2. Academic Validation
  3. The lncRNA THOR interacts with and stabilizes hnRNPD to promote cell proliferation and metastasis in breast cancer

The lncRNA THOR interacts with and stabilizes hnRNPD to promote cell proliferation and metastasis in breast cancer

  • Oncogene. 2022 Nov 3. doi: 10.1038/s41388-022-02495-4.
Hongtao Hu # 1 2 3,  Hanqiu Zhang # 2 3,  Yue Xing 4 5,  Yan Zhou 4 5,  Jianing Chen 4 5,  Cheng Li 3 6,  Jingjing Xu 2 3,  Yanyan Guo 2,  Jie Wang 2,  Qi He 2,  Xinmei Liu 3 6 7,  Jianzhong Sheng 8,  Erwei Song 4 5,  Yanting Wu 9,  Hefeng Huang 10 11 12
Affiliations

Affiliations

  • 1 Department of Gynecology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
  • 2 International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
  • 3 Shanghai Key Laboratory of Embryo Original Diseases, Shanghai, China.
  • 4 Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China.
  • 5 Breast Tumor Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China.
  • 6 Obstetrics and Gynecology Hospital, Institute of Reproduction and Development, Fudan University, Shanghai, China.
  • 7 Research Units of Embryo Original Diseases, Chinese Academy of Medical Sciences, Shanghai, China.
  • 8 Department of Pathology and Pathophysiology, School of Medicine, Zhejiang University, Hangzhou, China.
  • 9 Obstetrics and Gynecology Hospital, Institute of Reproduction and Development, Fudan University, Shanghai, China. yanting_wu@163.com.
  • 10 Shanghai Key Laboratory of Embryo Original Diseases, Shanghai, China. huanghefg@sjtu.edu.cn.
  • 11 Obstetrics and Gynecology Hospital, Institute of Reproduction and Development, Fudan University, Shanghai, China. huanghefg@sjtu.edu.cn.
  • 12 Research Units of Embryo Original Diseases, Chinese Academy of Medical Sciences, Shanghai, China. huanghefg@sjtu.edu.cn.
  • # Contributed equally.
PMID: 36329124 DOI: 10.1038/s41388-022-02495-4
Abstract

Emerging evidence shows that the lncRNA THOR is deeply involved in the development of various cancers. However, the effects and underlying molecular mechanisms of THOR in breast Cancer (BRCA) initiation and progression have not been fully elucidated. Here we show that THOR is critical for BRCA tumorigenesis by interacting with hnRNPD to regulate downstream signaling pathways. THOR expression was significantly higher in BRCA tissues than in normal tissues, and THOR upregulation was associated with a poor prognosis in BRCA patients. Functionally, THOR knockdown impaired cell proliferation, migration and invasion in BRCA cells in vitro and inhibited tumorigenesis and metastasis in a tumor xenograft model and THOR-deficient MMTV-PyMT model in vivo. Mechanistically, THOR bound to the hnRNPD protein and increased hnRNPD protein levels by maintaining hnRNPD protein stability through inhibition of the proteasome-dependent degradation pathway. The increased hnRNPD protein levels led to stabilization of its target mRNAs, including pyruvate dehydrogenase kinase 1 (PDK1), further activating downstream PI3K-AKT and MAPK signaling pathways to regulate BRCA cell proliferation and metastasis. Together, our findings indicate that THOR is a promising prognostic predictor for BRCA patients and that the THOR-hnRNPD-PDK1-MAPK/PI3K-AKT axis might be a potential therapeutic target for BRCA treatment.

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