LDB1 overexpression is a negative prognostic factor in colorectal cancer
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Sebastián A. García1,2, Anka Swiersy1, Praveen Radhakrishnan2, Vittorio Branchi3, Lahiri Kanth Nanduri1, Balázs Győrffy4,5, Alexander M. Betzler1, Ulrich Bork1,2, Christoph Kahlert1,2, Christoph Reißfelder1,2, Nuh N. Rahbari1,2, Jürgen Weitz1,2, Sebastian Schölch1,2
1Department of Gastrointestinal, Thoracic and Vascular Surgery, Medizinische Fakultät Carl Gustav Carus, Technische Universität Dresden, Fetscherstr. 74, 01307 Dresden, Germany
2Department of General, Gastrointestinal and Transplantation Surgery, University Hospital Heidelberg, Ruprecht-Karls-Universität Heidelberg, Im Neuenheimer Feld 110, 69120 Heidelberg, Germany
3Department of General, Gastrointestinal, Thoracic and Vascular Surgery, University Hospital Bonn, 53127 Bonn, Germany
4MTA TTK Lendület Cancer Biomarker Research Group, Magyar Tudósok körútja 2., H-1117, Budapest, Hungary
5Semmelweis University, 2nd Department of Pediatrics, Bókay u. 53-54., H-1083, Budapest, Hungary
Sebastian Schölch, email: [email protected]
Keywords: ldb1, wnt signaling, colorectal cancer, proximal, distal
Received: August 15, 2016 Accepted: September 30, 2016 Published: October 05, 2016
Background: 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 therefore aimed to evaluate the role of LDB1 in CRC.
Results: Overexpression 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 Methods: The 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.
Conclusions: LDB1 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.
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