Heparin-binding growth factor (HDGF) drives radioresistance in breast cancer by activating the STAT3 signaling pathway.
Ontology highlight
ABSTRACT:
SUBMITTER: Qiu L
PROVIDER: S-EPMC8353798 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
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.
| S-EPMC7687771 | biostudies-literature
Project description:Gremlin-1 (GREM1), one of the bone morphogenetic protein (BMP) antagonists, can directly bind to BMPs. GREM1 is involved in organogenesis, tissue differentiation, and organ fibrosis. Recently, numerous studies have reported the oncogenic role of GREM1 in cancer. However, the role of GREM1 in metastasis of breast cancer cells and its underlying mechanisms remain poorly understood. The role of GREM1 in breast cancer progression was assessed by measuring growth, migration, and invasion of breast cancer cells. An orthotopic breast cancer mouse model was used to investigate the role of GREM1 in lung metastasis of breast cancer cells. GREM1 knockdown suppressed the proliferation of breast cancer cells, while its overexpression increased their growth, migration, and invasion. Cells with Grem1-knockdown showed much lower tumor growth rates and lung metastasis than control cells. GREM1 enhanced the expression of matrix metalloproteinase 13 (MMP13). A positive correlation between GREM1 and MMP13 expression was observed in breast cancer patients. GREM1 activated signal transducer and activator of transcription 3 (STAT3) transcription factor involved in the expression of MMP13. Our study suggests that GREM1 can promote lung metastasis of breast cancer cells through the STAT3-MMP13 pathway. In addition, GREM1 might be a promising therapeutic target for breast cancer metastasis.
| S-EPMC7730512 | biostudies-literature
Project description:Background: Cancer cells inevitably develop resistance to radiation in lung cancer radiotherapy. However, the underlying mechanisms remain to be fully clarified. This study aimed to explore the roles and mechanisms of FGF1 intracellular binding protein (FIBP)?in lung cancer radioresistance. Methods: Expression levels of FIBP in human lung cancer and adjacent tissues were analyzed by immunohistochemical (IHC) staining. Cell growth and proliferation, EdU and CFSE assays, Neutral comet and clonogenic survival analysis as well as mouse xenograft model were performed to explore the functions of FIBP in vitro and in vivo. The underlying mechanisms were investigated by RNA sequencing, co-immunoprecipitation and dual luciferase reporter assays. Results: The expression levels of FIBP in lung cancer tissues were significantly upregulated compared with adjacent normal tissues and associated with worse overall survival. Functionally, we found that depletion of FIBP impairs lung cancer progression and radioresistance in vitro and in vivo. Mechanistically, we uncovered that FIBP interacts with STAT3 to enhance the transcriptional activity of STAT3, thereby inducing the expression of downstream target gene Eme1. Importantly, we also demonstrated that the biological effects of FIBP were partially dependent on Eme1 in lung cancer. Conclusions: These results reveal that FIBP modulates STAT3/Eme1 axis to drive lung cancer progression and radioresistance, indicating targeting FIBP may be a novel intervention strategy for lung cancer radiotherapy.
2022-06-06 | GSE196635 | GEO
Project description:HER2+ breast cancer (BC) is characterized by rapid growth, early recurrence, early metastasis, and chemoresistance. Trastuzumab is the most effective treatment for HER2+ BC and effectively reduces the risk of recurrence and death of patients. Resistance to trastuzumab results in cancer recurrence and metastasis, leading to poor prognosis of HER2+ BC. In the present study, we found that non-structural maintenance of chromosome condensin 1 complex subunit G (NCAPG) expression was highly upregulated in trastuzumab-resistant HER2+ BC. Ectopic NCAPG was positively correlated with tumor relapse and shorter survival in HER2+ BC patients. Moreover, overexpression of NCAPG promoted, while silencing of NCAPG reduced, the proliferative and anti-apoptotic capacity of HER2+ BC cells both in vitro and in vivo, indicating NCAPG reduces the sensitivity of HER2+ BC cells to trastuzumab and may confer trastuzumab resistance. Furthermore, our results suggest that NCAPG triggers a series of biological cascades by phosphorylating SRC and enhancing nuclear localization and activation of STAT3. To summarize, our study explores a crucial role for NCAPG in trastuzumab resistance and its underlying mechanisms in HER2+ BC, and suggests that NCAPG could be both a potential prognostic marker as well as a therapeutic target to effectively overcome trastuzumab resistance.
