Elongation and shortening of the cellular microtubule network is tightly regulated
by factors that coordinate polymer dynamics such as the microtubule de-stabilizing
protein stathmin (syn: oncoprotein-18, metablastin). We have recently described that
overexpression of stathmin induces proliferation and migration of hepatocellular carcinoma
(HCC) cells. In an expression profiling-based attempt to identify essential pathways
that regulate stathmin expression in HCC cells, we identified the far upstream sequence element (FUSE) binding protein (FBP)-1 as significantly co-regulated with stathmin at the
transcript- and protein levels (real-time PCR, western immunoblotting, tissue micro
arrays). The single-strand nucleic acid binding factor FBP-1 has been described as
a regulator of transcript processing and transcriptional activity. Overexpression
of FBP-1 in >50% of all HCCs significantly correlated with tumor dedifferentiation,
proliferation, and poor patient survival. In vitro, FBP-1 induced stathmin expression
and promoted tumor cell viability, proliferation, as well as motility in different
HCC cell lines (RNA interference, MTT-assay, BrdU-ELISA, ‘scratch’-assay). Surprisingly,
elevated expression of the transcriptional repressor FIR (FBP-interacting repressor)
positively correlated with FBP-1 and stathmin expression in HCC tissues at the transcript-
and protein levels. Indeed, FIR induced FBP-1 as well as stathmin expression in HCC
cells and supported tumor cell proliferation and migration. FIR induced FBP-1/stathmin
expression independently of exon-2, which codes for a repressor domain of FIR. In
summary, we have defined a novel pro-tumorigenic intracellular pathway regulated by
the factors FIR and FBP, which promotes the tumor-relevant processes motility (invasiveness)
and proliferation (tumor growth) by at least partly employing the microtubule-modifying
factor stathmin.
FBP-interacting repressor (FIR) - Hepatocellular carcinoma (HCC) - Stathmin - far
upstream sequence element (FUSE) binding protein (FBP)
