ZNF191 inhibits intrahepatic cholangiocarcinoma cell motility and metastasis through SAC1-mediated Cdc42 inactivation
Chenchen Cheng1, Hanghang Cheng2, Bingran Yao1
1Department of Pathology, School of Basic Medical Sciences, Fudan University, 138 Yi Xue Yuan Road, Shanghai, 200032, PR China.
Abstract:
Metastasis remains the primary cause of intrahepatic cholangiocarcinoma (ICC)-associated mortality. However, the underlying mechanism of ICC metastasis and how it is involved in cell motility remains largely unknown. In the present study, we showed that zinc finger transcription factor 191 (ZNF191) expression levels negatively correlated with metastasis and poor survival of patients with ICC. ZNF191 depletion promoted ICC cell migration, invasion, and motility in vitro, as well as metastases in vivo. Mechanistically, ZNF191 positively regulated mRNA and protein expression of phosphatidylinositol-3-phosphatase SAC1, a negative regulator of tumor metastasis. ZNF191 activated the SAC1 promoter and directly bound to the promoter at nt-1038 (ATTAATT). ZNF191 inhibited actin cytoskeletal assembly including focal adhesion and filopodia formation, as well as Rho GTPases cell division cycle 42 (Cdc42) activation, whereas SAC1 mediated the process. Moreover, SAC1 expression correlated positively with ZNF191 in human ICCs. ZCL278, a specific inhibitor of Cdc42, significantly blocked the effects of ZNF191 on ICC cell motility, migration, and invasion in vitro, as well as metastases in vivo. Thus, ZNF191 directly upregulates SAC1 transcription, then inhibits Cdc42 activation and actin cytoskeletal assembly in ICC cells, eventually inhibiting metastasis. Collectively, ZNF191 may serve as a new prognostic biomarker and potential therapeutic target for ICC metastasis.
Insights
Zinc finger transcription factor 191 (ZNF191) inhibits intrahepatic cholangiocarcinoma (ICC) metastasis by upregulating SAC1, which suppresses cell motility and invasion. Lower ZNF191 levels correlate with poorer patient survival.
Area of Science:
- Oncology
- Molecular Biology
Background:
- Metastasis is the leading cause of mortality in intrahepatic cholangiocarcinoma (ICC).
- The molecular mechanisms driving ICC metastasis and cell motility are not fully understood.
Purpose of the Study:
- To investigate the role of zinc finger transcription factor 191 (ZNF191) in ICC metastasis.
- To elucidate the underlying molecular mechanisms of ZNF191's function in ICC cell motility.
Main Methods:
- Correlation analysis of ZNF191 expression with patient survival and metastasis.
- In vitro and in vivo studies assessing ICC cell migration, invasion, and motility upon ZNF191 manipulation.
- Luciferase reporter assays to determine ZNF191's effect on the SAC1 promoter.
- Western blotting and Rho GTPase activation assays.
- Treatment with Cdc42 inhibitor ZCL278.
Main Results:
- ZNF191 expression negatively correlated with ICC metastasis and patient survival.
- ZNF191 depletion enhanced ICC cell migration, invasion, and motility.
- ZNF191 directly activated the SAC1 promoter and increased SAC1 expression.
- ZNF191 inhibited actin cytoskeletal assembly and Cdc42 activation, a process mediated by SAC1.
- SAC1 expression positively correlated with ZNF191 in human ICCs.
- Cdc42 inhibition blocked ZNF191's effects on ICC cell motility and metastasis.
Conclusions:
- ZNF191 suppresses ICC metastasis by directly upregulating SAC1 transcription.
- This pathway inhibits Cdc42 activation and actin cytoskeletal assembly, thereby reducing cell motility and invasion.
- ZNF191 represents a potential prognostic biomarker and therapeutic target for ICC metastasis.
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