| S-EPMC7368860 | biostudies-literature
Project description:Radiotherapy is effective for treating various types of tumors. However, some cancer cells survive after irradiation and repopulate tumors with highly malignant phenotypes that correlate with poor prognosis. It is not known how cancer cells survive and generate malignant tumors after irradiation. Here, we show that activating transcription factor 5 (ATF5) promotes radioresistance and malignancy in cancer cells after irradiation. In the G1-S phase of the cell cycle, cancer cells express high levels of ATF5, which promotes cell cycle progression and thereby increases radioresistance. Furthermore, ATF5 increases malignant phenotypes, such as cell growth and invasiveness, in cancer cells in vitro and in vivo. We have identified a new mechanism for the regeneration of highly malignant tumors after irradiation and shown that ATF5 plays a key role in the process.
| S-EPMC4467102 | biostudies-literature
Project description:BackgroundHepatocellular carcinoma (HCC) is the most common tumors in the worldwide, it develops resistance to radiotherapy during treatment, understanding the regulatory mechanisms of radioresistance generation is the urgent need for HCC therapy.MethodsqRT-PCR, western blot and immunohistochemistry were used to examine MCM3 expression. MTT assay, colony formation assay, terminal deoxynucleotidyl transferase nick end labeling assay and In vivo xenograft assay were used to determine the effect of MCM3 on radioresistance. Gene set enrichment analysis, luciferase reporter assay, western blot and qRT-PCR were used to examine the effect of MCM3 on NF-?B pathway.ResultsWe found DNA replication initiation protein Minichromosome Maintenance 3 (MCM3) was upregulated in HCC tissues and cells, patients with high MCM3 expression had poor outcome, it was an independent prognostic factor for HCC. Cells with high MCM3 expression or MCM3 overexpression increased the radioresistance determined by MTT assay, colony formation assay, TUNEL assay and orthotopic transplantation mouse model, while cells with low MCM3 expression or MCM3 knockdown reduced the radioresistance. Mechanism analysis showed MCM3 activated NF-?B pathway, characterized by increasing the nuclear translocation of p65, the expression of the downstream genes NF-?B pathway and the phosphorylation of IKK-? and I?B?. Inhibition of NF-?B in MCM3 overexpressing cells using small molecular inhibitor reduced the radioresistance, suggesting MCM3 increased radioresistance through activating NF-?B pathway. Moreover, we found MCM3 expression positively correlated with NF-?B pathway in clinic.ConclusionsOur findings revealed that MCM3 promoted radioresistance through activating NF-?B pathway, strengthening the role of MCM subunits in the tumor progression and providing a new target for HCC therapy.
| S-EPMC6580494 | biostudies-literature
Project description:This study was designed to research the influence of activating transcription factor 3 (ATF3) on the radioresistance of breast cancer. ATF3 expression was measured by qRT-PCR and immunohistochemistry. Cancerous cell lines were cultured in vitro, and the expression of ATF3 was gauged by both qRT-PCR and Western blot before and after the radiation therapy. Cellular cycle and apoptosis were analysed by flow cytometry. Changes in the expression of corresponding proteins in the downstream pathways were identified by Western blot. Tumour xenograft was used to evaluate the effect of ATF3 in vivo. ATF3 was observed stronger in breast cancer tissues and cells. After radiation therapy, the expression of ATF3 in breast cancer cells was up-regulated. Silencing ATF3 could promote G2/M phase block, facilitate cell apoptosis and decrease clonogenic survival rate. The overexpression of ATF3 could curb G2/M-phase block, cell apoptosis and increase clonogenic survival rate. Overexpression ATF3 could increase radioresistance by up-regulating the level of phosphorylation of Akt in the PI3K/Akt signalling pathway. Radioresistance of breast cancer cells could be alleviated by inhibiting the PI3K/Akt signalling pathway. ATF3 could also promote radioresistance in vivo. ATF3 gene was able to promote radioresistance of breast cancer cells.
