2. Academic Validation
  3. HOXD9/miR-451a/PSMB8 axis is implicated in the regulation of cell proliferation and metastasis via PI3K/AKT signaling pathway in human anaplastic thyroid carcinoma

HOXD9/miR-451a/PSMB8 axis is implicated in the regulation of cell proliferation and metastasis via PI3K/AKT signaling pathway in human anaplastic thyroid carcinoma

  • J Transl Med. 2023 Nov 16;21(1):817. doi: 10.1186/s12967-023-04538-0.
Yong Zhong # 1,  Fan Yu # 2,  Ling Yang # 1,  Yu Wang 3,  Lin Liu 1,  Chengyou Jia 1,  Haidong Cai 1,  Jianshe Yang 1,  Shiyang Sheng 1,  Zhongwei Lv 4 5,  Li Weng 6,  Bo Wu 7 8,  Xiaoping Zhang 9
Affiliations

Affiliations

  • 1 Department of Nuclear Medicine, Shanghai Tenth People's Hospital, Tongji University, Shanghai, 200072, China.
  • 2 Department of General Surgery, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 600 Yishan Road, Shanghai, 200233, China.
  • 3 Department of Head and Neck Surgery, Fudan University Shanghai Cancer Center, Shanghai, China.
  • 4 Department of Nuclear Medicine, Shanghai Tenth People's Hospital, Tongji University, Shanghai, 200072, China. shtjnmd@163.com.
  • 5 Department of Nuclear Medicine, Shanghai Tenth People's Hospital, Tongji University and Shanghai Center of Thyroid Diseases, No. 301 Middle Yanchang Road, Shanghai, 200072, China. shtjnmd@163.com.
  • 6 Department of Intervention, Tongren Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200336, China. 3822@shtrhospital.com.
  • 7 Department of General Surgery, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 600 Yishan Road, Shanghai, 200233, China. wubo7421@sohu.com.
  • 8 Center of Thyroid, Department of General Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, 200233, China. wubo7421@sohu.com.
  • 9 Department of Nuclear Medicine, Shanghai Tenth People's Hospital, Tongji University, Shanghai, 200072, China. zxpkxy@tongji.edu.cn.
  • # Contributed equally.
PMID: 37974228 DOI: 10.1186/s12967-023-04538-0
Abstract

Anaplastic thyroid carcinoma (ATC) is a deadly disease with a poor prognosis. Thus, there is a pressing need to determine the mechanism of ATC progression. The homeobox D9 (HOXD9) transcription factor has been associated with numerous malignancies but its role in ATC is unclear. In the present study, the carcinogenic potential of HOXD9 in ATC was investigated. We assessed the differential expression of HOXD9 on cell proliferation, migration, invasion, Apoptosis, and epithelial-mesenchymal transition (EMT) in ATC and explored the interactions between HOXD9, microRNA-451a (miR-451a), and Proteasome 20S subunit beta 8 (PSMB8). In addition, subcutaneous tumorigenesis and lung metastasis in mouse models were established to investigate the role of HOXD9 in ATC progression and metastasis in vivo. HOXD9 expression was enhanced in ATC tissues and cells. Knockdown of HOXD9 inhibited cell proliferation, migration, invasion, and EMT but increased Apoptosis in ATC cells. The UCSC Genome Browser and JASPAR database identified HOXD9 as an upstream regulator of miR-451a. The direct binding of miR-451a to the untranslated region (3'-UTR) of PSMB8 was established using a luciferase experiment. Blocking or activation of PI3K by LY294002 or 740Y-P could attenuate the effect of HOXD9 interference or overexpression on ATC progression. The PI3K/Akt signaling pathway was involved in HOXD9-stimulated ATC cell proliferation and EMT. Consistent with in vitro findings, the downregulation of HOXD9 in ATC cells impeded tumor growth and lung metastasis in vivo. Our research suggests that through PI3K/Akt signaling, the HOXD9/miR-451a/PSMB8 axis may have significance in the control of cell proliferation and metastasis in ATC. Thus, HOXD9 could serve as a potential target for the diagnosis of ATC.

Keywords

Anaplastic thyroid carcinoma; EMT; HOXD9; Metastasis; PI3K/AKT pathway; PSMB8; Proliferation; miR-451a.

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