The lectin-like oxidized LDL receptor-1: a new potential molecular target in colorectal cancer

Abstract

The identification of new biomarkers and targets for tailored therapy in human colorectal cancer (CRC) onset and progression is an interesting challenge.CRC tissue produces an excess of ox-LDL, suggesting a close correlation between lipid dysfunction and malignant transformation. Lectin-like oxidized LDL receptor-1 (LOX-1) is involved in several mechanisms closely linked to tumorigenesis.Here we report a tumor specific LOX-1 overexpression in human colon cancers: LOX-1 results strongly increased in the 72% of carcinomas (P<0.001), and strongly overexpressed in 90% of highly aggressive and metastatic tumours (P<0.001), as compared to normal mucosa. Moreover LOX-1 results modulated since the early stage of the disease (adenomas vs normal mucosa; P<0.001) suggesting an involvement in tumor insurgence and progression.The in vitro knockdown of LOX-1 in DLD-1 and HCT-8 colon cancer cells by siRNA and anti-LOX-1 antibody triggers to an impaired proliferation rate and affects the maintenance of cell growth and tumorigenicity. The wound-healing assay reveals an evident impairment in closing the scratch. Lastly knockdown of LOX-1 delineates a specific pattern of volatile compounds characterized by the presence of a butyrate derivative, suggesting a potential role of LOX-1 in tumor-specific epigenetic regulation in neoplastic cells.The role of LOX-1 as a novel biomarker and molecular target represents a concrete opportunity to improve current therapeutic strategies for CRC. In addition, the innovative application of a technology focused to the identification of LOX-1 driven volatiles specific to colorectal cancer provides a promising diagnostic tool for CRC screening and for monitoring the response to therapy.

Lectin-like oxidized low-density lipoprotein receptor-1 facilitates metastasis of gastric cancer through driving epithelial-mesenchymal transition and PI3K/Akt/GSK3β activation

“…Given the pivotal role of cancer cells migration and invasion in cancer progress, we performed transwell assay to evaluate the effect of LOX-1 on the migratory and invasive potential of GC cells in vitro . We found that LOX-1 promotes GC cells migration and invasion, which is consistent with previous studies conducted in other types of cancer cells91128. It has been known that EMT plays important role in the invasive and metastatic processes of cancer cells29.…”

“…Activation of LOX-1 promotes transformation, motility and growth of several cancer cells, while down-regulation of LOX-1 can prevent such processes9. Moreover, some studies have shown that LOX-1 overexpression is a significant prognosis of tumor progression in advanced-stage prostate cancer10, colorectal cancer11 and squamous non-small cell lung cancer12.…”

LOX-1 and Its Splice Variants: A New Challenge for Atherosclerosis and Cancer-Targeted Therapies

“…The shifting of acetylation pattern suggests a possible involvement of LOX-1 in epigenetic modulation of transcription of tumor suppressor genes [176]. …”

Cholesterol level regulates lectin-like oxidized low-density lipoprotein receptor-1 function

“…Several lipid metabolic genes, including orl1, are consistently overexpressed in diverse cancer cell lineages and, importantly, the expression of these genes is critical to cellular transformation, as well as in maintaining the transformed state. A meta-analysis of gene expression profiles of 950 cancer cell lines stored in the Gene Expression Atlas at the EMBL-EBI database (http://www.ebi.ac.uk/gxa/ gene/ENSG00000173391#) reveals that the LOX-1 gene is up-regulated in 57% of bladder and cervix cancer cells, 11% of mammary gland cancer cells, 10% of lung cancer cells, and in 20% of colon rectal cancer (CRC) cells [24,26,47]. The expression of LOX-1 is modulated since the early stage of tumor development, suggesting a potential role in the insurgence and progression of the disease and associated with more aggressive and metastatic stage tumors.…”

“…As in atherosclerosis, the ox-LDL-LOX-1 interaction activates the inflammatory pathway through NF-κB activation [39] increases the expression of proatherogenic molecules such as VEGF, MMP-2 and MMP-9 and, in cancer cells stimulates proliferation [24]. Depletion of LOX-1 receptors protects against tumorigenicity, motility and growth of these cells [26,47].…”