title: HOPX is methylated and exerts tumour-suppressive function through Ras-induced senescence in human lung cancer.
abstract: HOPX acts as a tumour suppressor in various cancers. However, the regulation of HOPX in human lung cancer as well as the mechanism underlying its tumour-suppressive function has not yet been well elucidated. Here we investigated the epigenetic regulation and molecular mechanism by which HOPX exerts growth inhibitory effects. We found that HOPX was down-regulated in 12 out of 13 lung cancer cell lines and in 69 out of 120 primary lung tumours at mRNA and protein levels. Patients with lung adenocarcinoma (ADC) exhibited significantly more positive staining of HOPX protein compared with lung squamous cell carcinoma (SCC) (p =0.036). Again in ADC, patients with higher HOPX expression had a significantly longer disease-free survival (p =0.001). Methylation analysis showed that down-regulation of HOPX was associated with DNA methylation (p =0.011). To analyse the function of HOPX in lung cancer cells, stable transfection with an expression vector of HOPX was performed. It turned out that HOPX inhibited tumour cell proliferation rate, migration, and invasion, and, more interestingly, forced expression of HOPX enhanced cellular senescence via activation of oncogenic Ras and the downstream MAPK pathway, which in turn led to decreased MDM2 and increased p21. On the contrary, knockdown of HOPX by siRNA resulted in reduced Ras activity, inactivation of the MAPK pathway, and decreased p21 levels, accompanied by reduced cellular senescence. Additionally, the HOPX-induced senescence pathway was also active in human bronchial epithelial cells. Taken together, our data suggest that down-regulation of HOPX was related to DNA methylation and that HOPX exerts tumour-suppressive activity by oncogenic Ras-induced cellular senescence in lung cancer cells.
authors.affiliation: Institute of Pathology, University Hospital Jena, Friedrich-Schiller-University Jena, Ziegelmühlenweg 1, 07743, Jena, Germany.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Chen
authors.forename: Linlin
authors.initials: L
authors.lastname: Yang
authors.forename: Tiantian
authors.initials: T
authors.lastname: Cui
authors.forename: Manuela
authors.initials: M
authors.lastname: Pacyna-Gengelbach
authors.forename: Iver
authors.initials: I
authors.lastname: Petersen
mesh_terms: D000230:Adenocarcinoma / Q000473:pathology / Q000503:physiopathology; D002289:Carcinoma, Non-Small-Cell Lung / Q000473:pathology / Q000503:physiopathology; D002294:Carcinoma, Squamous Cell / Q000473:pathology / Q000503:physiopathology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology; D049109:Cell Proliferation / Q000502:physiology; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000502:physiology*; D019175:DNA Methylation / Q000502:physiology*; D015536:Down-Regulation; D015972:Gene Expression Regulation, Neoplastic; D018398:Homeodomain Proteins / Q000235:genetics / Q000502:physiology*; D006801:Humans; D008175:Lung Neoplasms / Q000473:pathology* / Q000503:physiopathology*; D015398:Signal Transduction / Q000502:physiology; D055752:Small Cell Lung Carcinoma / Q000473:pathology / Q000503:physiopathology; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000502:physiology*; D018631:ras Proteins / Q000502:physiology*
chemical_list: C476884:HOPX protein, human; D018398:Homeodomain Proteins; D025521:Tumor Suppressor Proteins; D018631:ras Proteins
keywords: HOPX; Ras-induced senescence; lung cancer; methylation