Cell communication and signaling : CCS · 2026
Loss of cold shock domain-containing protein E1 (CSDE1) function enhances mRNA stability of interleukin-6 and promotes malignant transformation in endometrial cancer cells.
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Liu Yuanlin, Qiao Lianqiao, Wen Xiaoli, Wang Mengfei, Li Junyuan, Ding Yan, Tao Han, Dai Yilin, Wang Luhui, Gao Kun, Wan Xiaoping
Аннотация
BACKGROUND: RNA-binding proteins (RBPs) are indispensable effectors of post-transcriptional gene regulation and are increasingly recognized as pivotal modulators of oncogenic signaling pathways. Cold shock domain-containing protein E1 (CSDE1) has been reported to be dysregulated or mutated in several malignancies; however, its functional significance and the mechanistic basis of its involvement in endometrial cancer (EC) progression remain poorly understood.
METHODS: Bioinformatic analysis of The Cancer Genome Atlas (TCGA) was employed to characterize CSDE1 expression and mutation profiles in EC. CRISPR/Cas9-mediated knockout (KO) was used to establish CSDE1-deficient EC cell lines. The impact on cell proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT) was evaluated through standard functional assays. To identify downstream targets, transcriptomic profiling was integrated with RNA-protein interaction assay and mRNA stability analysis. Finally, functional rescue experiments were conducted using shRNA-mediated IL-6 silencing and pharmacological inhibition with the IL-6 antagonist Siltuximab.
RESULTS: CSDE1 is frequently mutated and significantly downregulated in EC tissues compared to normal controls. Loss of CSDE1 markedly accelerated EC cell proliferation, migration, invasion, and the acquisition of EMT-associated phenotypes. Transcriptomic analysis identified IL-6 as a prominent downstream target that is significantly upregulated upon CSDE1 depletion. Mechanistically, CSDE1 directly binds to IL-6 mRNA and negatively regulates its stability, thereby restraining IL-6 expression. Notably, both genetic silencing of IL-6 and pharmacological neutralization of IL-6 signaling with Siltuximab effectively abrogated the aggressive malignant phenotypes induced by CSDE1 loss.
CONCLUSIONS: These findings establish CSDE1 as a novel tumor suppressor in EC and elucidate a previously unrecognized post-transcriptional CSDE1-IL-6 regulatory axis. By linking RBP-mediated mRNA stability to oncogenic inflammatory signaling, our study provides critical insights into the molecular drivers of EC progression. Furthermore, we identify the IL-6 signaling pathway as a significant therapeutic vulnerability that could be exploited to treat CSDE1-deficient EC.
METHODS: Bioinformatic analysis of The Cancer Genome Atlas (TCGA) was employed to characterize CSDE1 expression and mutation profiles in EC. CRISPR/Cas9-mediated knockout (KO) was used to establish CSDE1-deficient EC cell lines. The impact on cell proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT) was evaluated through standard functional assays. To identify downstream targets, transcriptomic profiling was integrated with RNA-protein interaction assay and mRNA stability analysis. Finally, functional rescue experiments were conducted using shRNA-mediated IL-6 silencing and pharmacological inhibition with the IL-6 antagonist Siltuximab.
RESULTS: CSDE1 is frequently mutated and significantly downregulated in EC tissues compared to normal controls. Loss of CSDE1 markedly accelerated EC cell proliferation, migration, invasion, and the acquisition of EMT-associated phenotypes. Transcriptomic analysis identified IL-6 as a prominent downstream target that is significantly upregulated upon CSDE1 depletion. Mechanistically, CSDE1 directly binds to IL-6 mRNA and negatively regulates its stability, thereby restraining IL-6 expression. Notably, both genetic silencing of IL-6 and pharmacological neutralization of IL-6 signaling with Siltuximab effectively abrogated the aggressive malignant phenotypes induced by CSDE1 loss.
CONCLUSIONS: These findings establish CSDE1 as a novel tumor suppressor in EC and elucidate a previously unrecognized post-transcriptional CSDE1-IL-6 regulatory axis. By linking RBP-mediated mRNA stability to oncogenic inflammatory signaling, our study provides critical insights into the molecular drivers of EC progression. Furthermore, we identify the IL-6 signaling pathway as a significant therapeutic vulnerability that could be exploited to treat CSDE1-deficient EC.