IRAK2 Downregulation in Triple-Negative Breast Cancer Cells Decreases Cellular Growth In Vitro and Delays Tumour Progression in Murine Models

Ferraro, Francesca; Steinle, Anja; Narasimhan, Harini; Bleilevens, Andreas; Stolzenberg, Paula-Marie; Braunschweig, Till; Stickeler, Elmar; Maurer, Jochen

doi:10.3390/ijms24032520

Cited by 3 publications

(2 citation statements)

References 37 publications

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“…IRAK2 knockdown has led to a significant impairment of pancreatic cancer cell proliferation [ 11 ]. IRAK2 has also been found to be expressed in triple-negative breast cancer cells, and its downregulation decreases tumor growth [ 12 ]. A previous study has demonstrated an association between IRAK2 expression and post-radiotherapy (post-RT) outcomes [ 10 ]; however, its clinical application is limited because only a specific population (i.e., only early-stage I–II patients) was enrolled.…”

Section: Introductionmentioning

confidence: 99%

IRAK2, an Immune and Radiation-Response Gene, Correlates with Advanced Disease Features but Predicts Higher Post-Irradiation Local Control in Non-Metastatic and Resected Oral Cancer Patients

Lin

Hsieh

et al. 2023

IJMS

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Gene Ontology (GO) analysis can provide a comprehensive function analysis for investigating genes, allowing us to identify the potential biological roles of genes. The present study conducted GO analysis to explore the biological function of IRAK2 and performed a case analysis to define its clinical role in disease progression and mediating tumor response to RT. Methods: We performed a GO enrichment analysis on the RNA-seq data to validate radiation-induced gene expression. A total of 172 I-IVB specimens from oral squamous cell carcinoma patients were collected for clinical analysis, from which IRAK2 expression was analyzed by immunohistochemistry. This was a retrospective study conducted between IRAK2 expression and the outcomes of oral squamous cell carcinoma patients after radiotherapy treatment. We conducted Gene Ontology (GO) analysis to explore the biological function of IRAK2 and performed a case analysis to define its clinical role in mediating tumor response to radiotherapy. GO enrichment analysis to validate radiation-induced gene expression was performed. Clinically, 172 stage I-IVB resected oral cancer patients were used to validate IRAK2 expression in predicting clinical outcomes. GO enrichment analysis showed that IRAK2 is involved in 10 of the 14 most enriched GO categories for post-irradiation biological processes, focusing on stress response and immune modulation. Clinically, high IRAK2 expression was correlated with adverse disease features, including pT3-4 status (p = 0.01), advanced overall stage (p = 0.02), and positive bone invasion (p = 0.01). In patients who underwent radiotherapy, the IRAK2-high group was associated with reduced post-irradiation local recurrence (p = 0.025) compared to the IRAK2-low group. IRAK2 plays a crucial role in the radiation-induced response. Patients with high IRAK2 expression demonstrated more advanced disease features but predicted higher post-irradiation local control in a clinical setting. These findings support IRAK2 as a potential predictive biomarker for radiotherapy response in non-metastatic and resected oral cancer patients.

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Section: Introductionmentioning

confidence: 99%

IRAK2, an Immune and Radiation-Response Gene, Correlates with Advanced Disease Features but Predicts Higher Post-Irradiation Local Control in Non-Metastatic and Resected Oral Cancer Patients

Lin

Hsieh

et al. 2023

IJMS

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“…IRAK2 regulates various signaling pathways, including the nuclear factor-kappa B (NF-κB) signaling pathway [ 11 ]. IRAK2 can lead to TRAF6 ubiquitination, which is a key event in NF-κB activation [ 12 ].…”

Section: Introductionmentioning

confidence: 99%

Interleukin-1 receptor-associated kinase 2 promotes inflammatory reactions by activating the nuclear factor kappa-B signaling pathway in diabetic nephropathy

Liu,

Xu,

Cheng

et al. 2023

cejoi

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Diabetic nephropathy (DN) is a major complication of diabetes. Interleukin-1 receptor-associated kinase 2 (IRAK2) has been implicated in various diseases. This study aimed to investigate the role of IRAK2 in DN progression and its association with inflammation and the nuclear factor-kappa B (NF-κB) signaling pathway. DN model mice were generated by intraperitoneal injection of streptozotocin. IRAK2 expression was upregulated in the DN model mice. IRAK2 knockdown increased weight and reduced blood glucose levels in DN model mice. In addition, IRAK2 downregulation improved glomerular morphology in DN mice. IRAK2 knockdown reduced the levels of kidney damage biomarkers (24-h urinary protein, urine albumin-creatinine ratio, and plasma creatinine) and inflammatory cytokines (IL-6, tumor necrosis factor [TNF]-α, TNF-1R, and TNF-2R). Moreover, IRAK2 activated the NF-κB signaling pathway in DN model mice. Overexpression of NF-κB exacerbated DN progression, and IRAK2 knockdown reversed these effects. IRAK2 promoted DN progression and inflammation by activating the NF-κB signaling pathway. These findings suggest that IRAK2 is a potential therapeutic target for DN treatment.

