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Heparin-binding growth factor (HDGF) drives radioresistance in breast cancer by activating the STAT3 signaling pathway.

ABSTRACT: Although reports implicate radioresistance as an important obstacle for the management of breast cancer, its molecular mechanism is elusive. Herein, we found that high HDGF levels are expressed significantly in breast cancer and exhibit a positive association with poor survival prognosis. Heparin-binding growth factor (HDGF) was upregulated in radioresistant breast cancer cells, however, its knockdown could reduce breast cancer radioresistant both in vitro and in vivo. Additionally, the binding of RXRα to HDGF promoter blocked HDGF transcriptional activity, consequently inhibiting breast cancer radioresistance. The enhanced radioresistant activity of HDGF is induced by TKT and STAT3, impacting the STAT3-Tyr705 and STAT3-Ser727 phosphorylation and STAT3 transcriptional activity. Notably, HDGF depletion renders radioresistant hypersensitive to the drug that targets STAT3 phosphorylation. This article demonstrates the novel function of HDGF as a promising molecular target for predicting radioresistance in breast cancer.

SUBMITTER: Qiu L

PROVIDER: S-EPMC8353798 | biostudies-literature | 2021 Aug

REPOSITORIES: biostudies-literature

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Heparin-binding growth factor (HDGF) drives radioresistance in breast cancer by activating the STAT3 signaling pathway.

Qiu Lingyun L Ma Yan Y Chen Xiaohua X Zhou Liheng L Zhang Haibo H Zhong Guansheng G Zhang Lei L Tang Jianming J Tang Jianming J

Journal of translational medicine 20210810 1

Although reports implicate radioresistance as an important obstacle for the management of breast cancer, its molecular mechanism is elusive. Herein, we found that high HDGF levels are expressed significantly in breast cancer and exhibit a positive association with poor survival prognosis. Heparin-binding growth factor (HDGF) was upregulated in radioresistant breast cancer cells, however, its knockdown could reduce breast cancer radioresistant both in vitro and in vivo. Additionally, the binding ...[more]

PMID: 34376200

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Project description:BackgroundEmerging evidence suggests that circular RNAs play critical roles in disease development especially in cancers. Previous genome-wide RNA-seq studies found that a circular RNA derived from SOD2 gene was highly upregulated in hepatocellular carcinoma (HCC), however, the role of circSOD2 in HCC remains largely unknown.MethodsThe expression profiling of circSOD2 and microRNA in HCC patients were assessed by Real-Time Quantitative Reverse Transcription PCR (qRT-PCR). SiRNA or CRISPR-CAS9 were used to silence gene expression. The biological function of circSOD2 in HCC was investigated using in vitro and in vivo studies including, trans-well cell migration, cell apoptosis, cell cycle, CCK8, siRNA interference, western blots, and xenograft mouse model. The underlying molecular mechanism was determined by Chromatin Immunoprecipitation quantitative real time PCR (ChIP-qPCR), bioinformatic analysis, biotin-pull down, RNA immunoprecipitation, 5-mc DNA pulldown and luciferase assays.ResultsIn accordance with previous sequencing results, here, we demonstrated that circSOD2 was highly expressed in HCC tumor tissues compared with normal liver tissues. Mechanically, we showed that histone writer EP300 and WDR5 bind to circSOD2 promoter and trigger its promoter H3K27ac and H3K4me3 modification, respectively, which further activates circSOD2 expression. SiRNA mediated circSOD2 suppression impaired liver cancer cell growth, cell migration, prohibited cell cycle progression and in vivo tumor growth. By acting as a sponge, circSOD2 inhibits miR-502-5p expression and rescues miR-502-5p target gene DNMT3a expression. As a DNA methyltransferase, upregulated DNMA3a suppresses SOCS3 expression by increasing SOCS3 promoter DNA methylation. This event further accelerates SOCS3 downstream JAK2/STAT3 signaling pathway activation. In addition, we also found that activated STAT3 regulates circSOD2 expression in a feedback way.ConclusionThe novel signaling axis circSOD2/miR-502-5p/DNMT3a/JAK2/STAT3/circSOD2 provides a better understanding of HCC tumorigenesis. The molecular mechanism underlying this signaling axis offers new prevention and treatment of HCC.

Dataset Information

Heparin-binding growth factor (HDGF) drives radioresistance in breast cancer by activating the STAT3 signaling pathway.

Publications

Heparin-binding growth factor (HDGF) drives radioresistance in breast cancer by activating the STAT3 signaling pathway.

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