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Targeting Cyclin Y Inhibits STAT3 Activation to Enhance Radiosensitivity via Down-regulation of RRM2 in Lung Cancer

ABSTRACT: Purpose: Radioresistance is a main reason for the recurrence and metastasis of lung cancer. Cyclin Y is involved in normal physiological processes such as cell proliferation, growth and metabolism, as well as in the development of certain cancers. However, the function and mechanism of Cyclin Y in lung cancer are still unclear.Methods: Lung cancer cell lines were subjected to Cyclin Y knockdown using small interfering RNA (siRNA), and their growth and proliferation were assessed in vitro. Comet assay, γH2AX/Rad51 foci formation assay and clonogenic cell survival assay were performed to assess DNA damage and the DNA repair capacity. SgRNA transfection was applied to construct cell lines with stable Cyclin Y knockdown. Xenograft mouse models were used to validate the findings in vivo. RNA sequencing (RNA-seq) analysis was conducted to clarify the downstream target genes of Cyclin Y. Western blotting was employed to measure protein expression.Results: Cyclin Y was overexpressed in lung cancer, correlating with poor prognosis. Cyclin Y knockdown inhibited cell growth and proliferation, increased DNA damage, inhibited DNA damage repair and increased radiosensitivity in vitro and in vivo. RNA-seq analysis was used to reveal RRM2 as a downstream target gene of Cyclin Y. Cyclin Y depletion down-regulated the protein and mRNA levels of RRM2, leading to reduced STAT3 phosphorylation. Rescue experiments demonstrated that the effect of Cyclin Y on lung cancer was mediated partially by RRM2.Conclusions: We revealed for the first time that targeting Cyclin Y inhibits tumorigenesis and promotes radiosensitivity in lung cancer partially through the RRM2-STAT3 signaling pathway.

ORGANISM(S): Homo sapiens

PROVIDER: GSE246182 | GEO | 2024/10/01

REPOSITORIES: GEO

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Project description:Signal transducer and activator of transcription 3 (STAT3) is altered in several epithelial cancers and represents a potential therapeutic target. Here, STAT3 expression, activity and cellular functions were examined in two main histotypes of esophageal carcinomas. In situ, immunohistochemistry for STAT3 and STAT3-Tyr705 phosphorylation (P-STAT3) in esophageal squamous cell carcinomas (ESCC) and BarrettM-bM-^@M-^Ys adenocarcinomas (BAC) revealed similar STAT3 expression in ESCCs and BACs, but preferentially activated P-STAT3 in ESCCs. In vitro, strong STAT3 activation was seen by EGF-stimulation in OE21 (ESCC) cells, whilst OE33 (BAC) cells showed constitutive weak STAT3 activation. STAT3 knockdown significantly reduced cell proliferation of OE21 and OE33 cells and reduced cell migration in OE33, but not in OE21 cells. Transcriptome analysis identified STAT3-knockdown associated down-regulation of cell cycle processes and the selective down-regulation of cyclins and cyclin dependent kinaes associated genes in both OE21 and OE33 cells. Moreover, the transcriptome response showed changes in cell migration/invasion related genes that correlated with the associated phenotype measurements. This study demonstrates the importance of STAT3 expression and activation in esophageal carcinomas, whereby the extent differs between ESCCs and BACs. STAT3 knockdown significantly reduces cell proliferation in both types of esophageal cancer cells and inhibits migration in BAC cells. Thus, STAT3 may be further exploited as potential novel therapeutic target for esophageal cancers. The effect of STAT3 knock-down in OE33 and OE21 cells was calculated from three biologically independent experiments. 3x10e4 cells were seeded in triplicate in 24 well-plates and were transfected with twice 100nM STAT3 siRNA (pool of 4 STAT3 sequences, siGENOMEM-BM-.SMARTpoolM-BM-., Dharmacon RNAi Technologies, Thermo Fisher Scientific, Lafayette, USA) or SilencerM-BM-. negative siRNA control (Invitrogen/Life Technologies GmbH, Darmstadt, Germany) using 1M-BM-5l DharmaFECT (Dharmacon RNAi Technologies, Thermo Fisher Scientific, Lafayette, USA) transfection reagent for OE33 cells or siPORTTM NeoFXTM (Invitrogen/Life Technologies GmbH, Darmstadt, Germany) transfection reagent for OE21 cells. Differential gene regulation was quantified 72 hours after the first transfection by comparing separately for the OE21 and OE33 cells the STAT3 siRNA replicates and the respective cell lines containing the scrambled siRNA vector.

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Targeting Cyclin Y Inhibits STAT3 Activation to Enhance Radiosensitivity via Down-regulation of RRM2 in Lung Cancer

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