Oxidized LDL Triggers Pro-Oncogenic Signaling in Human Breast Mammary Epithelial Cells Partly via Stimulation of MiR-21

Khaidakov, Magomed; Mehta, Jawahar L.

doi:10.1371/journal.pone.0046973

Cited by 39 publications

(34 citation statements)

References 49 publications

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“…For example, one study showed that the serum oxLDL levels are associated with an increased risk of breast cancer27. Furthermore, oxLDL was reported to trigger proliferative and pro-inflammatory signalling in MCF10A cells partly by stimulation of MiR-2117. In addition, oxLDL (lectin-like) receptor 1 (OLR1), the main receptor for internalization of oxLDL, has been reported to play a major role in tumour growth in xenograft mouse models of breast cancer and is critical for cell transformation92829.…”

Section: Discussionmentioning

confidence: 99%

“…Two reports have demonstrated that both D-4F and L-4F significantly reduce tumour growth in xenograft mouse models of ovarian and colon cancer, and this effect is partly brought about by their binding to and removing lysophosphatidic acids1016. Recent data have also shown that internalization of oxidized low-density lipoprotein (oxLDL) by mammary epithelial cells may play a significant role in breast cancer by triggering a variety of proliferative and pro-inflammatory mechanisms17. However, the potential in vivo therapeutic effect of apoA-I or its mimetics on breast cancer has not been studied.…”

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confidence: 99%

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ApoA-I mimetic administration, but not increased apoA-I-containing HDL, inhibits tumour growth in a mouse model of inherited breast cancer

Cedó

García-León

Baila-Rueda

et al. 2016

Sci Rep

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Low levels of high-density lipoprotein cholesterol (HDLc) have been associated with breast cancer risk, but several epidemiologic studies have reported contradictory results with regard to the relationship between apolipoprotein (apo) A-I and breast cancer. We aimed to determine the effects of human apoA-I overexpression and administration of specific apoA-I mimetic peptide (D-4F) on tumour progression by using mammary tumour virus-polyoma middle T-antigen transgenic (PyMT) mice as a model of inherited breast cancer. Expression of human apoA-I in the mice did not affect tumour onset and growth in PyMT transgenic mice, despite an increase in the HDLc level. In contrast, D-4F treatment significantly increased tumour latency and inhibited the development of tumours. The effects of D-4F on tumour development were independent of 27-hydroxycholesterol. However, D-4F treatment reduced the plasma oxidized low-density lipoprotein (oxLDL) levels in mice and prevented oxLDL-mediated proliferative response in human breast adenocarcinoma MCF-7 cells. In conclusion, our study shows that D-4F, but not apoA-I-containing HDL, hinders tumour growth in mice with inherited breast cancer in association with a higher protection against LDL oxidative modification.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

ApoA-I mimetic administration, but not increased apoA-I-containing HDL, inhibits tumour growth in a mouse model of inherited breast cancer

Cedó

García-León

Baila-Rueda

et al. 2016

Sci Rep

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“…However, the proliferative effect of oxLDL was prevented in the C4-2/LOX-1(−) cell model, indicating that this effect is closely related to the activation of the LOX-1 receptor by oxLDL. In this sense, the proliferative effect promoted by oxLDL/LOX-1 has been described in muscle cells, endothelial cells and recently in breast cancer cells through activation pathways that involve p38 (MAPK), p44/42 MAPK, and NF- kB [6], [39]. However, the proliferative effects on prostate cancer cells had not yet been described.…”

