Aberrant Collagen Cross-linking in Human Oral Squamous Cell Carcinoma

Abstract

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.

Response to Letter to the Editor: “Aberrant Collagen Cross-linking in Human Oral Squamous Cell Carcinoma”

“…Sarode, Sarode, Gadbail, Gondivkar, and Patil for their interest in our work and providing their thoughts. We fully agree with the authors’ view on the diverse effects of lysyl oxidase–mediated collagen cross-linking on tumor progression, since the cross-linking pattern significantly changes as a result of many factors (e.g., cell type, remodeling) that affect the initiation, type, and maturation of cross-links (Yamauchi and Sricholpech 2012; Eyre and Weis 2013; Saito et al 2019).…”

Significance of HIF-1α Expression and LOXL-2 Localization in Progression of Oral Squamous Cell Carcinoma

“…In all the nodal stages, more number of cases showed high LOXL-2 expression in our study, though the results were non-significant. LOXL-2 catalyzed crosslinks have been shown to be positively correlating with advanced stage tumors and lymph node metastasis in OSCC (Saito et al, 2019).…”

“…These observations highlight the complex and paradoxical role of LOX family members in various types of cancer. (Saito et al, 2019) LOX expression is found to be upregulated by HIF-1α and is required for hypoxia-induced metastasis in human breast and head and neck tumors. (Cano et al, 2012) Secreted LOX and hypoxia are relevant to metastasis and premetastatic niche formation in breast cancer (Canesin et al, 2015).…”

Prelude and premise to the special issue: disruption of homeostasis-induced signaling and crosstalk in the carcinogenesis paradigm “Epistemology of the origin of cancer”

“…LOX mediates TGF-b1-induced fibrotic phenotypes in human skin-like tissues [92]. In terms of LOX isoforms, specifically, the enzymes lysyl hydroxylase 2 (LH2) or lysyl oxidase (LOX) and LOX-like 2 (LOXL2) are significantly upregulated and associated with poor patient prognosis in primary human oral squamous cell carcinoma (OSCC) [93]. The N-terminal neo-epitope site of LOXL2 is significantly elevated in serum from patients with breast, colorectal, lung, ovarian, pancreatic and prostate cancer, melanoma, IPF compared to healthy controls [94].…”