Post-Transcriptional Up-Regulation of PDGF-C by HuR in Advanced and Stressed Breast Cancer

Abstract

Breast cancer is a heterogeneous disease characterized by multiple genetic alterations leading to the activation of growth factor signaling pathways that promote cell proliferation. Platelet-derived growth factor-C (PDGF-C) is overexpressed in various malignancies; however, the involvement of PDGF-C in breast cancers and the mechanisms underlying PDGF-C deregulation remain unclear. Here, we show that PDGF-C is overexpressed in clinical breast cancers and correlates with poor prognosis. PDGF-C up-regulation was mediated by the human embryonic lethal abnormal vision-like protein HuR, which stabilizes the PDGF-C transcript by binding to two predicted AU-rich elements (AREs) in the 3'-untranslated region (3'-UTR). HuR is up-regulated in hydrogen peroxide-treated or ultraviolet-irradiated breast cancer cells. Clinically, HuR levels are correlated with PDGF-C expression and histological grade or pathological tumor-node-metastasis (pTNM) stage. Our OPEN ACCESSInt. J. Mol. Sci. 2014, 15 20307 findings reveal a novel mechanism underlying HuR-mediated breast cancer progression, and suggest that HuR and PDGF-C are potential molecular candidates for targeted therapy of breast cancers.

Current Evidence and Future Perspectives on HuR and Breast Cancer Development, Prognosis, and Treatment

“…SiRNA-mediated HuR silencing confirmed the stabilization of PDGF-C mRNA by HuR in MDA-MB-231 cells. HuR-mediated upregulation of PDGF-C appears to be involved in the responses against ultraviolet irradiation (30 J/m 2 ) and oxidative stress (H 2 O 2 , 800 μM, 24 hours) in MCF7 cells [84] .…”

“…Ultraviolet irradiation upregulates HuR protein levels in MCF7 cells in a dose-dependent manner [84] . Furthermore, anoxia (<0.01% O 2 ) increases cytoplasmic HuR expression levels in MCF7 cells.…”

“…More specifically, a significant translocation of the nuclear HuR to the cytoplasm after 12 hours of anoxic incubation, and translocation of majority of HuR to the cytoplasm after 24 hours was noted [90] . In addition, oxidative stress (H 2 O 2 , 800 μM, 24 hours) and induced G 2 /M cell cycle arrest (nocodazole, 100 ng/ml, 24 hours) upregulate HuR protein levels, whereas amino acid deprivation (16 hours) downregulates HuR protein levels [55] , [84] .…”

Post-transcriptional regulation of cytokine and growth factor signaling in cancer

“…EMTs are driven by many soluble growth factors, including FGFs, HGF, EGF, PDGFC, IGF, and their cognate receptors [135, 182]. For example, activation of the EGFR pathway in triple-negative breast cancer increases the cytoplasmic localization of ELAVL1, leading to stabilization and translation of ARE-containing mRNAs such as CA9, SNAI2, β-catenin and IL6, contributing to the development of a stem cell-like and aggressive basal-like breast cancer phenotype [183].…”

Hallmarks of cancer and AU‐rich elements

“…60 In patients, HuR overexpression and/or cytoplasmic localization have been shown to be associated with lymph node metastatic disease in several cancer types, such as breast and lung cancers. 110,187 An excellent coverage of the role of HuR in different cancer pathologies was given in this reference. 188…”