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Adipsin inhibits Irak2 mitochondrial translocation and improves fatty acid β-oxidation to alleviate diabetic cardiomyopathy

Jiang,

Man,

Zhang

et al. 2023

Military Med Res

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Background Diabetic cardiomyopathy (DCM) causes the myocardium to rely on fatty acid β-oxidation for energy. The accumulation of intracellular lipids and fatty acids in the myocardium usually results in lipotoxicity, which impairs myocardial function. Adipsin may play an important protective role in the pathogenesis of DCM. The aim of this study is to investigate the regulatory effect of Adipsin on DCM lipotoxicity and its molecular mechanism. Methods A high-fat diet (HFD)-induced type 2 diabetes mellitus model was constructed in mice with adipose tissue-specific overexpression of Adipsin (Adipsin-Tg). Liquid chromatography-tandem mass spectrometry (LC–MS/MS), glutathione-S-transferase (GST) pull-down technique, Co-immunoprecipitation (Co-IP) and immunofluorescence colocalization analyses were used to investigate the molecules which can directly interact with Adipsin. The immunocolloidal gold method was also used to detect the interaction between Adipsin and its downstream modulator. Results The expression of Adipsin was significantly downregulated in the HFD-induced DCM model (P < 0.05). Adipose tissue-specific overexpression of Adipsin significantly improved cardiac function and alleviated cardiac remodeling in DCM (P < 0.05). Adipsin overexpression also alleviated mitochondrial oxidative phosphorylation function in diabetic stress (P < 0.05). LC–MS/MS analysis, GST pull-down technique and Co-IP studies revealed that interleukin-1 receptor-associated kinase-like 2 (Irak2) was a downstream regulator of Adipsin. Immunofluorescence analysis also revealed that Adipsin was co-localized with Irak2 in cardiomyocytes. Immunocolloidal gold electron microscopy and Western blotting analysis indicated that Adipsin inhibited the mitochondrial translocation of Irak2 in DCM, thus dampening the interaction between Irak2 and prohibitin (Phb)-optic atrophy protein 1 (Opa1) on mitochondria and improving the structural integrity and function of mitochondria (P < 0.05). Interestingly, in the presence of Irak2 knockdown, Adipsin overexpression did not further alleviate myocardial mitochondrial destruction and cardiac dysfunction, suggesting a downstream role of Irak2 in Adipsin-induced responses (P < 0.05). Consistent with these findings, overexpression of Adipsin after Irak2 knockdown did not further reduce the accumulation of lipids and their metabolites in the cardiac myocardium, nor did it enhance the oxidation capacity of cardiomyocytes expose to palmitate (PA) (P < 0.05). These results indicated that Irak2 may be a downstream regulator of Adipsin. Conclusions Adipsin improves fatty acid β-oxidation and alleviates mitochondrial injury in DCM. The mechanism is related to Irak2 interaction and inhibition of Irak2 mitochondrial translocation.

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IRAK2 Downregulation in Triple-Negative Breast Cancer Cells Decreases Cellular Growth In Vitro and Delays Tumour Progression in Murine Models

Cited by 3 publications

References 37 publications

IRAK2, an Immune and Radiation-Response Gene, Correlates with Advanced Disease Features but Predicts Higher Post-Irradiation Local Control in Non-Metastatic and Resected Oral Cancer Patients

IRAK2, an Immune and Radiation-Response Gene, Correlates with Advanced Disease Features but Predicts Higher Post-Irradiation Local Control in Non-Metastatic and Resected Oral Cancer Patients

Interleukin-1 receptor-associated kinase 2 promotes inflammatory reactions by activating the nuclear factor kappa-B signaling pathway in diabetic nephropathy

Adipsin inhibits Irak2 mitochondrial translocation and improves fatty acid β-oxidation to alleviate diabetic cardiomyopathy

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