Abstract
The inflammatory tumor microenvironment has been implicated as a major player fueling tumor progression and an enabling characteristic of cancer, proline, glutamic acid, and leucine-rich protein 1 (PELP1) is a novel nuclear receptor coregulator that signals across diverse signaling networks, and its expression is altered in several cancers. However, investigations to find the role of PELP1 in inflammation-driven oncogenesis are limited. Molecular studies here, utilizing macrophage cell lines and animal models upon stimulation with lipopolysaccharide (LPS) or necrotic cells, showed that PELP1 is an inflammation-inducible gene. Studies on the PELP1 promoter and its mutant identified potential binding of c-Rel, an NF-κB transcription factor subunit, to PELP1 promoter upon LPS stimulation in macrophages. Recruitment of c-Rel onto the PELP1 promoter was validated by chromatin immunoprecipitation, further confirming LPS mediated PELP1 expression through c-Rel–specific transcriptional regulation. Macrophages that overexpress PELP1 induces granulocyte–macrophage colony-stimulating factor secretion, which mediates cancer progression in a paracrine manner. Results from preclinical studies with normal–inflammatory–tumor progression models demonstrated a progressive increase in the PELP1 expression, supporting this link between inflammation and cancer. In addition, animal studies demonstrated the connection of PELP1 in inflammation-directed cancer progression. Taken together, our findings provide the first report on c-Rel–specific transcriptional regulation of PELP1 in inflammation and possible granulocyte–macrophage colony-stimulating factor–mediated transformation potential of activated macrophages on epithelial cells in the inflammatory tumor microenvironment, reiterating the link between PELP1 and inflammation-induced oncogenesis. Understanding the regulatory mechanisms of PELP1 may help in designing better therapeutics to cure various inflammation-associated malignancies.
Highlights
RAW 264.7 cells were transfected with PELP1 promoter and stimulated with three different inflammation inducers (LPS/interferon gamma (IFN-γ)/tumor necrosis factor alpha (TNF-α))
Our results showed an increase in the PELP1 promoter– luciferase activity in stimulated cells, further confirming PELP1 as an inflammatory responsive gene (Fig. 1G)
We confirmed the specificity of c-Rel binding to the oligo probes by performing super shift assay where we observed the disappearance of transcription factor–DNA complex when the reaction was incubated with c-Rel–specific antibody (Fig. 3L)
Summary
Chronic inflammation fosters consistent acquisition of mutations and epigenetic variations [3] that induce genetic alterations in cells that trigger transcriptional activity of various proteins like NF-κB [4, 5], signal transducer and activator of transcription 3 (STAT3), and hypoxia-inducible factor 1α [6, 7] in tumor cells These proteins cooperate to produce inflammatory mediators like cytokines and chemokines, which sequentially recruit and activate various immune cells [8]. A recent report suggests that cytoplasmic PELP1 induces macrophage activation, which promotes epithelial cell migration in a paracrine manner through inflammatory cytokines and chemokines via NF-κB, inducing protumorigenic signaling associated with cancer initiation [25]. We utilized an in vivo animal model system to augment the clinical significance of PELP1 in inflammation and cancer progression
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