HMCN1 as a Conserved Biomarker of Epithelial--Mesenchymal Transition: A Cross-Cancer Analysis

Leng Yuan-xi¹Man yunan²Liu Ya-yun³Zhi Le^1*

• ¹Nanchang Hongdu Hospital of Traditional Chinese Medicine, Nanchang, China
• ²The First Affiliated Hospital of Guangxi Medical University, Nanning, China
• ³Jiangxi Provincial People's Hospital, Nanchang, China

The extracellular matrix (ECM) is a critical regulator of tumor progression, yet the systematic role of its large constituent, hemicentin-1 (HMCN1), across cancers remains poorly defined. Although emerging evidence implicates HMCN1 in cell invasion and migration, a comprehensive pan-cancer understanding of its function is lacking. This study conducted an integrative multi-omics analysis of HMCN1 across 33 cancer types, leveraging data from TCGA, GTEx, and CPTAC. We found that HMCN1 was frequently upregulated in tumors and associated with poor prognosis. Genomically, HMCN1 mutations correlated with genomic instability. HMCN1-high tumors were enriched in inflammatory immune subtypes and exhibited a dysfunctional tumor microenvironment, suggesting an immunomodulatory role. Mechanistically, pathway analysis consistently identified HMCN1 expression as being strongly associated with epithelial-mesenchymal transition (EMT). Given the prominent functional importance of HMCN1 in bone tumors, as evidenced by dependency scores, we selected osteosarcoma for functional validation. In vitro experiments confirmed that HMCN1 knockdown suppressed, while its overexpression enhanced, the migration and invasion of osteosarcoma cells. These effects were mediated through the regulation of key EMT markers. Our study establishes HMCN1 as a novel, conserved regulator of EMT and a candidate prognostic biomarker. The findings specifically in osteosarcoma provide a foundational rationale for developing HMCN1 as a potential therapeutic target.