التفاصيل البيبلوغرافية
| العنوان: |
Inflammation-induced PELP1 expression promotes tumorigenesis by activating GM-CSF paracrine secretion in the tumor microenvironment. |
| المؤلفون: |
Vuttaradhi, Veena Kumari1, Ezhil, Inemai1, Ramani, Divya1,2, Kanumuri, Rahul1,2, Raghavan, Swetha1, Balasubramanian, Vaishnavi2, Saravanan, Roshni2, Kanakarajan, Archana3, Joseph, Leena Dennis3, Pitani, Ravi Shankar4, Sundaram, Sandhya3, Sjolander, Anita5, Venkatraman, Ganesh2 ganeshv@sriramachandra.edu.in, Rayala, Suresh Kumar1 rayala@iitm.ac.in |
| المصدر: |
Journal of Biological Chemistry. Jan2022, Vol. 298 Issue 1, p1-20. 20p. |
| مصطلحات موضوعية: |
*TUMOR microenvironment, *GRANULOCYTES, *GRANULOCYTE-macrophage colony-stimulating factor, *GENETIC transcription regulation, *GLUTAMIC acid, *MACROPHAGES, EPITHELIAL cell tumors |
| مستخلص: |
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. [ABSTRACT FROM AUTHOR] |
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