| S-EPMC6156394 | biostudies-literature
Project description:Radiotherapy has been used in the clinic for more than one century and it is recognized as one of the main methods in the treatment of malignant tumors. Signal Transducers and Activators of Transcription 3 (STAT3) is reported to be upregulated in many tumor types, and it is believed to be involved in the tumorigenesis, development and malignant behaviors of tumors. Previous studies also found that STAT3 contributes to chemo-resistance of various tumor types. Recently, many studies reported that STAT3 is involved in the response of tumor cells to radiotherapy. But until now, the role of the STAT3 in radioresistance has not been systematically demonstrated. In this study, we will review the radioresistance induced by STAT3 and relative solutions will be discussed.
| S-EPMC7358404 | biostudies-literature
Project description:Heparin-binding epidermal growth factor-like growth factor (HB-EGF) is essential for maintaining normal function of the adult heart and is known to play an important role in myocardial remodeling. In the present study, we observed that heart-specific HB-EGF transgenic (TG) mice had systolic dysfunction with decreased fractional shortening (FS%), increased end-systolic diameter (LVIDs) at 5 months of age, increased heart fibrosis, and increased mRNA expression of Col1?1 and Col3?1 at 1, 3, 5 and 7 months of age compared to nontransgenic (NTG) littermates. However, the left ventricular anterior wall thickness at end-systole (LVAWs) of the TG mice was not different than the NTG mice. Phosphorylation levels of Akt, mTor and p70s6k were increased due to HB-EGF expression in TG mice compared with the NTG mice at 3 and 7 months of age. Additionally, activated Akt, mTor and p70s6k were co-localized with vimentin to cardiac fibroblasts isolated from TG mice. Furthermore, HB-EGF significantly increased phosphorylation levels of Akt, mTor and p70s6k and increased expression of type I collagen in cultured primary cardiac fibroblasts. Rapamycin (Rapa) and CRM197, inhibitors of mTor and HB-EGF respectively, could inhibit the expression of type I collagen in the cultured primary cardiac fibroblasts and Rapa suppressed interstitial fibrosis of the heart tissues in vivo. In addition, a BrdU assay showed that HB-EGF increased proliferation of cardiac fibroblasts by 30% compared with cells without HB-EGF treatment. HB-EGF-induced proliferation was completely diminished in the presence of Rapa. These results suggest that HB-EGF induced heart fibrosis and proliferation of cardiac fibroblasts occurs through activation of the Akt/mTor/p70s6k pathway.
| S-EPMC3440333 | biostudies-literature
Project description:Recent studies indicate a strong correlation of zinc transporter ZIP4 and pancreatic cancer progression; however, the underlying mechanisms are unclear. We have recently found that ZIP4 is overexpressed in pancreatic cancer. In this study, we investigated the signaling pathway through which ZIP4 regulates pancreatic cancer growth.The expression of cyclin D1, interleukin 6 (IL-6), and signal transducer and activator of transcription 3 (STAT3) in pancreatic cancer xenografts and cells were examined by real-time PCR, Bio-Plex cytokine assay, and Western blot, respectively. The activity of cAMP response element-binding protein (CREB) is examined by a promoter activity assay.Cyclin D1 was significantly increased in the ZIP4 overexpressing MIA PaCa-2 cells (MIA-ZIP4)-injected orthotopic xenografts and was downregulated in the ZIP4-silenced ASPC-1 (ASPC-shZIP4) group. The phosphorylation of STAT3, an upstream activator of cyclin D1, was increased in MIA-ZIP4 cells and decreased in ASPC-shZIP4 cells. IL-6, a known upstream activator for STAT3, was also found to be significantly increased in the MIA-ZIP4 cells and xenografts and decreased in the ASPC-shZIP4 group. Overexpression of ZIP4 led to a 75% increase of IL-6 promoter activity and caused increased phosphorylation of CREB.Our study suggest that ZIP4 overexpression causes increased IL-6 transcription through CREB, which in turn activates STAT3 and leads to increased cyclin D1 expression, resulting in increased cell proliferation and tumor progression in pancreatic cancer. These results elucidated a novel pathway in ZIP4-mediated pancreatic cancer growth and suggest new therapeutic targets, including ZIP4, IL-6, and STAT3, in pancreatic cancer treatment.
| S-EPMC2841320 | biostudies-literature