LDB1 overexpression is a negative prognostic factor in colorectal cancer.

Sebastián A García,Vittorio Branchi,Christoph Kahlert,Jürgen Weitz,Alexander M Betzler,Christoph Reißfelder,Lahiri Kanth Nanduri,Praveen Radhakrishnan,Sebastian Schölch,Balázs Győrffy,Nuh N Rahbari,Ulrich Bork,Anka Swiersy

doi:10.18632/oncotarget.12481

Abstract

BackgroundColorectal cancer (CRC) is the third most common cancer in western countries and is driven by the Wnt signaling pathway. LIM-domain-binding protein 1 (LDB1) interacts with the Wnt signaling pathway and has been connected to malignant diseases. We therefore aimed to evaluate the role of LDB1 in CRC.ResultsOverexpression of LDB1 in CRC is associated with strikingly reduced overall and metastasis free survival in all three independent patient cohorts. The expression of LDB1 positively correlates with genes involved in the Wnt signaling pathway (CTNNB1, AXIN2, MYC and CCND1). Overexpression of LDB1 in CRC cell lines induced Wnt pathway upregulation as well as increased invasivity and proliferation. Upon separate analysis, the role of LDB1 proved to be more prominent in proximal CRC, whereas distal CRC seems to be less influenced by LDB1.Materials and MethodsThe expression of LDB1 was measured via RT-qPCR in 59 clinical tumor and normal mucosa samples and correlated to clinical end-points. The role of LDB1 was examined in two additional large patient cohorts from publicly available microarray and RNAseq datasets. Functional characterization was done by lentiviral overexpression of LDB1 in CRC cell lines and TOP/FOP, proliferation and scratch assays.ConclusionsLDB1 has a strong role in CRC progression, confirmed in three large, independent patient cohorts. The in vitro data confirm an influence of LDB1 on the Wnt signaling pathway and tumor cell proliferation. LDB1 seems to have a more prominent role in proximal CRC, which confirms the different biology of proximal and distal CRC.

Highlights

Colorectal cancer (CRC) is one of the most common cancer entities worldwide [1]
The expression of LIM-domain-binding protein 1 (LDB1) positively correlates with genes involved in the Wnt signaling pathway (CTNNB1, AXIN2, MYC and CCND1)
The role of LDB1 proved to be more prominent in proximal CRC, whereas distal CRC seems to be less influenced by LDB1

Summary

Introduction

Colorectal cancer (CRC) is one of the most common cancer entities worldwide [1]. During the activation of the Wnt pathway, Wnt ligands bind to Frizzled receptors to induce the phosphorylation of LRP coreceptors [4]. LIM domain binding protein 1 (LDB1, known as CLIM2 and NLI) is an ubiquitous nuclear adaptor protein working as a transcriptional modulator [10]. Tamoxifen-induced knockout of Ldb results in drastic changes in the small intestine including a loss of Lgr5+ intestinal stem cells and significant activation of the Wnt pathway [14]. Colorectal cancer (CRC) is the third most common cancer in western countries and is driven by the Wnt signaling pathway. LIM-domain-binding protein 1 (LDB1) interacts with the Wnt signaling pathway and has been connected to malignant diseases. We aimed to evaluate the role of LDB1 in CRC

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