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Xiaoli Liu Division of Thyroid Surgery, China-Japan Union Hospital of Jilin University, Jilin Provincial Key Laboratory of Surgical Translational Medicine, Changchun, Jilin, China

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Chunhai Zhang Division of Thyroid Surgery, China-Japan Union Hospital of Jilin University, Jilin Provincial Key Laboratory of Surgical Translational Medicine, Changchun, Jilin, China

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Xiaomiao Wang Division of Thyroid Surgery, China-Japan Union Hospital of Jilin University, Jilin Provincial Key Laboratory of Surgical Translational Medicine, Changchun, Jilin, China

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Can Cui Division of Thyroid Surgery, China-Japan Union Hospital of Jilin University, Jilin Provincial Key Laboratory of Surgical Translational Medicine, Changchun, Jilin, China

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Hanwen Cui Division of Thyroid Surgery, China-Japan Union Hospital of Jilin University, Jilin Provincial Key Laboratory of Surgical Translational Medicine, Changchun, Jilin, China

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Baishu Zhu Division of Thyroid Surgery, China-Japan Union Hospital of Jilin University, Jilin Provincial Key Laboratory of Surgical Translational Medicine, Changchun, Jilin, China

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Anqi Chen Division of Thyroid Surgery, China-Japan Union Hospital of Jilin University, Jilin Provincial Key Laboratory of Surgical Translational Medicine, Changchun, Jilin, China

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Lu Zhang Division of Thyroid Surgery, China-Japan Union Hospital of Jilin University, Jilin Provincial Key Laboratory of Surgical Translational Medicine, Changchun, Jilin, China

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Jingwei Xin Division of Thyroid Surgery, China-Japan Union Hospital of Jilin University, Jilin Provincial Key Laboratory of Surgical Translational Medicine, Changchun, Jilin, China

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Qingfeng Fu Division of Thyroid Surgery, China-Japan Union Hospital of Jilin University, Jilin Provincial Key Laboratory of Surgical Translational Medicine, Changchun, Jilin, China

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Gianlorenzo Dionigi Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy
Division of Surgery, Istituto Auxologico Italiano, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Milan, Italy

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Hui Sun Division of Thyroid Surgery, China-Japan Union Hospital of Jilin University, Jilin Provincial Key Laboratory of Surgical Translational Medicine, Changchun, Jilin, China

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Lymphatic metastasis is the leading cause responsible for recurrence and progression in papillary thyroid cancer (PTC), where dysregulation of long non-coding RNAs (lncRNAs) has been extensively demonstrated to be implicated. However, the specific lymphatic node metastatsis-related lncRNAs remain not identified in PTC yet. Lymphatic node metastatsis-related lncRNA, MFSD4A-AS1, was explored in the PTC dataset from The Cancer Genome Atlas and our clinical samples. The roles of MFSD4A-AS1 in lymphatic metastasis were investigated in vitro and in vivo. Bioinformatic analysis, luciferase assay and RNA immunoprecipitation assay were performed to identify the potential targets and the underlying pathway of MFSD4A-AS1 in lymphatic metastasis of PTC. MFSD4A-AS1 was specifically upregulated in PTC tissues with lymphatic metastasis. Upregulating MFSD4A-AS1 promoted mesh formation and migration of human umbilical vein endothelial cells and invasion and migration of PTC cells. Importantly and consistently, MFSD4A-AS1 promoted lymphatic metastasis of PTC cells in vivo by inducing the lymphangiogenic formation and enhancing the invasive capability of PTC cells. Mechanistic dissection further revealed that MFSD4A-AS1 functioned as competing endogenous RNA to sequester miR-30c-2-3p, miR-145-3p and miR-139-5p to disrupt the miRNA-mediated inhibition of vascular endothelial growth factors A and C, and further activated transforming growth factor (TGF)-β signaling by sponging miR-30c-2-3p that targeted TGFBR2 and USP15, both of which synergistically promoted lymphangiogenesis and lymphatic metastasis of PTC. Our results unravel novel dual mechanisms by which MFSD4A-AS1 promotes lymphatic metastasis of PTC, which will facilitate the development of anti-lymphatic metastatic therapeutic strategy in PTC.

