Differential expression of the LOX family genes in human colorectal adenocarcinomas

Abstract

Abstract. Lysyl oxidase (LOX) is an amine oxidase that catalyzes the cross-linking of collage or elastin in the extracellular matrix, regulating the tensile strength and structural integrity of connective tissues. Recently, four paralogues (LOXL, LOXL2, LOXL3 and LOXL4) of LOX have been identified in humans, each containing the functional domains required for the amine oxidase activity toward collagen and elastin. Paradoxical roles of the LOX family members have been reported in various neoplastic tissues as tumor suppressors or promoters depending on tumor status and type. To address expression of the LOX family genes in colorectal adenocarcinomas, we performed real-time PCR analysis with matched tumor/normal tissue specimens from 104 patients. The expression of the LOX family genes was not statistically associated with tumor location, stage, growth type, or differentiation status. However, upregulation of LOX, LOXL2 and LOXL4 was significantly correlated with absence of lymphovascular invasion (P=0.012, 0.014 and 0.005, respectively), suggesting that the oxygen tension in or around the tumors may be an important regulator for the differential expression of LOX, LOXL2 and LOXL4 in colorectal cancer. Additionally, expression of LOX, but not the other LOX family genes, was significantly upregulated in patients with a diffuse cytoplasmic expression pattern of CEA, indicating that LOX upregulation may be associated with increased invasiveness and metastatic potential in colorectal cancer.

The HIF-1–Inducible Lysyl Oxidase Activates HIF-1 via the Akt Pathway in a Positive Regulation Loop and Synergizes with HIF-1 in Promoting Tumor Cell Growth

“…Overexpression of LOX gene has been described in colorectal cancers (15). We thus first analyzed LOX protein expression by immunohistochemistry with a specific antibody (19) on 19 colorectal samples.…”

“…Whereas in one study LOX was shown to be silenced (14), LOX upregulation was also described, and was correlated with hypoxia (15). In this type of cancer, HIF-1a is often overexpressed at very high levels, promoting colonic tumorigenesis (16,17) and potentially stimulating LOX expression.…”

Tumor Cell Invasion Can Be Blocked by Modulators of Collagen Fibril Alignment That Control Assembly of the Extracellular Matrix

“…LOX expression is often associated with specific tissues and biologic processes (9), and dysregulated expression was identified in many pathologic states (10)(11)(12). Elevated LOX expression is linked to the disrupted collagen morphology and increased tissue stiffness often found in tumors, leading to aberrant cellular behavior (10,13).…”

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“…However, work from both us and other groups observed an association of LOX overexpression and CRC progression [15,20,27,28]. One important issue is, in these studies, that the authors did not profile the nuclear localisation of LOX protein.…”