piRNA-1742 promotes renal cell carcinoma malignancy by regulating USP8 stability through binding to hnRNPU and thereby inhibiting MUC12 ubiquitination

  • Exp Mol Med. 2023 Jun 19. doi: 10.1038/s12276-023-01010-3.
Wentao Zhang  #  1  2 ,  Zongtai Zheng  #  3 ,  Keyi Wang  #  1  2 ,  Weipu Mao  #  1  2  4 ,  Xue Li  5 ,  Guangchun Wang  1  2 ,  Yuanyuan Zhang  6 ,  Jianhua Huang  1  2 ,  Ning Zhang  7 ,  Pengfei Wu  1  2 ,  Ji Liu  1  2 ,  Haimin Zhang  1  2 ,  Jianping Che  1  2 ,  Bo Peng  8  9 ,  Junhua Zheng  10  11 ,  Wei Li  12  13  14 ,  Xudong Yao  15  16
Affiliations
  • 1. Department of Urology, Shanghai Tenth People's Hospital, Tongji University, Shanghai, P. R. China.
  • 2. Urologic Cancer Institute, School of Medicine, Tongji University, Shanghai, P. R. China.
  • 3. Department of Urology, Guangdong Second Provincial General Hospital, Guangzhou, P. R. China.
  • 4. Department of Urology, Affiliated Zhongda Hospital of Southeast University, Nanjing, P. R. China.
  • 5. Department of Pathology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, P. R. China.
  • 6. Institute for Regenerative Medicine, Wake Forest University, Winston-Salem, NC, USA.
  • 7. Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
  • 8. Department of Urology, Shanghai Tenth People's Hospital, Tongji University, Shanghai, P. R. China. [email protected].
  • 9. Urologic Cancer Institute, School of Medicine, Tongji University, Shanghai, P. R. China. [email protected].
  • 10. State Key Laboratory of Oncogenes and Related Genes, Shanghai Jiao Tong University, Shanghai, P. R. China. [email protected].
  • 11. Department of Urology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, P. R. China. [email protected].
  • 12. Department of Urology, Shanghai Tenth People's Hospital, Tongji University, Shanghai, P. R. China. [email protected].
  • 13. Urologic Cancer Institute, School of Medicine, Tongji University, Shanghai, P. R. China. [email protected].
  • 14. Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA. [email protected].
  • 15. Department of Urology, Shanghai Tenth People's Hospital, Tongji University, Shanghai, P. R. China. [email protected].
  • 16. Urologic Cancer Institute, School of Medicine, Tongji University, Shanghai, P. R. China. [email protected].
  • # Contributed equally.
PMID: 37332045 DOI: 10.1038/s12276-023-01010-3
Abstract

Accumulating studies have confirmed that PIWI-interacting RNAs (piRNAs) are considered epigenetic effectors in Cancer. We performed piRNA microarray expression analysis on renal cell carcinoma (RCC) tumor tissues and paired normal tissues and performed a series of in vivo and in vitro experiments to explore piRNAs associated with RCC progression and investigate their functional mechanisms. We found that piR-1742 was highly expressed in RCC tumors and that patients with high piR-1742 expression had a poor prognosis. Inhibition of piR-1742 significantly reduced tumor growth in RCC xenograft and Organoid models. Mechanistically, piRNA-1742 regulates the stability of USP8 mRNA by binding directly to hnRNPU, which acts as a deubiquitinating enzyme that inhibits the ubiquitination of MUC12 and promotes the development of malignant RCC. Subsequently, nanotherapeutic systems loaded with piRNA-1742 inhibitors were found to effectively inhibit the metastasis and growth of RCC in vivo. Therefore, this study highlights the functional importance of piRNA-related ubiquitination in RCC and demonstrates the development of a related nanotherapeutic system, possibly contributing to the development of therapeutic approaches for RCC.

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