roles for AIP in regulating proteins associated with cancer and metastasis to induce tumorigenic and metastatic properties in colon cancer cells driving liver metastasis.
肝转移是结直肠癌（CRC）相关死亡的主要原因。芳香烃受体相互作用蛋白（AIP）是一种假定的芳香烃受体介导信号的阳性中间物，在高度转移性的人 KM12SM CRC 细胞和其他高度转移性的 CRC 细胞中过度表达。
采用荟萃分析和免疫组织化学方法评估 AIP 的相关性。通过功能获得实验以及体外和体内实验评估 AIP 介导的细胞功能和信号转导机制。
观察到 AIP 高表达与 CRC 患者生存不良显著相关。功能获得和定量蛋白质组学实验表明，AIP 增加了同源 KM12C（转移性差）和 KM12SM（高度转移至肝脏）CRC 细胞的致瘤性和转移性。AIP 过表达使上皮-间充质转化（EMT）标志物失调，并诱导几个转录因子和钙黏蛋白-17 的激活。前者诱导 AKT、SRC 和 JNK 激酶的信号激活，增加 CRC 细胞的黏附、迁移和侵袭。在体内，表达 AIP 的 KM12 细胞诱导肿瘤生长和肝转移。此外，异位表达 AIP 的 KM12C（转移性差）细胞变得可转移至肝脏。
我们的数据揭示了 AIP 在调节与癌症和转移相关的蛋白质方面的新作用，从而诱导结肠癌细胞的致瘤性和转移性，促进肝转移。