Section: Discussionmentioning

confidence: 99%

Lectin-Like Oxidized LDL Receptor-1 Is an Enhancer of Tumor Angiogenesis in Human Prostate Cancer Cells

et al. 2014

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Altered expression and function of lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) has been associated with several diseases such as endothelial dysfunction, atherosclerosis and obesity. In these pathologies, oxLDL/LOX-1 activates signaling pathways that promote cell proliferation, cell motility and angiogenesis. Recent studies have indicated that olr1 mRNA is over-expressed in stage III and IV of human prostatic adenocarcinomas. However, the function of LOX-1 in prostate cancer angiogenesis remains to be determined. Our aim was to analyze the contribution of oxLDL and LOX-1 to tumor angiogenesis using C4-2 prostate cancer cells. We analyzed the expression of pro-angiogenic molecules and angiogenesis on prostate cancer tumor xenografts, using prostate cancer cell models with overexpression or knockdown of LOX-1 receptor. Our results demonstrate that the activation of LOX-1 using oxLDL increases cell proliferation, and the expression of the pro-angiogenic molecules VEGF, MMP-2, and MMP-9 in a dose-dependent manner. Noticeably, these effects were prevented in the C4-2 prostate cancer model when LOX-1 expression was knocked down. The angiogenic effect of LOX-1 activated with oxLDL was further demonstrated using the aortic ring assay and the xenograft model of tumor growth on chorioallantoic membrane of chicken embryos. Consequently, we propose that LOX-1 activation by oxLDL is an important event that enhances tumor angiogenesis in human prostate cancer cells.

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“…Previous studies have described interactions among OLR1 and different miRNAs; within them, particularly interesting are hsa‐let7‐g and hsa‐miR‐21 that are expressed mainly in endothelial cells and are associated with the apoptosis regulation.…”

Section: Introductionmentioning

confidence: 99%

The human rs1050286 polymorphism alters LOX‐1 expression through modifying miR‐24 binding

Morini

Rizzacasa

Pucci

et al. 2015

J Cellular Molecular Medi

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The up‐regulation of lectin‐like oxidized low‐density lipoprotein receptor‐1 (LOX‐1), encoded by the OLR1 gene, plays a fundamental role in the pathogenesis of atherosclerosis. Moreover, OLR1 polymorphisms were associated with increased susceptibility to acute myocardial infarction (AMI) and coronary artery diseases (CAD). In these pathologies, the identification of therapeutic approaches that can inhibit or reduce LOX‐1 overexpression is crucial. Predictive analysis showed a putative hsa‐miR‐24 binding site in the 3′UTR of OLR1, ‘naturally’ mutated by the presence of the rs1050286 single nucleotide polymorphism (SNP). Luciferase assays revealed that miR‐24 targets OLR1 3′UTR‐G, but not 3′UTR‐A (P < 0.0005). The functional relevance of miR‐24 in regulating the expression of OLR1 was established by overexpressing miR‐24 in human cell lines heterozygous (A/G, HeLa) and homozygous (A/A, HepG2) for rs1050286 SNP. Accordingly, HeLa (A/G), but not HepG2 (A/A), showed a significant down‐regulation of OLR1 both at RNA and protein level. Our results indicate that rs1050286 SNP significantly affects miR‐24 binding affinity to the 3′UTR of OLR1, causing a more efficient post‐transcriptional gene repression in the presence of the G allele. On this basis, we considered that OLR1 rs1050286 SNP may contribute to modify OLR1 susceptibility to AMI and CAD, so ORL1 SNPs screening could help to stratify patients risk.

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Oxidized LDL Triggers Pro-Oncogenic Signaling in Human Breast Mammary Epithelial Cells Partly via Stimulation of MiR-21

Cited by 39 publications

References 49 publications

ApoA-I mimetic administration, but not increased apoA-I-containing HDL, inhibits tumour growth in a mouse model of inherited breast cancer

ApoA-I mimetic administration, but not increased apoA-I-containing HDL, inhibits tumour growth in a mouse model of inherited breast cancer

Lectin-Like Oxidized LDL Receptor-1 Is an Enhancer of Tumor Angiogenesis in Human Prostate Cancer Cells

The human rs1050286 polymorphism alters LOX‐1 expression through modifying miR‐24 binding

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