Tumor progression is a complex process involving extracellular matrix (ECM) remodeling and stiffening. However, the mechanisms that govern these processes and their roles in
tumor progression are still poorly understood. In this study, we performed bioinformatics, immunohistochemical, and biochemical analyses to examine if
collagen cross-linking is associated with
tumor stage and regional
lymph node metastasis (RLNM) in
oral squamous cell carcinoma (OSCC). We found that the genes encoding key
enzymes for cross-linking are frequently overexpressed in oral, head, and
neck cancers. Specifically, the
enzymes lysyl hydroxylase 2 (LH2) or
lysyl oxidase (LOX) and LOX-like 2 (LOXL2) were significantly upregulated in late-stage
tumors and associated with poor patient prognosis. The
protein levels of these
enzymes in the primary human OSCC were also significantly increased in late-stage
tumors and markedly elevated in the RLNM-positive
tumors. Notably, while overall LOX/LOXL2-catalyzed
collagen cross-links were enriched in late-stage and RLNM-positive
tumors, LH2-mediated stable cross-links were significantly increased. To our knowledge, this is the first study to investigate the association of
collagen cross-linking and expression of key
enzymes regulating this process with OSCC stage. The data indicate a critical role for
collagen cross-linking in OSCC
tumor progression and
metastasis, which may provide insights into development of novel therapeutic strategies to prevent OSCC progression.