Page 150 - SRPSKO DRUŠTVO ISTRAŽIVAČA RAKA

Serbian Association for Cancer Research SDIRSACR

role in tumorigenesis.

Acknowledgments and funding: IMGGE work program for 2025, Ministry of Education, Science and Technological
Development of the Republic of Serbia, 451-03-136/2023-03/200042 and SENSOGENE (Science Fund of the Republic
of Serbia, PROMIS, #6052315).

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Comprehensive analysis of lysyl oxidase family gene expression and prognostic significance in colorectal
cancer

Işıl Özdemir, Nevin Belder

Biotechnology Institute, Ankara University, Ankara, Turkey

Keywords: colorectal neoplasms, hypoxia, biomarkers, prognosis, molecular targeted therapy

Background: Colorectal cancer (CRC) remains a major cause of cancer-related mortality despite advances in diagnosis
and therapy. Given its clinical and molecular heterogeneity, novel biomarkers and therapeutic targets are urgently
needed. The lysyl oxidase (LOX) family, comprising LOX and four LOX-like proteins (LOXL1–4), plays a central role in
extracellular matrix remodeling via collagen and elastin cross-linking. Emerging evidence implicates LOX family
members in tumor proliferation, invasion, and metastasis; however, their prognostic significance and mechanistic roles
in CRC remain poorly defined. Therefore, we aimed to conduct a comprehensive analysis of the LOX family in colorectal
cancer.
Materials and Methods: We conducted a comprehensive analysis of LOX family gene expression using multiple
independent colorectal cancer (CRC) datasets from the GEO database. Associations with clinicopathological features,
molecular subtypes, and survival outcomes were systematically evaluated. Gene set enrichment analysis (GSEA) was
performed to explore potential biological pathways associated with the most relevant LOX genes. The key candidate
genes were further validated in CRC cell lines compared to normal colonic epithelium using quantitative real-time PCR
(qRT-PCR).
Results and Conclusions: Most LOX family members exhibited dysregulated expression in CRC, with LOX and LOXL2
showing the most consistent and robust upregulation across multiple datasets. Elevated expression levels of several
members were significantly associated with advanced tumor stage, and poorer prognosis. Notably, LOX and LOXL2
expression was enriched in right-sided CIMP-high, MSI-H, and BRAF-mutant tumors. These two genes emerged as the
most promising candidates and were selected for further analysis. GSEA revealed that high LOX and LOXL2 expression
was strongly associated with the activation of epithelial–mesenchymal transition (EMT), hypoxia, IL2–STAT5 signaling,
and inflammatory pathways, with a shared EMT-related gene signature observed across datasets. Subsequent validation
confirmed significant upregulation of LOX and LOXL2 in CRC cell lines compared to normal colonic epithelium (p < 0.05).
Together, these findings suggest that LOX and LOXL2 may drive aggressive, mesenchymal-like phenotypes in CRC and
represent promising diagnostic biomarkers or therapeutic targets, particularly in inflammation-associated molecular
subtypes.

Acknowledgments and funding: This study was supported by the TUBITAK with grant number 122S340. Işıl Özdemir
was also supported through the TÜBİTAK 2247-C STAR Intern Researcher Scholarship Programme, within the scope of
the same project.

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