2. Academic Validation
  3. DYRK1A reinforces epithelial-mesenchymal transition and metastasis of hepatocellular carcinoma via cooperatively activating STAT3 and SMAD

DYRK1A reinforces epithelial-mesenchymal transition and metastasis of hepatocellular carcinoma via cooperatively activating STAT3 and SMAD

  • J Biomed Sci. 2022 Jun 2;29(1):34. doi: 10.1186/s12929-022-00817-y.
Yang-Ling Li  # 1,  Man-Man Zhang  # 2 3,  Lin-Wen Wu 2 3,  Ye-Han Liu 2 3,  Zuo-Yan Zhang 2 3,  Ling-Hui Zeng 4,  Neng-Ming Lin 5 6 7,  Chong Zhang 8
Affiliations

Affiliations

  • 1 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.
  • 2 School of Medicine, Zhejiang University City College, No.51 Huzhou Street, Hangzhou, 310015, Zhejiang, China.
  • 3 College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, Zhejiang, China.
  • 4 School of Medicine, Zhejiang University City College, No.51 Huzhou Street, Hangzhou, 310015, Zhejiang, China. zenglh@zucc.edu.cn.
  • 5 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. lnm1013@zju.edu.cn.
  • 6 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. lnm1013@zju.edu.cn.
  • 7 Westlake Laboratory of Life Sciences and Biomedicine of Zhejiang Province, Hangzhou, 310024, China. lnm1013@zju.edu.cn.
  • 8 School of Medicine, Zhejiang University City College, No.51 Huzhou Street, Hangzhou, 310015, Zhejiang, China. zhangchong@zucc.edu.cn.
  • # Contributed equally.
PMID: 35655269 DOI: 10.1186/s12929-022-00817-y
Abstract

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.

Keywords

DYRK1A; EMT; Hepatocellular carcinoma; Metastasis; TSC1.

Figures
Products