Coordinated Expression of Stathmin Family Members by Far Upstream Sequence Element-Binding Protein-1 Increases Motility in Non–Small Cell Lung Cancer

¹Institute of Pathology, University of Heidelberg, ²Department of Thoracic Surgery and ³Translational Research Unit, Thoraxklinik Heidelberg, University of Heidelberg; ⁴Division of Molecular Genome Analysis and ⁵Department of Radiooncology, German Cancer Research Center, Heidelberg, Germany

^* To whom correspondence should be addressed. E-mail: kai.breuhahn{at}med.uni-heidelberg.de.

	Abstract

Dynamic instability of the microtubule network modulates processes such as cell division and motility, as well as cellular morphology. Overexpression of the microtubule-destabilizing phosphoprotein stathmin is frequent in human malignancies and represents a promising therapeutic target. Although stathmin inhibition gives rise to antineoplastic effects, additional and functionally redundant microtubule-interacting proteins may attenuate the efficiency of this therapeutic approach. We have systematically analyzed the expression and potential protumorigenic effects of stathmin family members in human non–small cell lung cancer (NSCLC). Both stathmin and stathmin-like 3 (SCLIP) were overexpressed in adenocarcinoma as well as squamous cell carcinoma (SCC) tissues and induced tumor cell proliferation, migration, and matrix invasion in respective cell lines. Accordingly, reduced stathmin and SCLIP levels affected cell morphology and were associated with a less malignant phenotype. Combined inhibition of both factors caused additive effects on tumor cell motility, indicating partial functional redundancy. Because stathmin and SCLIP expression significantly correlated in NSCLC tissues, we searched for common upstream regulators and identified the far upstream sequence element-binding protein-1 (FBP-1) as a pivotal inducer of several stathmin family members. Our results indicate that the coordinated overexpression of microtubule-destabilizing factors by FBP-1 is a critical step to facilitate microtubule dynamics and subsequently increases proliferation and motility of tumor cells. [Cancer Res 2009;69(6):2234–43]

Key Words: stathmin, SCLIP, FBP-1, NSCLC, migration