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Overexpression of far upstream element binding proteins: a mechanism regulating proliferation and migration in liver
Mona Malz1, Achim Weber, Stephan Singer
1Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany.
Unlabelled:
Microtubule-dependent effects are partly regulated by factors that coordinate polymer dynamics such as the microtubule-destabilizing protein stathmin (oncoprotein 18). In cancer cells, increased microtubule turnover affects cell morphology and cellular processes that rely on microtubule dynamics such as mitosis and migration. However, the molecular mechanisms deregulating modifiers of microtubule activity in human hepatocarcinogenesis are poorly understood. Based on profiling data of human hepatocellular carcinoma (HCC), we identified far upstream element binding proteins (FBPs) as significantly coregulated with stathmin. Coordinated overexpression of two FBP family members (FBP-1 and FBP-2) in >70% of all analyzed human HCCs significantly correlated with poor patient survival. In vitro, FBP-1 predominantly induced tumor cell proliferation, while FBP-2 primarily supported migration in different HCC cell lines. Surprisingly, reduction of FBP-2 levels was associated with elevated FBP-1 expression, suggesting a regulatory interplay of FBP family members that functionally discriminate between cell division and mobility. Expression of FBP-1 correlated with stathmin expression in HCC tissues and inhibition of FBP-1 but not of FBP-2 drastically reduced stathmin at the transcript and protein levels. In contrast, further overexpression of FBP-1 did not affect stathmin bioavailability. Accordingly, analyzing nuclear and cytoplasmic areas of HCC cells revealed that reduced FBP-1 levels affected cell morphology and were associated with a less malignant phenotype.
Conclusion:
The coordinated activation of FBP-1 and FBP-2 represents a novel and frequent pro-tumorigenic mechanism promoting proliferation (tumor growth) and motility (dissemination) of human liver cancer cells. FBPs promote tumor-relevant functions by at least partly employing the microtubule-destabilizing factor stathmin and represent a new potential target structure for HCC treatment.
Insights
Far upstream element binding proteins (FBPs) drive liver cancer by promoting cell proliferation and migration, partly through the microtubule-destabilizing protein stathmin. Targeting FBPs offers a new therapeutic strategy for hepatocellular carcinoma (HCC).
Area of Science:
- Molecular Biology
- Oncology
- Cell Biology
Background:
- Microtubule dynamics are crucial for cancer cell functions like mitosis and migration.
- Stathmin (oncoprotein 18) is a key regulator of microtubule destabilization.
- Molecular mechanisms deregulating microtubule modifiers in hepatocarcinogenesis are not well understood.
Purpose of the Study:
- To investigate the role of far upstream element binding proteins (FBPs) in human hepatocellular carcinoma (HCC).
- To explore the relationship between FBPs, stathmin, and tumor progression.
- To identify potential therapeutic targets for HCC treatment.
Main Methods:
- Profiling data analysis of human HCC tissues.
- In vitro studies using HCC cell lines to assess FBP-1 and FBP-2 functions.
- Analysis of stathmin expression in relation to FBP levels.
- Assessment of cell morphology and malignant phenotype.
Main Results:
- FBPs, specifically FBP-1 and FBP-2, were significantly coregulated with stathmin in HCC.
- Co-overexpression of FBP-1 and FBP-2 correlated with poor patient survival.
- FBP-1 promoted proliferation, while FBP-2 enhanced migration in HCC cell lines.
- FBP-1 expression correlated with stathmin levels; FBP-1 inhibition reduced stathmin.
Conclusions:
- Coordinated activation of FBP-1 and FBP-2 is a novel mechanism promoting liver cancer proliferation and motility.
- FBPs utilize stathmin to promote tumor-relevant functions.
- FBPs represent a potential therapeutic target for HCC.
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