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Li Cong, Jessica Gasser, Jessica Zhao, Baofeng Yang, Fanghong Li, and Allan Z Zhao

Obesity is one of the well-established risk factors for endometrial cancer. Recent clinical studies have demonstrated that circulating adiponectin concentrations are inversely correlated with the incidence of endometrial carcinoma. Such epidemiological findings are consistent with the paradoxical observations that adiponectin levels are reduced in obesity. This study investigated the direct effects of adiponectin on two endometrial carcinoma cell lines, HEC-1-A and RL95–2. These cell lines express both variants of adiponectin receptors, adipo-R1 and adipo-R2. Adiponectin treatment leads to suppression of cell proliferation in both cell types, which is primarily due to the significant increase of cell populations at G1/G0-phase and to the induction of apoptosis. The inhibition of growth in these two cell lines appears to be mediated by different signaling pathways. Although adiponectin treatment markedly increases the phosphorylation (Thr172) of AMP-activated protein kinase α in both HEC-1-A and RL95–2 within 30 min, prolonged exposure (48 h) leads to inactivation of Akt as well as reduction of cyclin D1 protein expression in HEC-1-A cells. In contrast, similar treatment of RL95–2 cells with adiponectin, while having no effects on Akt activity and cyclin D1 expression, causes a decrease in cyclin E2 expression and the activity of mitogen-activated kinase (p42/44). We conclude that adiponectin exerts direct anti-proliferative effects on HEC-1-A and RL95–2 cells by inducing cell cycle arrest and apoptosis. Depending on the genotypes of the endometrial cancer cells, the inhibitory effects of adiponectin are associated with the reduction of different pro-growth regulators of cell cycle and signaling proteins. Our study thus provides a cellular mechanism underlying the linkages between endometrial cancer and obesity.

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J Yang, Y-L Zhao, Z-Q Wu, Y-L Si, Y-G Meng, X-B Fu, Y-M Mu, and W-D Han

LRP16 is a special member of the macro domain superfamily, containing only a stand-alone macro domain functional module. Previous study demonstrated that the estrogenically regulated LRP16 cooperates with the estrogen receptor α and enhances the receptor's transcriptional activity in an estrogen-dependent manner. Here, we discovered that LRP16 binds to androgen receptor (AR) via its macro domain and amplifies the transactivation function of AR in response to androgen. Similarly, we also discovered that LRP16 acts as a potential coactivator to amplify the transactivation of at least other four nuclear receptors (NRs). Importantly, we show that the single macro domain in LRP16 can serve as the AR coactivator. RNA interference knockdown of LRP16 leads to impaired AR function and greatly attenuates the coactivation of AR by other AR coactivators such as ART-27 and steroid receptor coactivator-1. This interference also markedly inhibits the androgen-stimulated proliferation of androgen-sensitive LNCaP prostate cancer cells. However, LRP16 knockdown did not significantly affect the growth rate of AR-negative PC-3 prostate cancer cells. Furthermore, we observed the induction effect of LRP16 expression by androgen and established a feedforward mechanism that activated AR transactivation. Our results suggest that the macro domain protein LRP16 represents a novel type of cofactor of NR. They also indicate that LRP16 plays an essential role in AR transactivation.

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Yang Zhao, Cangang Zhang, Yanan Zhu, Xi Ding, Yikun Zhou, Hongjun Lv, Yuxuan Lin, Yuan Wu, Bingyin Shi, and Jiao Fu

The immunosuppressive microenvironment is associated with poor prognosis in papillary thyroid cancer (PTC); however, the molecular mechanisms involved are unknown. Among the triggering receptors expressed on myeloid cell (TREM) family, we found that TREM1 expression in PTC was significantly higher than that in normal tissues. TREM1 overexpression was associated with BRAFV600E profiles and advanced tumor stages. Furthermore, TREM1 mRNA expression was negatively correlated with promoter methylation status. Specifically, hypomethylation of CpG site cg06196379 in the TREM1 promoter was related with poor patient disease-free survival (DFS) and a high PTC recurrence rate. Mechanistically, TREM1 was mainly expressed in malignant epithelial cells but not in macrophages in PTC by single-cell analysis. PTC tissues with high TREM1 levels had enhanced infiltration of regulatory T cells (Tregs) and decreased infiltration of CD8+ T cells. Our study confirms that hypomethylation-mediated overexpression of TREM1 in PTC cells promotes an immunosuppressive microenvironment by enhancing Treg infiltration. We recommend the future use of therapeutic strategy targeting TREM1 for the treatment of PTC.

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Vivian Rosery, Henning Reis, Konstantinos Savvatakis, Bernd Kowall, Martin Stuschke, Andreas Paul, Alexander Dechêne, JiaJin Yang, Ben Zhao, Arianna Borgers, Stefan Kasper, Martin Schuler, Phyllis F Cheung, and Jens T Siveke

The tumor immune microenvironment (TME) represents a key determinant for responses to cancer treatment. However, the immune phenotype of highly proliferative gastroenteropancreatic neuroendocrine neoplasms (GEP-NEN) is still largely elusive. In this retrospective study, we characterized the TME of high-grade (G3, Ki-67 > 20%) GEP-NEN. We analyzed formalin-fixed paraffin-embedded samples from 37 patients with GEP-NEN G3 by immunohistochemistry and multiplex immunofluorescence to address the abundance and spatial interaction of relevant immune subsets. We focused on the expression of immune checkpoint molecules PD-1 and PD-L1, the cytotoxic T-cell marker CD8, and the tumor-associated macrophage marker CD206. Findings were correlated with overall survival (OS) from the date of a cancer diagnosis. Patients with PD-L1-positive tumors (CPS ≥ 1) and intense PD-1+CD8+ immune cell infiltration showed the most favorable median OS. Multiplex immunofluorescence staining of ten representative tissue samples illustrated intratumoral heterogeneity of PD-L1 expression. Dense PD-1+CD8+ immune cell infiltrates were observed in PD-L1-positive tumor regions but not in PD-L1-negative regions. Proximity analysis revealed a spatial interaction between PD-1+CD8+ cells and PD-L1-positive cells. Our data suggest a pre-existing antitumor immune response in the TME in a subgroup of GEP-NEN G3. This supports a targeted clinical exploration of immunotherapeutic approaches.