HIF-1α induced NID1 expression promotes pulmonary metastases via the PI3K-AKT pathway in salivary gland adenoid cystic carcinoma. (August 2022)

• Record Type: Journal Article
• Authors: Han, Nannan; Li, Xing; Wang, Yupu; Li, Huasheng; Zhang, Chunye; Zhao, Xiaomei; Zhang, Zun; Ruan, Min; Zhang, Chenping
• Is Part Of: Oral oncology. Volume 131(2022)
• Publication Date: 2022-08
• Subjects: Salivary gland adenoid cystic carcinoma (SACC) -- Nidogen 1 (NID1) -- PI3K/AKT pathway -- Epithelial-mesenchymal transition -- Hypoxia‐inducible factor 1α (HIF-1α) -- Pulmonary metastases; Mouth -- Cancer -- Periodicals; Mouth -- Tumors -- Periodicals; Mouth Diseases -- Periodicals; Mouth Neoplasms -- Periodicals; Bouche -- Cancer -- Périodiques; Bouche -- Tumeurs -- Périodiques; Tumeurs -- Périodiques; Electronic journals; 616.9943105
• DOI: 10.1016/j.oraloncology.2022.105940
• Languages: English
• ISSNs: 1368-8375

Abstract

Highlights: Lung metastasis is the leading cause of death in salivary adenoid cystic carcinoma (SACC) patients, which highlighting the urgent need to find novel biomarker for prevention and treatment of lung metastasis of SACC. Expression of NID1 in SACC cases was significantly higher than that in normal gland, which was positively associated with lung metastasis and poor prognosis. HIF-1α activated NID1 overexpression promoted cancer cell invasion and migration via PI3K/AKT-EMT pathway in SACC. Abstract: Background: This study aimed to investigate the potential role of nidogen 1 (NID1), a basement membrane component, in the growth and metastasis of salivary gland adenoid cystic carcinoma (SACC) and the underlying molecular mechanism. Methods: High-throughput next-generation sequencing was used to compare the gene expression profiles of SACC with and without lung metastasis. Luciferase gene reporter assays were used to measure the NID1 promoter activity. BALB/c nude mice were used to establish a lung metastasis model of SACC to evaluate the prometastatic activity of NID1 . ChIP and dual-luciferase reporter assays were performed to confirm the HIF-1α-binding site in the NID1 promoter. Results: NID1 expression in SACC was significantly increased and associated with lung metastasis ( P = 0.011). The elevated NID1 expression was a predictor of poor outcomes in patients with SACC ( P < 0.05). Overexpression of NID1 promoted cancer cell migration and invasion through PI3K/AKT pathway activation and subsequent epithelial–mesenchymal transition (EMT), as indicated by the upregulation of N-cadherin and vimentin. Furthermore, in vivo live monitoring of a mouse model of lung cancer demonstrated the pro-metastatic role of NID1 in SACC cell lung metastasis. Hypoxia-inducible factor 1α ( HIF‐1α) upregulation via transfection of an HIF-1α -overexpressing plasmid enhanced HIF-1α binding to the NID1 promoter and the subsequent transcriptional activity and expression of NID1. Conclusion: HIF‐1α-activated NID1 overexpression promotes SACC cell metastasis via PI3K/AKT pathway activation and EMT. Thus, NID1 could be a novel biomarker and therapeutic target for preventing metastasis and treating patients with SACC in future.