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Background <p>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.</p> Methods <p>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 <i>CSDE1</i>-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.</p> Results <p>CSDE1 is frequently mutated and significantly downregulated in EC tissues compared to normal controls. Loss of <i>CSDE1</i> 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.</p> Conclusions <p>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 <i>CSDE1</i>-deficient EC.</p>

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Loss of cold shock domain-containing protein E1 (CSDE1) function enhances mRNA stability of interleukin-6 and promotes malignant transformation in endometrial cancer cells

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月23日

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  • Yuanlin Liu,
  • Lianqiao Qiao,
  • Xiaoli Wen,
  • Mengfei Wang,
  • Junyuan Li,
  • Yan Ding,
  • Han Tao,
  • Yilin Dai,
  • Luhui Wang,
  • Kun Gao,
  • Xiaoping Wan

摘要

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.