RESUMEN

Thyroid cancer (TC) is one of the most common endocrine system cancers, and its incidence is elevating. There is an urgent need to develop a deeper understanding of TC pathogenesis and explore new therapeutic target for its treatment. This study aimed to investigate the effects of pleckstrin homology and RhoGEF domain containing G4 (PLEKHG4) on the progression of TC. Herein, 29 pairs of TC and adjacent tissues were used to assess the expression of PLEKHG4. A xenograft model of mouse was established by subcutaneously injected with TC cells. Lung metastasis model was established through left ventricular injection. The results revealed that PLEKHG4 was up-regulated in human TC tissues. PLEKHG4 level was correlated with clinicopathological parameters of TC patients. In vitro assays revealed that PLEKHG4 promoted TC cell proliferation, migration, invasion, and epithelial-mesenchymal transformation. Knockdown of PLEKHG4 led to the opposite effects, and the loss of PLEKHG4 enhanced the apoptosis ability and inhibited the stemness properties of TC cells. These findings were further confirmed by the in vivo growth and lung metastasis of TC tumor. Mechanistically, PLEKHG4 promoted the activation of RhoGTPases RhoA, Cdc42, and Rac1. The inhibitors of these RhoGTPases reversed the PLEKHG4-induced malignant phenotypes. Additionally, ubiquitin-conjugating enzyme E2O (UBE2O), a large E2 ubiquitin-conjugating enzyme acted as an ubiquitin enzyme of PLEKHG4, facilitated its ubiquitination and degradation. In conclusion, PLEKHG4, regulated by UBE2O, promoted the thyroid cancer progression via activating the RhoGTPases pathway. UBE2O/PLEKHG4/RhoGTPases axis is expected to be a novel a therapeutic target for TC treatment.

Asunto(s)

Neoplasias de la Tiroides , Enzimas Ubiquitina-Conjugadoras , Humanos , Animales , Ratones , Apoptosis/genética , Proliferación Celular , Factores de Intercambio de Guanina Nucleótido Rho , Línea Celular Tumoral , Movimiento Celular/genética

RESUMEN

BACKGROUND: UBE2O, as a member of the ubiquitin-conjugating enzyme family, is abnormally expressed and exhibits abnormal functions in human malignancies. However, the function of UBE2O in head and neck squamous cell carcinoma (HNSCC) remains unknown. Therefore, our study aims to investigate the role of UBE2O in HNSCC progression and the underlying mechanisms. METHODS: The expression of UBE2O in HNSCC patients was investigated with data from the Cancer Genome Atlas (TCGA) and from a separate primary tumor cohort. The function of UBE2O in HNSCC cells was studied by cell viability assay, colony formation assay, wound healing assay, and cell migration and invasion chamber assay. The effect of UBE2O on tumor growth in vivo was determined in a subcutaneous xenograft model of HNSCC. RESULTS: TCGA data showed that UBE2O mRNA expression was dramatically increased in HNSCC tissues and that patients with high expression of UBE2O transcripts had a worse survival prognosis than patients with low expression of UBE2O transcripts. Gain-of-function and loss-of-function analyses revealed that oncogenic UBE2O enhanced the proliferation, migration and invasion of HNSCC cells in vitro. Further, mechanistic analysis revealed that UBE2O induced the epithelial-mesenchymal transition (EMT) phenotype and also potentiated TGF-ß1-induced EMT, and thus leading to an enhanced capacity of migration and invasion in HNSCC. Finally, xenograft models showed that UBE2O knockout obviously inhibited the occurrence of EMT, angiogenesis and tumor growth in HNSCC in vivo. CONCLUSION: Our study indicates that UBE2O acts as an oncogene to promote the malignant progression and EMT of HNSCC.