title: Oncogenic Kras expression in postmitotic neurons leads to S100A8-S100A9 protein overexpression and gliosis.
abstract: Previous studies suggest that up-regulation of Ras signaling in neurons promotes gliosis and astrocytoma formation in a cell nonautonomous manner. However, the underlying mechanisms remain unknown. To address this question, we generated compound mice (LSL Kras G12D/+;CamKII-Cre) that express oncogenic Kras from its endogenous locus in postmitotic neurons after birth. These mice developed progressive gliosis, which is associated with hyperactivation of Ras signaling pathways. Microarray analysis identified S100A8 and S100A9 as two secreted molecules that are significantly overexpressed in mutant cortices. In contrast to their usual predominant expression in myeloid cells, we found that overexpression of S100A8 and S100A9 in the mutant cortex is primarily in neurons. This neuronal expression pattern is associated with increased infiltration of microglia in mutant cortex. Moreover, purified S100A8-S100A9 but not S100A8 or S100A9 alone promotes growth of primary astrocytes in vitro through both TLR4 and receptor of advanced glycation end product receptors. In summary, our results identify overexpression of S100A8-S100A9 in neurons as an early step in oncogenic Kras-induced gliosis. These molecules expressed in nonhematopoietic cells may be involved in tumorigenesis at a stage much earlier than what has been reported previously.
authors.affiliation: McArdle Laboratory for Cancer Research, University of Wisconsin-Madison, Madison, Wisconsin 53706, USA.
authors.forename: Myung-Jeom
authors.initials: MJ
authors.lastname: Ryu
authors.forename: Yangang
authors.initials: Y
authors.lastname: Liu
authors.forename: Xiaofen
authors.initials: X
authors.lastname: Zhong
authors.forename: Juan
authors.initials: J
authors.lastname: Du
authors.forename: Nicholas
authors.initials: N
authors.lastname: Peterson
authors.forename: Guangyao
authors.initials: G
authors.lastname: Kong
authors.forename: Hongda
authors.initials: H
authors.lastname: Li
authors.forename: Jinyong
authors.initials: J
authors.lastname: Wang
authors.forename: Shahriar
authors.initials: S
authors.lastname: Salamat
authors.forename: Qiang
authors.initials: Q
authors.lastname: Chang
authors.forename: Jing
authors.initials: J
authors.lastname: Zhang
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000166:cytology / Q000502:physiology; D001932:Brain Neoplasms / Q000235:genetics / Q000503:physiopathology; D040501:Calgranulin A / Q000235:genetics* / Q000378:metabolism; D040502:Calgranulin B / Q000235:genetics* / Q000378:metabolism; D002540:Cerebral Cortex / Q000166:cytology; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology; D005909:Glioblastoma / Q000235:genetics / Q000503:physiopathology; D005911:Gliosis / Q000235:genetics* / Q000503:physiopathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008938:Mitosis / Q000502:physiology; D022423:Myeloid Cells / Q000166:cytology / Q000502:physiology; D009474:Neurons / Q000166:cytology / Q000502:physiology*; D011230:Precancerous Conditions / Q000235:genetics / Q000503:physiopathology; D061251:Primary Cell Culture; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras); D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D051197:Toll-Like Receptor 4 / Q000378:metabolism; D018631:ras Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D040501:Calgranulin A; D040502:Calgranulin B; C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins