Inflammation-induced PELP1 expression promotes tumorigenesis by activating GM-CSF paracrine secretion in the tumor microenvironment.

Autor:	Vuttaradhi VK; Molecular Oncology Laboratory, Department of Biotechnology, Indian Institute of Technology Madras, Chennai, Tamil Nadu, India., Ezhil I; Molecular Oncology Laboratory, Department of Biotechnology, Indian Institute of Technology Madras, Chennai, Tamil Nadu, India., Ramani D; Molecular Oncology Laboratory, Department of Biotechnology, Indian Institute of Technology Madras, Chennai, Tamil Nadu, India; Department of Human Genetics, Sri Ramachandra Faculty of Biomedical Sciences & Technology, Sri Ramachandra Institute of Higher Education and Research, Chennai, Tamil Nadu, India., Kanumuri R; Molecular Oncology Laboratory, Department of Biotechnology, Indian Institute of Technology Madras, Chennai, Tamil Nadu, India; Department of Human Genetics, Sri Ramachandra Faculty of Biomedical Sciences & Technology, Sri Ramachandra Institute of Higher Education and Research, Chennai, Tamil Nadu, India., Raghavan S; Molecular Oncology Laboratory, Department of Biotechnology, Indian Institute of Technology Madras, Chennai, Tamil Nadu, India., Balasubramanian V; Department of Human Genetics, Sri Ramachandra Faculty of Biomedical Sciences & Technology, Sri Ramachandra Institute of Higher Education and Research, Chennai, Tamil Nadu, India., Saravanan R; Department of Human Genetics, Sri Ramachandra Faculty of Biomedical Sciences & Technology, Sri Ramachandra Institute of Higher Education and Research, Chennai, Tamil Nadu, India., Kanakarajan A; Department of Pathology, Sri Ramachandra Medical College, Sri Ramachandra Institute of Higher Education and Research, Chennai, Tamil Nadu, India., Joseph LD; Department of Pathology, Sri Ramachandra Medical College, Sri Ramachandra Institute of Higher Education and Research, Chennai, Tamil Nadu, India., Pitani RS; Department of Community Medicine, Sri Ramachandra Medical College, Sri Ramachandra Institute of Higher Education and Research, Chennai, Tamil Nadu, India., Sundaram S; Department of Pathology, Sri Ramachandra Medical College, Sri Ramachandra Institute of Higher Education and Research, Chennai, Tamil Nadu, India., Sjolander A; Cell Pathology, Department of Translational Medicine, Clinical Research Centre, Skåne University Hospital, Lund University, Malmö, Sweden., Venkatraman G; Department of Human Genetics, Sri Ramachandra Faculty of Biomedical Sciences & Technology, Sri Ramachandra Institute of Higher Education and Research, Chennai, Tamil Nadu, India. Electronic address: ganeshv@sriramachandra.edu.in., Rayala SK; Molecular Oncology Laboratory, Department of Biotechnology, Indian Institute of Technology Madras, Chennai, Tamil Nadu, India. Electronic address: rayala@iitm.ac.in.
Jazyk:	angličtina
Zdroj:	The Journal of biological chemistry [J Biol Chem] 2022 Jan; Vol. 298 (1), pp. 101406. Date of Electronic Publication: 2021 Nov 11.
DOI:	10.1016/j.jbc.2021.101406
Abstrakt:	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. Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article. (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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