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Xiang Zhang Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China

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Ya Hu Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China

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Mengyi Wang Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China

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Ronghua Zhang Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China

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PeiPei Wang Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China

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Ming Cui Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China

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Zhe Su Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China

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Xiang Gao Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China

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Quan Liao Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China

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Yupei Zhao Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China

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Parathyroid carcinoma (PCa) is a rare endocrine neoplasia that typically has unfavourable outcomes. The contribution of long non-coding RNAs (lncRNAs) to the development of malignant and benign parathyroid tumours remains largely unknown. In this study, we explored transcriptomic profiling of lncRNA and mRNA expression in 6 PCa, 6 parathyroid adenoma (PAd) and 4 normal parathyroid (PaN) tissues. In total, 2641 lncRNA transcripts and 2165 mRNA transcripts were differentially expressed between PCa and PAd. Enrichment analysis demonstrated that dysregulated transcripts were involved mainly in the extracellular matrix (ECM)–receptor interaction and energy metabolism pathways. Bioinformatics analysis suggested that ATF3, ID1, FOXM1, EZH2 and MITF may be crucial to parathyroid carcinogenesis. Series test of cluster analysis segregated differentially expressed lncRNAs and mRNAs into several expression profile models, among which the ‘plateau’ profile representing components specific to parathyroid carcinogenesis was selected to build a co-expression network. Seven lncRNAs and three mRNAs were selected for quantitative RT-PCR validation in 16 PCa, 41 PAd and 4 PaN samples. Receiver-operator characteristic curves analysis showed that lncRNA PVT1 and GLIS2-AS1 yielded the area under the curve values of 0.871 and 0.860, respectively. Higher hybridization signals were observed in PCa for PVT1 and PAd for GLIS2-AS1. In conclusion, the current evidence indicates that PAd and PCa partially share common signalling molecules and pathways, but have independent transcriptional events. Differentially expressed lncRNAs and mRNAs have intricate interactions and are involved in parathyroid tumourigenesis. The lncRNA PVT1 and GLIS2-AS1 may be new potential markers for the diagnosis of PCa.

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Xiang Zhang Department of General Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China

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Ya Hu Department of General Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China

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Ming Cui Department of General Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China

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Mengyi Wang Department of General Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China

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Xiaobin Li Department of General Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China

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Yalu Zhang Department of General Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China

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Sen Yang Department of General Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China

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Surong Hua Department of General Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China

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Meiping Shen Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China

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Quan Liao Department of General Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China

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Tumour microenvironment has been recognized as a crucial factor influencing disease progression. However, relevant features and functions are insufficiently understood in parathyroid neoplasia. Single-cell RNA sequencing was performed to profile the transcriptome of 27,251 cells from 4 parathyroid adenoma (PA) tissue samples. External transcriptomic datasets and immunofluorescence staining of a tissue microarray were set for expression validation. Eight major cell types and various subpopulations were finely identified in PA. We found that a subcluster of tumour endocrine cells with low copy number variation probably presented as a resting state. Diverse infiltrating immune cell subtypes were identified, constructing an immunosuppressive microenvironment. Tumour-associated macrophages, which indicated an anti-inflammatory phenotype, were significantly increased in PA. Inflammatory tumour-associated fibroblasts (iTAFs) were newly verified and highlighted on the role of stromal-immune crosstalk. Positive correlation between iTAFs and increased CD163+ macrophages was uncovered. Moreover, CXCL12 receptor signalling is important for tumour angiogenesis and immune infiltration. Our findings provide a comprehensive landscape interpreting tumour cell heterogeneity, cell diversity, and immune regulation in parathyroid neoplasia. The valuable resources may promote the understanding of parathyroid tumour microenvironment.

