Dataset Information

IL13Rα2 Is Involved in the Progress of Renal Cell Carcinoma through the JAK2/FOXO3 Pathway.

ABSTRACT: Previously, we reported a close relationship between type II IL4Rα and IL13Rα1 complex and poor outcomes in renal cell carcinoma (RCC). In this study, we investigated the clinicopathologically significant oncogenic role of IL13Rα2, a kind of the independent receptor for IL13, in 229 RCC patients. The high expression of IL13Rα2 was closely related to relapse-free survival in specific cancers in univariate and multivariate analysis. Then, the oncogenic role of IL13Rα2 was evaluated by performing in vitro assays for cell proliferation, cell cycle arrest, and apoptosis in A498, ACHN, Caki1, and Caki2, four kinds of RCC cells after transfection of siRNA against IL13Rα2. Cell proliferation was suppressed, and apoptosis was induced in A498, ACHN, Caki1, and Caki2 cells by knockdown of IL13Rα2. Interestingly, the knockdown of IL13Rα2 decreased the phosphorylation of JAK2 and increased the expression of FOXO3. Furthermore, the knockdown of IL13Rα2 reduced the protein interaction among IL13Rα2, phosphorylated JAK2, and FOXO3. Since phosphorylation of JAK2 was regulated by IL13Rα2, we tried to screen a novel JAK2 inhibitor from the FDA-approved drug library and selected telmisartan, a clinically used medicine against hypertension, as one of the strongest candidates. Telmisartan treatment decreased the cell proliferation rate and increased apoptosis in A498, ACHN, Caki1, and Caki2 cells. Mechanistically, telmisartan treatment decreased the phosphorylation of JAK2 and increased the expression of FOXO3. Taken together, these results suggest that IL13Rα2 regulates the progression of RCC via the JAK2/FOXO3-signaling path pathway, which might be targeted as the novel therapeutic option for RCC patients.

SUBMITTER: Kang MA

PROVIDER: S-EPMC8068290 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Similar Datasets

Project description:BackgroundActivation of renal fibroblasts is a critical mechanism in the process of renal fibrosis. As a commonly used herbal formula, Shenkang (SK) has been found to attenuate renal fibrosis and renal parenchyma destruction. However, the effect of SK on renal fibroblast activation in unilateral ureteral obstruction (UUO) mice and its molecular mechanism remain undetermined. The present study was performed to elucidate the effect of SK on renal fibroblast activation and renal fibrosis, as well as the potential underlying mechanism, in both NRK-49F cells and UUO mice.MethodsNRK-49F cells were stimulated with 10 ng/ml TGF-β1 for 48 h. After SK treatment, the CCK-8 method was used to evaluate cell viability. Thirty-six C57BL/6 mice were randomly divided into the sham group, UUO group, angiotensin receptor blocker (ARB) group, and SK high-, moderate- and low-dose groups. UUO was induced in mice except those in the sham group. Drugs were administered 1 day later. On the 13th day, the fractional anisotropy (FA) value was determined by MRI to evaluate the degree of renal fibrosis. After 14 days, serum indexes were assessed. Hematoxylin and eosin (HE) and Sirius red staining were used to observe pathological morphology and the degree of fibrosis of the affected kidney. Western blotting and PCR were used to assess the expression of related molecules in both cells and animals at the protein and gene levels.ResultsOur results showed that SK reduced extracellular matrix (ECM) and α-smooth muscle actin (α-SMA) expression both in vitro and in vivo and attenuated renal fibrosis and the pathological lesion degree after UUO, suppressing JAK2/STAT3 activation. Furthermore, we found that SK regulated the JAK2/STAT3 pathway regulators peroxiredoxin 5 (Prdx5) in vitro and suppressor of cytokine signaling protein 1 (SOCS1) and SOCS3 in vivo.ConclusionsThese results indicated that SK inhibited fibroblast activation by regulating the JAK2/STAT3 pathway, which may be a mechanism underlying its protective action in renal fibrosis.

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

IL13Rα2 Is Involved in the Progress of Renal Cell Carcinoma through the JAK2/FOXO3 Pathway.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets