Aryl-hydrocarbon receptor-interacting protein regulates tumorigenic and metastatic properties of colorectal cancer cells driving liver metastasis

• Published in: British journal of cancer Vol. 126; no. 11; pp. 1604 - 1615
• Main Authors: Solís-Fernández, Guillermo, Montero-Calle, Ana, Sánchez-Martínez, Maricruz, Peláez-García, Alberto, Fernández-Aceñero, María Jesús, Pallarés, Pilar, Alonso-Navarro, Miren, Mendiola, Marta, Hendrix, Jelle, Hardisson, David, Bartolomé, Rubén A., Hofkens, Johan, Rocha, Susana, Barderas, Rodrigo
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.06.2022; Nature Publishing Group
• Subjects: 631/67/322; 692/4028/67/1504/1885; AKT protein; Biomedical and Life Sciences; Biomedicine; Cadherins; Cancer Research; Carcinogenesis - genetics; Cell Line, Tumor; Cell Movement; Colon cancer; Colonic Neoplasms; Colorectal cancer; Colorectal carcinoma; Colorectal Neoplasms - pathology; Drug Resistance; Epidemiology; Epithelial-Mesenchymal Transition; Experiments; Gene Expression Regulation, Neoplastic; Hepatocytes; Humans; Hydrocarbons; Immunohistochemistry; Kinases; Liver; Liver cancer; Liver Neoplasms - secondary; Mesenchyme; Metastases; Metastasis; Molecular Medicine; Neoplasm Metastasis; Oncology; Proteomics; Rectal Neoplasms; Transcription activation; Transcription factors; Tumors
• ISSN: 0007-0920; 1532-1827
• DOI: 10.1038/s41416-022-01762-1

Background 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. Methods 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. Results 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. Conclusions 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.