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CCT2 prevented β-catenin proteasomal degradation to sustain cancer stem cell traits and promote tumor progression in epithelial ovarian cancer

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Abstract

Background

Epithelial ovarian cancer (EOC) is featured by rapid progression and dismal outcomes clinically. Chaperonin Containing TCP1 Subunit 2 (CCT2) was identified as a crucial regulator for tumor progression, however, its exact role in EOC remained largely unknown.

Methods

CCT2 expression and prognostic value in EOC samples were assessed according to TCGA dataset. Proliferation and mobility potentials were assessed by CCK8, colony-formation, wound healing, and Transwell assays. Cancer stem cell (CSC) traits were evaluated by RT-PCR, WB assays, sphere-forming assay and chemoresistance analysis. Bioinformatic analysis, co-IP assays and ubiquitin assays were performed to explore the mechanisms of CCT2 on EOC cells.

Results

CCT2 highly expressed in EOC tissues and predicted poor prognosis of EOC patients by TCGA analysis. Silencing CCT2 significantly restrained cell proliferation, migration, and invasion. Moreover, CCT2 could effectively trigger epithelial-mesenchymal transition to confer extensive invasion potentials to EOC cells, Importantly, CCT2 positively correlated with CSC markers in EOC, and CCT2 knockdown impaired CSC traits and sensitize EOC cells to conventional chemotherapy regimens. Contrarily, overexpressing CCT2 achieved opposite results. Mechanistically, CCT2 exerted its pro-oncogene function by triggering Wnt/β-catenin signaling. Specifically, CCT2 could recruit HSP105-PP2A complex, a well-established dephosphorylation complex, to β-catenin via direct physical interaction to prevent phosphorylation-induced proteasomal degradation of β-catenin, resulting in intracellular accumulation of active β-catenin and increased signaling activity.

Conclusions

CCT2 was a novel promotor for EOC progression and a crucial sustainer for CSC traits mainly by preventing β-catenin degradation. Targeting CCT2 may represent a promising therapeutic strategy for EOC.

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Data availability

The authors declare that the data supporting the findings of this study are available within the paper and its Supplementary Information files. Raw data are available from the corresponding author upon reasonable request.

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Authors and Affiliations

  1. Department of Laboratory Medicine, Zhoushan Hospital of Zhejiang Province, Zhoushan, 316021, Zhejiang, China

    Jiayao Chen, Qiong Hu & Chenhao Zhou

  2. Pathological Diagnosis Center, Zhoushan Hospital of Zhejiang Province, Zhoushan, 316021, Zhejiang, China

    Danwen Jin

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Contributions

JC designed, drafted, and supervised the project. QH performed statistical analyses. CZ and DJ research literatures. All authors revised the manuscript.

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Correspondence to Jiayao Chen.

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Chen, J., Hu, Q., Zhou, C. et al. CCT2 prevented β-catenin proteasomal degradation to sustain cancer stem cell traits and promote tumor progression in epithelial ovarian cancer. Mol Biol Rep 51, 54 (2024). https://doi.org/10.1007/s11033-023-09047-3

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