In:
Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 110, No. 4 ( 2013-01-22)
Abstract:
Inflammation is a two-edged sword in tumorigenesis: The right type of inflammation can lead to tumor rejection, but chronic inflammation can be protumorigenic, with cytokines and reactive oxygen and nitrogen species promoting growth, inhibiting apoptosis, increasing vascularization, and limiting antitumor immune responses within the tumor microenvironment ( 4 , 5 ). Here, we describe evidence of increased cancer development and chronic inflammation in Smg1 mice at death, as well as elevated tissue cytokine levels before disease onset. These data suggest that Smg1 heterozygous mice are predisposed to elevated/altered inflammatory responses that, with age, lead to either cancer development or chronic inflammatory disease ( Fig. P1 ). Because Smg1 heterozygous mice had exhibited both hematopoietic cancer development and inflammation, we next analyzed the composition of the hematopoietic compartment. Major cell populations (i.e., CD4 + and CD8 + T cells, B cells, macrophages, granulocytes) were present in equivalent amounts in the spleen, thymus, lymph node, and bone marrow from Smg1 heterozygous and WT mice. However, we noted significantly different cytokine mRNA levels in the tissues of Smg1 heterozygous and WT mice. Specifically, Smg1 heterozygous mice showed elevated levels of IL-6 , IL-1β , and Csf-1 in tissues. The increased production of IL-6 was also detectable in the serum. These increased cytokine levels were present in healthy Smg1 heterozygous mice and predated the onset of either cancer development or severe chronic inflammation. We also detected oxidative damage in hyperplastic spleens from Smg1 heterozygous mice, indicating that the levels of reactive oxygen and nitrogen species are also elevated. Pathological analysis of the Smg1 heterozygous mice revealed increased susceptibility to two key types of cancer: papillary lung adenocarcinoma and non-Hodgkin lymphoma of follicular cell origin. To understand the basis for the shortened lifespan, we measured the efficiency of pathways in which Smg1 is thought to play a role. We first examined NMD, the most well-characterized Smg1 -dependent pathway; we used four different assays to measure NMD but found no evidence of defective NMD in Smg1 heterozygous mice. We next examined DNA damage responses both in vitro and in vivo. Neither cells nor mice showed enhanced radiosensitivity compared with WT littermates. We further examined telomere maintenance, hypoxia, and oxidative stress response but found no significant difference between Smg1 heterozygous and WT mice. SMG1 is a member of the phosphoinositide kinase-like kinase family of proteins whose other members, such as ATM, ATR, and mammalian target of rapamycin, are known to play roles in genomic stability and stress responses ( 1 ). SMG1 has a well-established role in a process known as nonsense-mediated decay (NMD), by which cells degrade mRNA transcripts that contain premature stop codons and limit the production of truncated proteins that may adversely affect cellular processes ( 2 ). SMG1 has also been proposed to play a role in telomere maintenance and the responses to DNA damage, hypoxia, and oxidative stress ( 3 ). In this study, we generated a mouse model of Smg1 deficiency and found that Smg1 KO mice died early during development. Smg1 KO embryos were not identified 8.5 d postcoitum. Our findings further revealed that Smg1 heterozygous mice had a shorter lifespan than their WT littermates and were predisposed to both cancer development and chronic inflammation. This phenotype could not be accounted for by defects in the characterized roles of Smg1 . However, we also noted that Smg1 heterozygous mice showed elevated tissue cytokines and oxidative damage, suggesting that Smg1 plays a role in regulation of inflammation and cancer development and may act as a tumor suppressor.
Type of Medium:
Online Resource
ISSN:
0027-8424
,
1091-6490
DOI:
10.1073/pnas.1215696110
Language:
English
Publisher:
Proceedings of the National Academy of Sciences
Publication Date:
2013
detail.hit.zdb_id:
209104-5
detail.hit.zdb_id:
1461794-8
SSG:
11
SSG:
12
Bookmarklink