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Chen Wang Department of Nuclear Medicine, Peking Union Medical College Hospital, Beijing, China
Beijing Key Laboratory of Molecular Targeted Diagnosis and Therapy in Nuclear Medicine, Beijing, China

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Xin Zhang Department of Nuclear Medicine, Peking Union Medical College Hospital, Beijing, China
Beijing Key Laboratory of Molecular Targeted Diagnosis and Therapy in Nuclear Medicine, Beijing, China

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Xue Yang Department of Oncology, The Affiliated Hospital of Qingdao University, Qingdao, China

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Hui Li Department of Nuclear Medicine, Peking Union Medical College Hospital, Beijing, China
Beijing Key Laboratory of Molecular Targeted Diagnosis and Therapy in Nuclear Medicine, Beijing, China

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Ruixue Cui Department of Nuclear Medicine, Peking Union Medical College Hospital, Beijing, China
Beijing Key Laboratory of Molecular Targeted Diagnosis and Therapy in Nuclear Medicine, Beijing, China

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Wenmin Guan Department of Radiology, Peking Union Medical College Hospital, Beijing, China

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Xin Li Department of Nuclear Medicine, Zhejiang Cancer Hospital, Hangzhou, China

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Zhaohui Zhu Department of Nuclear Medicine, Peking Union Medical College Hospital, Beijing, China
Beijing Key Laboratory of Molecular Targeted Diagnosis and Therapy in Nuclear Medicine, Beijing, China

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Yansong Lin Department of Nuclear Medicine, Peking Union Medical College Hospital, Beijing, China
Beijing Key Laboratory of Molecular Targeted Diagnosis and Therapy in Nuclear Medicine, Beijing, China

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This work evaluated the use of the positron emission tomography (PET)/computed tomography (CT) technique to assess the early therapeutic response and predict the prognosis of patients with radioactive iodine-refractory differentiated thyroid cancer (RAIR-DTC) who underwent apatinib therapy. Standardised uptake value (SUV), metabolic tumour volume (MTV) and total lesion glycolysis (TLG), derived from 18F-FDG PET/CT and SUV from 68Ga-NOTA-PRGD2 PET/CT were evaluated. Tumour response was evaluated using the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. Sixteen of 20 patients achieved partial response (PR) and four of 20 had stable disease (SD) after apatinib therapy. Six progression-free survival (PFS) events occurred. A strong correlation was observed between the best change in the sum of the longest diameters of target lesions (ΔCT%) and 18F-FDG PET/CT indices after the completion of the first treatment cycle (ΔMTV% (P = 0.0019), ΔTLG% (P = 0.0021) and ΔSUVmax% (P = 0.0443)). A significant difference in PFS was observed between patients with ΔMTV% <−45% and ≥−45% (P = 0.0019) and between patients with ΔTLG% <−80% and ≥−80% (P = 0.0065). Ten of 11 patients presented a decrease in SUVmax on 68Ga-NOTA-PRGD2 PET/CT after two cycles of apatinib therapy and showed PR, whereas one patient presenting an increase in SUVmax only showed SD as the best response. When a cut-off value of the target/background ratio at −20% was used, two PFS curves showed a significant difference (P = 0.0016). Hence, early assessment by 18F-FDG and 68Ga-NOTA-PRGD2 PET/CT was effective in the prediction and evaluation of RAIR-DTC treated with apatinib.

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Luming Wu Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China

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Jing Xie Department of Pathology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China

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Yan Qi Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China

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Tingwei Su Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China

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Lei Jiang Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China

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Weiwei Zhou Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China

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Yiran Jiang Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China

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Cui Zhang Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China

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Xu Zhong Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China

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Yanan Cao Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China

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Weiqing Wang Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China
Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai Key Laboratory for Endocrine Tumor, State Key Laboratory of Medical Genomics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China

