<i>LDB1</i>overexpression is a negative prognostic factor in colorectal cancer

Abstract

// Sebasti&aacute;n A. Garc&iacute;a 1, 2 , Anka Swiersy 1 , Praveen Radhakrishnan 2 , Vittorio Branchi 3 , Lahiri Kanth Nanduri 1 , Bal&aacute;zs Győrffy 4, 5 , Alexander M. Betzler 1 , Ulrich Bork 1, 2 , Christoph Kahlert 1, 2 , Christoph Rei&szlig;felder 1, 2 , Nuh N. Rahbari 1, 2 , J&uuml;rgen Weitz 1, 2 , Sebastian Sch&ouml;lch 1, 2 1 Department of Gastrointestinal, Thoracic and Vascular Surgery, Medizinische Fakult&auml;t Carl Gustav Carus, Technische Universit&auml;t Dresden, Fetscherstr. 74, 01307 Dresden, Germany 2 Department of General, Gastrointestinal and Transplantation Surgery, University Hospital Heidelberg, Ruprecht-Karls-Universit&auml;t Heidelberg, Im Neuenheimer Feld 110, 69120 Heidelberg, Germany 3 Department of General, Gastrointestinal, Thoracic and Vascular Surgery, University Hospital Bonn, 53127 Bonn, Germany 4 MTA TTK Lend&uuml;let Cancer Biomarker Research Group, Magyar Tud&oacute;sok k&ouml;r&uacute;tja 2., H-1117, Budapest, Hungary 5 Semmelweis University, 2nd Department of Pediatrics, B&oacute;kay u. 53-54., H-1083, Budapest, Hungary Correspondence to: Sebastian Sch&ouml;lch, email: [e-mail] Keywords: ldb1, wnt signaling, colorectal cancer, proximal, distal Received: August 15, 2016&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; Accepted: September 30, 2016&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; Published: October 05, 2016 ABSTRACT 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.