Theranostics 2020; 10(3):1433-1453. doi:10.7150/thno.38507
MicroRNA-204-5p is a tumor suppressor and potential therapeutic target in head and neck squamous cell carcinoma
1. Department of Oral and Maxillofacial Surgery, Guanghua School of Stomatology, Hospital of Stomatology, Sun Yat-sen University, Guangzhou 510055, China.
2. Guangdong Provincial Key Laboratory of Stomatology, Sun Yat-sen University, Guangzhou 510080, China.
3. Department of Oral Pathology, Guanghua School of Stomatology, Hospital of Stomatology, Sun Yat-sen University, Guangzhou 510055,China.
4. Department of Operative Dentistry and Endodontics, Guanghua School of Stomatology, Hospital of Stomatology, Sun Yat-sen University, Guangzhou 510055, China.
5. School of Life Science, Sun Yat-sen University, Guangzhou 510275, China.
6. South China Institute of Biomedine, Guangzhou 510535, China.
7. State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou 510060, China.
8. Department of Medicinal Chemistry, School of Pharmacy, and the Massey Cancer Center, Virginia Commonwealth University, Richmond, Virginia 23298-0540, United States.
9. Institute for Structural Biology, Drug Discovery and Development, Virginia Commonwealth University, Richmond, Virginia 23298-0540, Unites States.
*These authors contributed equally to this work.
Zhuang Z, Yu P, Xie N, Wu Y, Liu H, Zhang M, Tao Y, Wang W, Yin H, Zou B, Hou J, Liu X, Li J, Huang H, Wang C. MicroRNA-204-5p is a tumor suppressor and potential therapeutic target in head and neck squamous cell carcinoma. Theranostics 2020; 10(3):1433-1453. doi:10.7150/thno.38507. Available from http://www.thno.org/v10p1433.htm
Elucidation of the molecular mechanisms governing aggressiveness of HNSCC may provide clinical therapeutic strategies for patients. In this study, a novel hub miR-204-5p functioning as tumor suppressor has been identified and explored in HNSCC.
Methods: A novel hub miR-204-5p was identified based on miRNA microarray, bioinformatics analysis and validated in different HNSCC patient cohorts. The functional role of miR-204-5p and its downstream and upstream regulatory machinery were investigated by gain-of-function and loss-of-function assays in vitro and in vivo. Interactions among miR-204-5p and SNAI2/SUZ12/HDAC1/STAT3 complex were examined by a series of molecular biology experiments. Then, the clinical relevance of miR-204-5p and its targets were evaluated in HNSCC samples. HNSCC patient-derived xenograft (PDX) model was used to assess the therapeutic value of miR-204-5p.
Results: We reveal that miR-204-5p as a tumor suppressor is commonly repressed in HNSCC, which can inhibit tumor growth, metastasis and stemness. Mechanically, miR-204-5p suppresses epithelial-mesenchymal transition (EMT) and STAT3 signaling by targeting SNAI2, SUZ12, HDAC1 and JAK2. Among these targets, we further showed that SNAI2, SUZ12, and HDAC1 form a repressive complex on CDH1 promoter to maintain EMT in HNSCC. In turn, the SNAI2/SUZ12/HDAC1 complex interacts with STAT3 on miR-204-5p-regulatory regions to suppress the transcription of miR-204-5p. Moreover, we also show that decrease of miR-204-5p indicates a poor prognosis in HNSCC patients and administration of agomiR-204-5p inhibits tumor growth and metastasis in HNSCC PDX models.
Conclusion: miR-204-5p-SNAI2/SUZ12/HDAC1/STAT3 regulatory circuit has a critical role in maintaining aggressiveness of HNSCC, suggesting that miR-204-5p might serve as a promising therapeutic target for clinical intervention.
Keywords: miR-204-5p, tumor suppressor, metastasis, tumorigencity, head and neck squamous cell carcinoma