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Adrenal incidentalomas are the most frequent human neoplasms. Recent genomic investigations on functional adrenocortical tumors have demonstrated that somatic mutations in PRKACA and KCNJ5 responsible for the development of adrenocortical adenomas (ACAs) are associated with hypercortisolism and aldosteronism, respectively. Several studies have identified CTNNB1 mutations in ACAs and have been mostly involved in the tumorigenesis of non-functional ACA (NFACA). However, integrated genomic characterization of NFACAs is lacking. In the current study, we utilized pan-genomic methods to comprehensively analyze 60 NFACA samples. A total of 1264 somatic mutations in coding regions among the 60 samples were identified, with a median of 15 non-silent mutations per tumor. Twenty-two NFACAs (36.67%) had genetic alterations in CTNNB1. We also identified several somatic mutations in genes of the cAMP/PKA pathway and KCNJ5. Histone modification genes (KMT2A, KMT2C, and KMT2D) were altered in 10% of cases. Germline mutations of MEN1 and RET were also found. Finally, by comparison of our transcriptome data with those available in the TCGA, we illustrated the molecular characterization of NFACA. We revealed the genetic profiling and molecular landscape of NFACA. Wnt/β-catenin pathway activation as shown ssby nuclear and/or cytoplasmic β-catenin accumulation is frequent, occurring in about one–third of ACA cases. cytochrome P450 enzymes could be markers to reveal the functional status of adrenocortical tumors. These observations strongly suggest the involvement of the Wnt/β-catenin pathway in benign adrenal tumorigenesis and possibly in the regulation of steroid secretion.

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Luming Wu Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China

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Jing Xie Department of Pathology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China

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Yan Qi Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China

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Tingwei Su Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China

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Lei Jiang Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China

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Weiwei Zhou Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China

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Yiran Jiang Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China

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Cui Zhang Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China

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Xu Zhong Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China

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Yanan Cao Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China

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Weiqing Wang Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China
Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai Key Laboratory for Endocrine Tumor, State Key Laboratory of Medical Genomics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China

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Zhi-yuan Pang Department of Breast Surgery, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute, Shenyang, Liaoning, China

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Yun-tao Wei Department of Breast Surgery, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute, Shenyang, Liaoning, China

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Mu-yan Shang Department of Breast Surgery, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute, Shenyang, Liaoning, China

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Shuang Li Department of Breast Surgery, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute, Shenyang, Liaoning, China

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Yang Li Department of Breast Surgery, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute, Shenyang, Liaoning, China

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Quan-xiu Jin Department of Breast Surgery, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute, Shenyang, Liaoning, China

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Zhi-xuan Liao Department of Breast Surgery, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute, Shenyang, Liaoning, China

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Ming-ke Cui Department of Breast Surgery, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute, Shenyang, Liaoning, China

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Xiao-yan Liu Department of Breast Surgery, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute, Shenyang, Liaoning, China

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Qiang Zhang Department of Breast Surgery, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute, Shenyang, Liaoning, China

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Aberrant leptin signaling and overexpression of fibroblast growth factor receptor 1 (FGFR1) are both implicated in the pathogenesis of letrozole resistance in breast cancer (BCa), but it remains unknown whether these two pathways are involved in letrozole resistance in a coordinated manner. Here, we demonstrate that expression levels of the pre-B-cell leukemia homeobox transcription factor 3 (PBX3), a pioneer factor that governs divergent biological processes, were significantly upregulated in letrozole-resistant BCa cells and tissues, and this upregulation correlated to a poorer progression-free survival in patients. By leveraging a patient-derived xenograft model with pharmacological approaches, we demonstrated that leptin activated PBX3 expression in a STAT3 (signal transducer and activator of transcription 3)-dependent manner. Our loss- and gain-of-function study further showed that PBX3 attenuated response to letrozole by potentiating BCa cell survival and anchorage-independent growth in BCa cells. By profiling BCa cells with ectopic PBX3 expression, we revealed that PBX3 conferred letrozole resistance via transactivation of the FGFR1 signaling, and this molecular event must coordinate a synergistic transcription activation programs through interacting with MTA1-HDAC2 (metastasis-associated 1-histone deacetylase 2) complex. Overall, the available data reveal a novel role of leptin/PBX3 cascade linking energy homeostasis (i.e. hyperleptinemia) and endocrine therapy failure (i.e. letrozole resistance) in BCa.

