Malz Mona, Weber Achim, Singer Stephan, Riehmer Vera, Bissinger Michaela, Riener Marc-Oliver, Longerich Thomas, Soll Christopher, Vogel Arndt, Angel Peter, Schirmacher Peter, Breuhahn Kai
Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany.
Hepatology. 2009 Oct;50(4):1130-9. doi: 10.1002/hep.23051.
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.
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.
微管依赖性效应部分受协调聚合物动力学的因素调节，如微管去稳定蛋白癌蛋白18（原癌蛋白18）。在癌细胞中，微管周转率增加会影响细胞形态和依赖微管动力学的细胞过程，如有丝分裂和迁移。然而，人类肝癌发生过程中失调微管活性调节因子的分子机制尚不清楚。基于人类肝细胞癌（HCC）的分析数据，我们确定远上游元件结合蛋白（FBP）与癌蛋白18显著共调节。在所有分析的人类HCC中，超过70%的两种FBP家族成员（FBP-1和FBP-2）的协同过表达与患者的不良生存显著相关。在体外，FBP-1主要诱导肿瘤细胞增殖，而FBP-2主要支持不同HCC细胞系的迁移。令人惊讶的是，FBP-2水平的降低与FBP-1表达的升高相关，这表明FBP家族成员之间存在调节相互作用，在功能上区分细胞分裂和迁移。FBP-1的表达与HCC组织中癌蛋白18的表达相关，抑制FBP-1而非FBP-2可在转录和蛋白质水平上显著降低癌蛋白18。相反，FBP-1的进一步过表达不影响癌蛋白18的生物利用度。因此，分析HCC细胞的核区和胞质区发现，FBP-1水平的降低影响细胞形态，并与恶性程度较低的表型相关。
FBP-1和FBP-2的协同激活代表了一种新的常见促肿瘤发生机制，促进人类肝癌细胞的增殖（肿瘤生长）和运动（扩散）。FBP至少部分通过微管去稳定因子癌蛋白18促进肿瘤相关功能，是HCC治疗的新潜在靶点结构。
