title: RHOB influences lung adenocarcinoma metastasis and resistance in a host-sensitive manner.
abstract: Lung adenocarcinoma (ADC) is the most common lung cancer subtype and presents a high mortality rate. Clinical recurrence is often associated with the emergence of metastasis and treatment resistance. The purpose of this study was to identify genes with high prometastatic activity which could potentially account for treatment resistance. Global transcriptomic profiling was performed by robust microarray analysis in highly metastatic subpopulations. Extensive in vitro and in vivo functional studies were achieved by overexpression and by silencing gene expression. We identified the small GTPase RHOB as a gene that promotes early and late stages of metastasis in ADC. Gene silencing of RHOB prevented metastatic activity in a systemic murine model of bone metastasis. These effects were highly dependent on tumor-host interactions. Clinical analysis revealed a marked association between high RHOB levels and poor survival. Consistently, high RHOB levels promote metastasis progression, taxane-chemoresistance, and contribute to the survival advantage to γ-irradiation. We postulate that RHOB belongs to a novel class of "genes of recurrence" that have a dual role in metastasis and treatment resistance.
authors: Division of Oncology, Adhesion and Metastasis Laboratory, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain.
authors: Diego
authors: D
authors: Luis-Ravelo
authors: Division of Oncology, Adhesion and Metastasis Laboratory, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain.
authors: Iker
authors: I
authors: Antón
authors: Division of Oncology, Adhesion and Metastasis Laboratory, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain.
authors: Carolina
authors: C
authors: Zandueta
authors: Division of Oncology, Adhesion and Metastasis Laboratory, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain.
authors: Karmele
authors: K
authors: Valencia
authors: Biomarkers Laboratory, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain.
authors: María-José
authors: MJ
authors: Pajares
authors: Biomarkers Laboratory, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain.
authors: Jackeline
authors: J
authors: Agorreta
authors: Biomarkers Laboratory, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain.
authors: Luis
authors: L
authors: Montuenga
authors: Division of Oncology, Adhesion and Metastasis Laboratory, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain.
authors: Silvestre
authors: S
authors: Vicent
authors: Department of Pathology, The University of Texas - M. D. Anderson Cancer Center, Houston, TX, USA.
authors: Ignacio I
authors: II
authors: Wistuba
authors: Bioinformatics and Functional Genomics Research Group, Cancer Research Center, University of Salamanca (CSIC/USAL), Salamanca, Spain.
authors: Javier
authors: J
authors: De Las Rivas
authors: Division of Oncology, Adhesion and Metastasis Laboratory, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain. Electronic address: flecanda@unav.es.
authors: Fernando
authors: F
authors: Lecanda
mesh_terms: D000230:Adenocarcinoma / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D001859:Bone Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics / Q000473:pathology / Q000556:secondary; D001952:Bridged-Ring Compounds / Q000494:pharmacology; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D064593:Heterografts; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D009368:Neoplasm Transplantation; D043823:Taxoids / Q000494:pharmacology; D020743:rhoB GTP-Binding Protein / Q000235:genetics / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D001952:Bridged-Ring Compounds; D009363:Neoplasm Proteins; D043823:Taxoids; C080625:taxane; D020743:rhoB GTP-Binding Protein
keywords: Chemotherapy; Drug target; GTPase; MMP; Microenvironment; Non-cell autonomous; Radiotheraphy; Tumor-stroma