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Jingqi Fu Program of Environmental Toxicology, School of Public Health, China Medical University, Shenyang, People’s Republic of China

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Hongzhi Zheng Department of Geriatric Endocrinology, The First Affiliated Hospital, China Medical University, Shenyang, People’s Republic of China

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Qi Cui Program of Environmental Toxicology, School of Public Health, China Medical University, Shenyang, People’s Republic of China

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Chengjie Chen Program of Environmental Toxicology, School of Public Health, China Medical University, Shenyang, People’s Republic of China

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Simeng Bao Program of Environmental Toxicology, School of Public Health, China Medical University, Shenyang, People’s Republic of China

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Jing Sun Program of Environmental Toxicology, School of Public Health, China Medical University, Shenyang, People’s Republic of China

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Lu Li Program of Environmental Toxicology, School of Public Health, China Medical University, Shenyang, People’s Republic of China

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Bei Yang Department of Histology and Embryology, School of Basic Medical Sciences, China Medical University, Shenyang, People’s Republic of China

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Huihui Wang Program of Environmental Toxicology, School of Public Health, China Medical University, Shenyang, People’s Republic of China

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Yongyong Hou Program of Environmental Toxicology, School of Public Health, China Medical University, Shenyang, People’s Republic of China

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Yuanyuan Xu Program of Environmental Toxicology, School of Public Health, China Medical University, Shenyang, People’s Republic of China

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Yuanhong Xu Department of Pancreatic Surgery, The First Affiliated Hospital, China Medical University, Shenyang, People’s Republic of China

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Qiang Zhang Department of Environmental Health, Rollins School of Public Health, Emory University, Atlanta, Georgia, USA

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Jingbo Pi Program of Environmental Toxicology, School of Public Health, China Medical University, Shenyang, People’s Republic of China

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The transcription factor nuclear factor erythroid 2-like 1 (NFE2L1 or NRF1) is involved in various critical cell processes such as maintenance of ubiquitin-proteasome system and regulation of the cellular antioxidant response. We previously determined that pancreatic β-cell-specific Nfe2l1-knockout mice had hyperinsulinemia and that silencing of Nfe2l1 in mouse islets or MIN6 insulinoma β-cells induced elevated basal insulin release and altered glucose metabolism. Hypoglycemia is a major issue with aggressive insulinomas, although a role of NFE2L1 in this pathology is not defined. In the present work, we studied the tumorigenicity of Nfe2l1-deficient insulinoma MIN6 cells (Nfe2l1-KD) and sensitivity to chemotherapy. Nfe2l1-KD cells grew faster and were more aggressive than Scramble cells in vitro. In a mouse allograft transplantation model, insulinomas arising from Nfe2l1-KD cells were more aggressive and chemoresistant. The conclusion was amplified using streptozotocin (STZ) administration in an allograft transplantation model in diabetic Akita background mice. Furthermore, Nfe2l1-KD cells were resistant to damage by the chemotherapeutic drugs STZ and 5-fluorouracil, which was linked to binding of hexokinase 1 with mitochondria, enhanced mitochondrial membrane potential and closed mitochondrial potential transition pore. Overall, both in vitro and in vivo data from Nfe2l1-KD insulinoma cells provided evidence of a previously un-appreciated action of NFE2L1 in suppression of tumorigenesis. Nfe2l1 silencing desensitizes insulinoma cells and derived tumors to chemotherapeutic-induced damage, likely via metabolic reprograming. These data indicate that NFE2L1 could potentially play an important role in the carcinogenic process and impact chemosensitivity, at least within a subset of pancreatic endocrine tumors.

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Xiao-Hua Jiang Shanghai Clinical Center for Endocrine and Metabolic Diseases,, Laboratory for Endocrine and Metabolic Diseases,, Department of Radiological Medicine,, Laboratoire Genetique et Cancer,, Shanghai Key Laboratory for Endocrine Tumours,, Shanghai Institute of Endocrinology and Metabolism and Chinese-French Laboratory of Genomics and Life Sciences, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, 197 Ruijin 2nd Road, Shanghai 200025, China

