Abstract
p204, a murine member of the interferon-inducible p200 protein family, and its human analogue, IFI16, have been shown to function as tumor suppressors in vitro, but the molecular events involved, in particular in vivo, remain unclear. Herein we induced the Lewis Lung carcinoma (LLC) murine model of human lung cancer in p204 null mice (KO) and their control littermates (WT). We compared the transcriptome in spleen from WT and p204 KO mice using a high-throughput RNA-sequencing array. A total 30.02 Gb of clean data were obtained, and overall Q30% was greater than 90.54%. More than 75% of clean data from 12 transcriptome samples were mapped to exons. The results showed that only 11 genes exhibited altered expression in untreated p204 KO mice relative to untreated WT mice, while 393 altered genes were identified in tumor-bearing p204 KO mice when compared with tumor-bearing WT mice. Further differentially expressed gene cluster and gene ontology consortium classification revealed that numerous cytokines and their receptors, chemoattractant molecules, and adhesion molecules were significantly induced in p204 KO mice. This study provides novel insights to the p204 network in anti-tumor immune response and also presents a foundation for future work concerning p204-mediated gene expressions and pathways.
Highlights
Interferon-inducible p204, encoded by gene Ifi[204], belongs to the p200 protein family and has been implicated as an important molecule in innate immune response[1,2]
The expression of p204 was significantly induced during myoblast fusion, and overexpression of p204 accelerated the fusion of myoblasts to myotubes in both differentiation medium and growth medium23. p204 promoted myoblast differentiation, at least in part, by overcoming the inhibition of myoblast differentiation by inhibitor of DNA binding (Id) proteins24. p204 directly bound to Id proteins (Id1, Id2, and Id3) through its second HIN-200 domain, and overexpression of p204 resulted in a reduction in the level of Id proteins and the loss of Id-mediated inhibition of MyoD and E47 binding to DNA24. p204 is involved in osteoblast differentiation and overexpression of p204 enhanced BMP-2-induced osteoblast differentiation in vitro by acting as a transcriptional coactivator of core-binding factor α 1 (Cbfα1)[22]
To identify the function of p204 in anti-tumor immunity, we injected control group wild type (WT) and p204 KO mice with PBS and experimental group WT and p204 KO mice with Lewis lung cells (n = 3 per group). 28 days after tumor-inoculation, all mice were sacrificed and spleens were collected for RNA-Seq and transcriptome analysis
Summary
Interferon-inducible p204, encoded by gene Ifi[204], belongs to the p200 protein family and has been implicated as an important molecule in innate immune response[1,2]. P200 family members are induced in response to IFN stimulation; the genomic loci of p200 family clusters becomes transcriptionally activated after interferon treatment[5], and their expression is significantly induced by IFN-γ in myeloid lineage cells[6], suggesting an important role of p200 proteins in innate immunity. The two HIN-200 domains of p204 bind retinoblastoma tumor suppressor protein (pRb) and overexpression of p204 in pRB positive cells delayed G0/G1 progression into S phase and impaired E2F-mediated transcriptional activity, while p204 lost its ability to inhibit cell proliferation in pRb null cells, indicating that p204 inhibition of cell proliferation occurs through a pRb-dependent mechanism[27]. This study provides novel insights concerning the IFI204 mediated anti-tumor network
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