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.

中文翻译：

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炎症诱导的 PELP1 表达通过激活肿瘤微环境中的 GM-CSF 旁分泌分泌来促进肿瘤发生。

炎症性肿瘤微环境被认为是促进肿瘤进展的主要因素，也是癌症的促进特征，脯氨酸、谷氨酸和富含亮氨酸的蛋白 1 (PELP1) 是一种新型核受体共调节因子，可跨多种信号网络发出信号，其表达在多种癌症中发生改变。然而，关于 PELP1 在炎症驱动的肿瘤发生中的作用的研究是有限的。利用脂多糖 (LPS) 或坏死细胞刺激后的巨噬细胞系和动物模型进行的分子研究表明，PELP1 是一种炎症诱导基因。对 PELP1 启动子及其突变体的研究发现，在巨噬细胞受到 LPS 刺激后，c-Rel（一种 NF-κB 转录因子亚基）可能与 PELP1 启动子结合。通过染色质免疫沉淀验证了 c-Rel 招募到 PELP1 启动子上的情况，进一步证实了 LPS 通过 c-Rel 特异性转录调控介导的 PELP1 表达。过度表达 PELP1 的巨噬细胞会诱导粒细胞-巨噬细胞集落刺激因子分泌，从而以旁分泌方式介导癌症进展。正常炎症肿瘤进展模型的临床前研究结果表明，PELP1 表达逐渐增加，支持炎症和癌症之间的这种联系。此外，动物研究证明了 PELP1 在炎症导向的癌症进展中的联系。总而言之，我们的研究结果首次报告了炎症中 PELP1 的 c-Rel 特异性转录调控，以及炎症肿瘤微环境中上皮细胞上活化巨噬细胞可能由粒细胞巨噬细胞集落刺激因子介导的转化潜力，重申了两者之间的联系PELP1 和炎症诱导的肿瘤发生。了解 PELP1 的调节机制可能有助于设计更好的疗法来治疗各种与炎症相关的恶性肿瘤。