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LINC00654 promotes ovarian cancer progression by facilitating nuclear export of HuR and stabilizing oncogenic mRNAs

Oncogene volume 44, pages 3422–3436 (2025)Cite this article

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Abstract

Ovarian cancer (OC) remains a significant challenge in oncology due to its late diagnosis and poor prognosis. Emerging evidence suggests that long non-coding RNAs (lncRNAs) play critical roles in cancer biology. Herein, we reported that LINC00654 was highly expressed in OC tissues and correlated with poor patient prognosis. In addition, LINC00654 silencing restrained OC cell proliferation and migration in vitro and in vivo. Mechanically, LINC00654 was identified to directly interact with Human antigen R (HuR), a known RNA-binding protein, through RNA pull-down, RNA immunoprecipitation (RIP), and cross‑linking immunoprecipitation (CLIP). Further analysis revealed that LINC00654 could induce the translocation of HuR from the nucleus to the cytosol, where it regulated the stability of its target oncogenes, such as VASH2. The stabilization of VASH2 subsequently activated the TGF-β pathway, which is known to play a critical role in cancer progression. Taken together, these findings establish a specific mechanism by which LINC00654 interacts with HuR, facilitates its nuclear export, and stabilizes VASH2, thereby activating the TGF-β pathway and promoting OC progression. This insight into LINC00654’s role in OC provides potential therapeutic targets for intervention.

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Fig. 1: LINC00654 is upregulated in OC and predicts poor prognosis.
Fig. 2: LINC00654 knockdown suppresses OC cell proliferation and migratory ability in vitro.
Fig. 3: LINC00654 knockdown suppresses OC cell proliferation and metastasis in vivo.
Fig. 4: LINC00654 interacts with HuR in OC cells.
Fig. 5: Effects of HuR knockdown on OC cell viability and migratory capacity in vitro.
Fig. 6: Identification of LINC00654 and HuR downstream targets in OC.
Fig. 7: “LINC00654-HuR” stabilizes the VASH2 mRNA transcript via its 3′UTR.
Fig. 8: Targeting the TGF-β pathway reverses the oncogenic effects of LINC00654 on OC progression.
Fig. 9: Proposed mechanism for LINC00654 regulation of HuR and its effects on OC cell proliferation and migration.

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Data availability

The mass spectrometry proteomics data are available in the ProteomeXchange Consortium through the PRIDE partner repository (accession number PXD051820). The RNA-Seq datasets generated during the current study are available in the ArrayExpress repository (accession number E-MTAB-14741). All data are available from the corresponding author upon reasonable request.

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Funding

This work was supported by the National Natural Science Foundation of China (82001576) and the Suzhou Gu Su Health Talent Research Project (GSWS2023056).

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Author notes

  1. These authors contributed equally: Cong Shen, Ruican Cao, Qiao Zhou, Tao Zhou.

Authors and Affiliations

  1. State Key Laboratory of Reproductive Medicine and Offspring Health, Center for Reproduction and Genetics, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School of Nanjing Medical University, Suzhou, China

    Cong Shen, Ruican Cao, Tiantian Wu, Gaigai Wang, Longwei Qiao & Ting Wang

  2. Department of Reproduction, The Affiliated Obstetrics and Gynecology Hospital of Nanjing Medical University, Nanjing Maternity and Child Health Care Hospital, Nanjing, China

    Qiao Zhou

  3. Research Institute for Reproductive Medicine and Genetic Diseases, Wuxi Maternity and Child Health Care Hospital, Wuxi, China

    Tao Zhou

  4. State Key Laboratory of Reproductive Medicine and Offspring Health, Department of Histology and Embryology, School of Basic Medical Sciences, Nanjing Medical University, Nanjing, China

    Wenxin Gao

  5. Department of Gynaecology, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School of Nanjing Medical University, Suzhou, China

    Guannan Feng

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Contributions

CS: conceptualization, funding acquisition, investigation, supervision, writing revised draft. RC: data curation, formal analysis, writing – original draft. QZ: investigation, data curation. TZ: data curation, visualization. TTW, investigation, data curation. WG, investigation, methodology. GW: investigation, validation. GF: conceptualization, supervision, project administration. LQ: funding acquisition, supervision. TW: supervision, project administration.

Corresponding authors

Correspondence to Cong Shen, Guannan Feng, Longwei Qiao or Ting Wang.

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The authors declare no competing interests.

Ethics statement

All human procedures received approval from the Ethical Committee of the Affiliated Suzhou Hospital of Nanjing Medical University (No. 2022012), adhering to the World Medical Association’s Declaration of Helsinki, and written informed consent was obtained from each patient. All animal procedures were approved by the Animal Ethics Committee of Nanjing Medical University (No. 2402015) and performed according to the ARRIVE guidelines.

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Shen, C., Cao, R., Zhou, Q. et al. LINC00654 promotes ovarian cancer progression by facilitating nuclear export of HuR and stabilizing oncogenic mRNAs. Oncogene 44, 3422–3436 (2025). https://doi.org/10.1038/s41388-025-03500-2

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