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Jie-Li Lu Shanghai Clinical Center for Endocrine and Metabolic Diseases,, Laboratory for Endocrine and Metabolic Diseases,, Department of Radiological Medicine,, Laboratoire Genetique et Cancer,, Shanghai Key Laboratory for Endocrine Tumours,, Shanghai Institute of Endocrinology and Metabolism and Chinese-French Laboratory of Genomics and Life Sciences, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, 197 Ruijin 2nd Road, Shanghai 200025, China

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Bin Cui Shanghai Clinical Center for Endocrine and Metabolic Diseases,, Laboratory for Endocrine and Metabolic Diseases,, Department of Radiological Medicine,, Laboratoire Genetique et Cancer,, Shanghai Key Laboratory for Endocrine Tumours,, Shanghai Institute of Endocrinology and Metabolism and Chinese-French Laboratory of Genomics and Life Sciences, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, 197 Ruijin 2nd Road, Shanghai 200025, China
Shanghai Clinical Center for Endocrine and Metabolic Diseases,, Laboratory for Endocrine and Metabolic Diseases,, Department of Radiological Medicine,, Laboratoire Genetique et Cancer,, Shanghai Key Laboratory for Endocrine Tumours,, Shanghai Institute of Endocrinology and Metabolism and Chinese-French Laboratory of Genomics and Life Sciences, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, 197 Ruijin 2nd Road, Shanghai 200025, China

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Yong-Ju Zhao Shanghai Clinical Center for Endocrine and Metabolic Diseases,, Laboratory for Endocrine and Metabolic Diseases,, Department of Radiological Medicine,, Laboratoire Genetique et Cancer,, Shanghai Key Laboratory for Endocrine Tumours,, Shanghai Institute of Endocrinology and Metabolism and Chinese-French Laboratory of Genomics and Life Sciences, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, 197 Ruijin 2nd Road, Shanghai 200025, China

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Wei-qing Wang Shanghai Clinical Center for Endocrine and Metabolic Diseases,, Laboratory for Endocrine and Metabolic Diseases,, Department of Radiological Medicine,, Laboratoire Genetique et Cancer,, Shanghai Key Laboratory for Endocrine Tumours,, Shanghai Institute of Endocrinology and Metabolism and Chinese-French Laboratory of Genomics and Life Sciences, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, 197 Ruijin 2nd Road, Shanghai 200025, China

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Jian-Min Liu Shanghai Clinical Center for Endocrine and Metabolic Diseases,, Laboratory for Endocrine and Metabolic Diseases,, Department of Radiological Medicine,, Laboratoire Genetique et Cancer,, Shanghai Key Laboratory for Endocrine Tumours,, Shanghai Institute of Endocrinology and Metabolism and Chinese-French Laboratory of Genomics and Life Sciences, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, 197 Ruijin 2nd Road, Shanghai 200025, China

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Wen-Qiang Fang Shanghai Clinical Center for Endocrine and Metabolic Diseases,, Laboratory for Endocrine and Metabolic Diseases,, Department of Radiological Medicine,, Laboratoire Genetique et Cancer,, Shanghai Key Laboratory for Endocrine Tumours,, Shanghai Institute of Endocrinology and Metabolism and Chinese-French Laboratory of Genomics and Life Sciences, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, 197 Ruijin 2nd Road, Shanghai 200025, China

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Ya-Nan Cao Shanghai Clinical Center for Endocrine and Metabolic Diseases,, Laboratory for Endocrine and Metabolic Diseases,, Department of Radiological Medicine,, Laboratoire Genetique et Cancer,, Shanghai Key Laboratory for Endocrine Tumours,, Shanghai Institute of Endocrinology and Metabolism and Chinese-French Laboratory of Genomics and Life Sciences, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, 197 Ruijin 2nd Road, Shanghai 200025, China

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Yan Ge Shanghai Clinical Center for Endocrine and Metabolic Diseases,, Laboratory for Endocrine and Metabolic Diseases,, Department of Radiological Medicine,, Laboratoire Genetique et Cancer,, Shanghai Key Laboratory for Endocrine Tumours,, Shanghai Institute of Endocrinology and Metabolism and Chinese-French Laboratory of Genomics and Life Sciences, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, 197 Ruijin 2nd Road, Shanghai 200025, China

