- 作者: Yang-ling Li, Man-man Zhang, Lin-wen Wu, Ye-han Liu, Zuo-yan Zhang, Ling-hui Zeng, Neng-ming Lin & Chong Zhang
- 作者服務機構: 1.College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, Zhejiang, China 2.Department of Clinical Pharmacology, Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang Province, Affiliated Hangzhou First People’s Hospital, Zhejiang University School of Medicine, No.261 Huansha Road, Hangzhou, 310006, Zhejiang, China 3.Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang Province, Affiliated Hangzhou First People’s Hospital, Zhejiang University School of Medicine, Hangzhou, 310006, Zhejiang, China 4.School of Medicine, Zhejiang University City College, No.51 Huzhou Street, Hangzhou, 310015, Zhejiang, China 5.Westlake Laboratory of Life Sciences and Biomedicine of Zhejiang Province, Hangzhou, 310024, China 6.Yang-ling Li and Man-man Zhang contributed equally to this work
- 中文摘要:
- 英文摘要:
Background
Hepatocellular carcinoma (HCC) accounts for the majority of liver cancer cases, while metastasis is considered the leading cause of HCC-related death. However, the currently available treatment strategies for efficient suppression of metastasis are limited. Therefore, novel therapeutic targets to inhibit metastasis and effectively treat HCC are urgently required.
Methods
Wound healing and Transwell assays were used to determine the migration and invasion abilities of HCC cells in vitro. Quantitative real-time PCR (qRT-PCR), protein array, immunofluorescence, and immunoprecipitation experiments were used to study the mechanism of DYRK1A-mediated metastasis. A tail vein metastasis model and H&E staining were utilized to assess metastatic potential in vivo.
Results
The results of the current study demonstrated that dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) was upregulated in HCC tissues compared with normal liver tissues. Additionally, the level of DYRK1A was increased in primary HCC tissues of patients with metastasis compared with those of patients without metastasis, and DYRK1A overexpression correlated with worse outcomes in liver cancer patients. Gain- and loss-of-function studies suggested that DYRK1A enhanced the invasion and migration abilities of HCC cells by promoting epithelial-mesenchymal transition (EMT). Regarding the promoting effect of DYRK1A on cell invasion, the results showed that DYRK1A was coexpressed with TGF-β/SMAD and STAT3 signalling components in clinical tumour samples obtained from patients with HCC. DYRK1A also activated TGF-β/SMAD signalling by interacting with tuberous sclerosis 1 (TSC1) and enhanced metastasis of HCC cells by activating STAT3. Furthermore, DYRK1A promoted EMT by cooperatively activating STAT3/SMAD signalling.
Conclusion
Overall, the present study not only uncovered the promoting effect of DYRK1A on HCC metastasis and revealed the mechanism but also provided a new approach to predict and treat metastatic HCC. - 中文關鍵字:
- 英文關鍵字: Hepatocellular carcinoma, DYRK1A, EMT, Metastasis, TSC1