Vol.:(0123456789) 1 3 Journal of Molecular Histology https://doi.org/10.1007/s10735-020-09888-3 ORIGINAL PAPER Integrin‑linked kinase (ILK) regulates KRAS, IPP complex and Ras suppressor‑1 (RSU1) promoting lung adenocarcinoma progression and poor survival Sofa Nikou 1  · Marina Arbi 2  · Foteinos‑Ioannis D. Dimitrakopoulos 3  · Chaido Sirinian 3  · Panagiota Chadla 1  · Ioanna Pappa 1  · Giannoula Ntaliarda 4  · Georgios T. Stathopoulos 4,5  · Helen Papadaki 1  · Vasiliki Zolota 6  · Zoi Lygerou 2  · Haralabos P. Kalofonos 3,7  · Vasiliki Bravou 1 Received: 26 April 2020 / Accepted: 13 June 2020 © Springer Nature B.V. 2020 Abstract Integrin-linked kinase (ILK) forms a heterotrimeric protein complex with PINCH and PARVIN (IPP) in Focal Adhesions (FAs) that acts as a signaling platform between the cell and its microenvironment regulating important cancer-related func- tions. We aimed to elucidate the role of ILK in lung adenocarcinoma (LUADC) focusing on a possible link with KRAS oncogene. We used immunohistochemistry on human tissue samples and KRAS-driven LUADC in mice, analysis of large scale publicly available RNA sequencing data, ILK overexpression and pharmacological inhibition as well as knockdown of KRAS in lung cancer cells. ILK, PINCH1 and PARVB (IPP) proteins are overexpressed in human LUADC and KRAS-driven LUADC in mice representing poor prognostic indicators. Genes implicated in ILK signaling are signifcantly enriched in KRAS-driven LUADC. Silencing of KRAS, as well as, overexpression and pharmacological inhibition of ILK in lung cancer cells provide evidence of a two-way association between ILK and KRAS. Upregulation of PINCH, PARVB and Ras sup- pressor-1 (RSU1) expression was demonstrated in ILK overexpressing lung cancer cells in addition to a signifcant positive correlation between these factors in tissue samples, while KRAS silencing downregulates IPP and RSU1. Pharmacological inhibition of ILK in KRAS mutant lung cancer cells suppresses cell growth, migration, EMT and increases sensitivity to platinum-based chemotherapy. ILK promotes an aggressive lung cancer phenotype with prognostic and therapeutic value through functions that involve KRAS, IPP complex and RSU1, rendering ILK a promising biomarker and therapeutic target in lung adenocarcinoma. Keywords ILK · KRAS · Lung cancer · PARVB · PINCH · Ras suppressor-1 Abbreviations ECM Extracellular matrix EMT Epithelial to mesenchymal transition ERK1/2 Extracellular regulated kinase Electronic supplementary material The online version of this article (https://doi.org/10.1007/s10735-020-09888-3) contains supplementary material, which is available to authorized users. * Vasiliki Bravou vibra@upatras.gr 1 Department of Anatomy-Histology-Embryology, Medical School, University of Patras, 26500 Patras, Greece 2 Department of General Biology, Medical School, University of Patras, 26504 Patras, Greece 3 Clinical and Molecular Oncology Laboratory, Division of Oncology, Medical School, University of Patras, 26504 Rio, Greece 4 Laboratory for Molecular Respiratory Carcinogenesis, Department of Physiology, Faculty of Medicine, University of Patras, 2504 Rio, Achaia, Greece 5 Comprehensive Pneumology Center (CPC) and Institute for Lung Biology and Disease (iLBD), University Hospital, Ludwig-Maximilians University and Helmholtz Zentrum München, Member of the German Center for Lung Research (DZL), Munich, Bavaria, Germany 6 Department of Pathology, University Hospital of Patras, 26504 Patras, Greece 7 Division of Oncology, Department of Internal Medicine, University Hospital of Patras, 26504 Rio, Greece