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Chang-xian Zhang Shanghai Clinical Center for Endocrine and Metabolic Diseases,, Laboratory for Endocrine and Metabolic Diseases,, Department of Radiological Medicine,, Laboratoire Genetique et Cancer,, Shanghai Key Laboratory for Endocrine Tumours,, Shanghai Institute of Endocrinology and Metabolism and Chinese-French Laboratory of Genomics and Life Sciences, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, 197 Ruijin 2nd Road, Shanghai 200025, China

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Huguette Casse Shanghai Clinical Center for Endocrine and Metabolic Diseases,, Laboratory for Endocrine and Metabolic Diseases,, Department of Radiological Medicine,, Laboratoire Genetique et Cancer,, Shanghai Key Laboratory for Endocrine Tumours,, Shanghai Institute of Endocrinology and Metabolism and Chinese-French Laboratory of Genomics and Life Sciences, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, 197 Ruijin 2nd Road, Shanghai 200025, China

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Xiao-Ying Li Shanghai Clinical Center for Endocrine and Metabolic Diseases,, Laboratory for Endocrine and Metabolic Diseases,, Department of Radiological Medicine,, Laboratoire Genetique et Cancer,, Shanghai Key Laboratory for Endocrine Tumours,, Shanghai Institute of Endocrinology and Metabolism and Chinese-French Laboratory of Genomics and Life Sciences, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, 197 Ruijin 2nd Road, Shanghai 200025, China
Shanghai Clinical Center for Endocrine and Metabolic Diseases,, Laboratory for Endocrine and Metabolic Diseases,, Department of Radiological Medicine,, Laboratoire Genetique et Cancer,, Shanghai Key Laboratory for Endocrine Tumours,, Shanghai Institute of Endocrinology and Metabolism and Chinese-French Laboratory of Genomics and Life Sciences, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, 197 Ruijin 2nd Road, Shanghai 200025, China

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Guang Ning Shanghai Clinical Center for Endocrine and Metabolic Diseases,, Laboratory for Endocrine and Metabolic Diseases,, Department of Radiological Medicine,, Laboratoire Genetique et Cancer,, Shanghai Key Laboratory for Endocrine Tumours,, Shanghai Institute of Endocrinology and Metabolism and Chinese-French Laboratory of Genomics and Life Sciences, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, 197 Ruijin 2nd Road, Shanghai 200025, China
Shanghai Clinical Center for Endocrine and Metabolic Diseases,, Laboratory for Endocrine and Metabolic Diseases,, Department of Radiological Medicine,, Laboratoire Genetique et Cancer,, Shanghai Key Laboratory for Endocrine Tumours,, Shanghai Institute of Endocrinology and Metabolism and Chinese-French Laboratory of Genomics and Life Sciences, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, 197 Ruijin 2nd Road, Shanghai 200025, China

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Multiple endocrine neoplasia type 1 (MEN1) is an inherited tumour syndrome characterized by the development of tumours of the parathyroid, anterior pituitary and pancreatic islets, etc. Heterozygous germ line mutations of MEN1 gene are responsible for the onset of MEN1. We investigated the probands and 31 family members from eight unrelated Chinese families associated with MEN1 and identified four novel mutations, namely 373_374ins18, 822delT, 259delT and 1092delC, as well as three previously reported mutations, such as 357_360delCTGT, 427_428delTA and R108X (CGA>TGA) of MEN1 gene. Furthermore, we detected a loss of heterozygosity (LOH) at chromosome 11q in the removed tumours, including gastrinoma, insulinoma and parathyroid adenoma from two probands of MEN1 families. RT-PCR and direct sequencing showed that mutant MEN1 transcripts remained in the MEN1-associated endocrine tumours, whereas normal menin proteins could not be detected in those tumours by either immunohistochemistry or immunoblotting. In conclusion, MEN1 heterozygous mutations are associated with LOH and menin absence, which are present in MEN1-associated endocrine tumours.

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