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

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.

A foundational atlas of autism protein interactions reveals molecular convergence

“…Given the role of DCAF7 as a WD40 repeat containing scaffold protein 96,97 , these results present the intriguing possibility that DCAF7 functions as a scaffold, facilitating interactions with other hcASD proteins. In addition to capturing some well documented interactions, such as CREBBP 98 , TRAF2 98,99 and TSC1 [98][99][100] , we also found KIAA0232, a hcASD gene with unknown function, to interact with DCAF7 and DYRK1A. By performing sequential AP-MS of FLAG-tagged DYRK1A and Strep-tagged KIAA0232, we identified DCAF7 as a shared interactor, confirming that DYRK1A, DCAF7 and KIAA0232 interact with each other (Figures 5E, F).…”

“…The interaction received a high overall score (ipTM = 0.931, Table S4 ), the interface matches the recognized binding motif 84,85 ( Figure 4D ), is modeled with high per-residue confidence ( Figure 4E ), and the residues involved directly in the interface are among the most conserved ( Figure 4F ). We overexpressed WT DYRK1A and DYRK1A Δ80–100 in HEK293T cells and confirmed that DYRK1A Δ80–100 lost interaction with DCAF7 but not with FAM54C, a protein that has been shown to bind the DYRK1A catalytic kinase domain (residues 156-479) 86 (Figure S4E, Table S4) Together, these findings demonstrate that AF can identify a direct PPI between DYRK1A-DCAF7 and highlight a specific interface that mediates this interaction.…”

“…(E) Amount of DYRK1A, FAM53C, and DCAF7 detected in AP-MS with Strep-tagged DYRK1A or DYRK1A Δ 80–100 . Significant interactions (SAINT 1-BFDR ≳ 0.95) are colored in red.…”

TSPAN6 reinforces the malignant progression of glioblastoma via interacting with CDK5RAP3 and regulating STAT3 signaling pathway

“…The procedures of Western blotting and immunoprecipitation were carried out according to previous studies 16 .…”

Deciphering STAT3 signaling potential in hepatocellular carcinoma: tumorigenesis, treatment resistance, and pharmacological significance

“…To this end, DYRK1A promotes the expression of STAT3 and accelerates its nuclear translocation; DYRK1A also interacts with TSC1 to phosphorylate the Smad2/Smad3 complex. Subsequently, it translocates to the nucleus, and the interaction of the Smad2/Smad3 complex with STAT3 signaling induces EMT and enhances metastasis of HCC cells [ 102 ]. Moreover, STAT3 can create positive feedback loops with upstream mediators that facilitate HCC cell metastasis and invasion.…”