title: Elucidation of changes in molecular signalling leading to increased cellular transformation in oncogenically progressed human bronchial epithelial cells exposed to radiations of increasing LET.
abstract: The early transcriptional response and subsequent induction of anchorage-independent growth after exposure to particles of high Z and energy (HZE) as well as γ-rays were examined in human bronchial epithelial cells (HBEC3KT) immortalised without viral oncogenes and an isogenic variant cell line whose p53 expression was suppressed but that expressed an active mutant K-RAS(V12) (HBEC3KT-P53KRAS). Cell survival following irradiation showed that HBEC3KT-P53KRAS cells were more radioresistant than HBEC3KT cells irrespective of the radiation species. In addition, radiation enhanced the ability of the surviving HBEC3KT-P53RAS cells but not the surviving HBEC3KT cells to grow in anchorage-independent fashion (soft agar colony formation). HZE particle irradiation was far more efficient than γ-rays at rendering HBEC3KT-P53RAS cells permissive for soft agar growth. Gene expression profiles after radiation showed that the molecular response to radiation for HBEC3KT-P53RAS, similar to that for HBEC3KT cells, varies with radiation quality. Several pathways associated with anchorage independent growth, including the HIF-1α, mTOR, IGF-1, RhoA and ERK/MAPK pathways, were over-represented in the irradiated HBEC3KT-P53RAS cells compared to parental HBEC3KT cells. These results suggest that oncogenically progressed human lung epithelial cells are at greater risk for cellular transformation and carcinogenic risk after ionising radiation, but particularly so after HZE radiations. These results have implication for: (i) terrestrial radiation and suggests the possibility of enhanced carcinogenic risk from diagnostic CT screens used for early lung cancer detection; (ii) enhanced carcinogenic risk from heavy particles used in radiotherapy; and (iii) for space radiation, raising the possibility that astronauts harbouring epithelial regions of dysplasia or hyperplasia within the lung that contain oncogenic changes, may have a greater risk for lung cancers based upon their exposure to heavy particles present in the deep space environment.
authors.affiliation: Department of Radiation Oncology.
authors.forename: Liang-Hao
authors.initials: LH
authors.lastname: Ding
authors.affiliation: Department of Radiation Oncology.
authors.forename: Seongmi
authors.initials: S
authors.lastname: Park
authors.affiliation: Department of Clinical Sciences, Hamon Center for Therapeutic Oncology Research.
authors.forename: Yang
authors.initials: Y
authors.lastname: Xie
authors.affiliation: Department of Pharmacology, Hamon Center for Therapeutic Oncology Research.
authors.forename: Luc
authors.initials: L
authors.lastname: Girard
authors.affiliation: Hamon Center for Therapeutic Oncology Research, Department of Pharmacology, Department of Internal Medicine and Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, 6000 Harry Hines Blvd, Dallas, TX 75390-8593, USA.
authors.forename: John D
authors.initials: JD
authors.lastname: Minna
authors.affiliation: Department of Radiation Oncology, Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, 6000 Harry Hines Blvd, Dallas, TX 75390-8593, USA michael.story@utsouthwestern.edu.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Story
mesh_terms: D001980:Bronchi / Q000166:cytology; D002460:Cell Line; D002471:Cell Transformation, Neoplastic; D004307:Dose-Response Relationship, Radiation; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology / Q000528:radiation effects*; D006801:Humans; D018499:Linear Energy Transfer; D011839:Radiation, Ionizing; D020545:Respiratory Mucosa / Q000378:metabolism / Q000473:pathology / Q000528:radiation effects*; D015398:Signal Transduction / Q000528:radiation effects*; D059467:Transcriptome / Q000528:radiation effects*