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

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.

• Authors: Nannan Han, Xing Li, Yupu Wang, Huasheng Li, Chunye Zhang, Xiaomei Zhao, Zun Zhang, Min Ruan, Chenping Zhang
• Journal: Oral oncology (Oral Oncol) Vol. 131 Pg. 105940 (08 2022) ISSN: 1879-0593 [Electronic] England
• PMID: 35689951 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2022 Elsevier Ltd. All rights reserved.

Chemical References

• Hypoxia-Inducible Factor 1, alpha Subunit
• Membrane Glycoproteins
• nidogen
• Proto-Oncogene Proteins c-akt

Topics

• Animals
• Carcinoma, Adenoid Cystic (pathology)
• Cell Line, Tumor
• Cell Movement (genetics)
• Epithelial-Mesenchymal Transition (physiology)
• Gene Expression Regulation, Neoplastic
• Hypoxia-Inducible Factor 1, alpha Subunit (pharmacology)
• Lung Neoplasms (secondary)
• Membrane Glycoproteins
• Mice
• Mice, Nude
• Phosphatidylinositol 3-Kinases (metabolism)
• Proto-Oncogene Proteins c-akt (metabolism)
• Salivary Gland Neoplasms (pathology)
• Salivary Glands (metabolism)
• Signal Transduction