title: Cholesterol Synthetase DHCR24 Induced by Insulin Aggravates Cancer Invasion and Progesterone Resistance in Endometrial Carcinoma.
abstract: 3β-Hydroxysteroid-Δ24 reductase (DHCR24), the final enzyme of the cholesterol biosynthetic pathway, has been associated with urogenital neoplasms. However, the function of DHCR24 in endometrial cancer (EC) remains largely elusive. Here, we analyzed the expression profile of DHCR24 and the progesterone receptor (PGR) in our tissue microarray of EC (n = 258), the existing EC database in GEO (Gene Expression Omnibus), and TCGA (The Cancer Genome Atlas). We found that DHCR24 was significantly elevated in patients with EC, and that the up-regulation of DHCR24 was associated with advanced clinical stage, histological grading, vascular invasion, lymphatic metastasis, and reduced overall survival. In addition, DHCR24 expression could be induced by insulin though STAT3, which directly binds to the promoter elements of DHCR24, as demonstrated by ChIP-PCR and luciferase assays. Furthermore, genetically silencing DHCR24 inhibited the metastatic ability of endometrial cancer cells and up-regulated PGR expression, which made cells more sensitive to progestin. Taken together, we have demonstrated for the first time the crucial role of the insulin/STAT3/DHCR24/PGR axis in the progression of EC by modulating the metastasis and progesterone response, which could serve as potential therapeutic targets for the treatment of EC with progesterone receptor loss.
authors.affiliation: Department of Obstetrics and Gynecology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, No. 600 Yishan Road, Shanghai 200233, P. R. China.
authors.forename: Miao
authors.initials: M
authors.lastname: Dai
authors.affiliation: Department of Obstetrics and Gynecology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, No. 600 Yishan Road, Shanghai 200233, P. R. China.
authors.forename: Xiao-Lu
authors.initials: XL
authors.lastname: Zhu
authors.affiliation: Department of Obstetrics and Gynecology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, No. 600 Yishan Road, Shanghai 200233, P. R. China.
authors.forename: Fei
authors.initials: F
authors.lastname: Liu
authors.affiliation: Department of Obstetrics and Gynecology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, No. 600 Yishan Road, Shanghai 200233, P. R. China.
authors.forename: Qin-Yang
authors.initials: QY
authors.lastname: Xu
authors.affiliation: Department of Obstetrics and Gynecology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, No. 600 Yishan Road, Shanghai 200233, P. R. China.
authors.forename: Qiu-Lin
authors.initials: QL
authors.lastname: Ge
authors.affiliation: State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200240, P. R. China.
authors.forename: Shu-Heng
authors.initials: SH
authors.lastname: Jiang
authors.affiliation: State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200240, P. R. China.
authors.forename: Xiao-Mei
authors.initials: XM
authors.lastname: Yang
authors.affiliation: State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200240, P. R. China.
authors.forename: Jun
authors.initials: J
authors.lastname: Li
authors.affiliation: State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200240, P. R. China.
authors.forename: Ya-Hui
authors.initials: YH
authors.lastname: Wang
authors.affiliation: Department of Obstetrics and Gynecology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, No. 600 Yishan Road, Shanghai 200233, P. R. China.
authors.forename: Qing-Kai
authors.initials: QK
authors.lastname: Wu
authors.affiliation: Department of Obstetrics and Gynecology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, No. 600 Yishan Road, Shanghai 200233, P. R. China.
authors.forename: Zhi-Hong
authors.initials: ZH
authors.lastname: Ai
authors.affiliation: Department of Obstetrics and Gynecology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, No. 600 Yishan Road, Shanghai 200233, P. R. China.
authors.forename: Yin-Cheng
authors.initials: YC
authors.lastname: Teng
authors.affiliation: State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200240, P. R. China.
authors.forename: Zhi-Gang
authors.initials: ZG
authors.lastname: Zhang
mesh_terms: D000368:Aged; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D016889:Endometrial Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics / Q000473:pathology*; D004717:Endometrium / Q000002:abnormalities* / Q000201:enzymology / Q000473:pathology; D004790:Enzyme Induction / Q000187:drug effects; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D020868:Gene Silencing / Q000187:drug effects; D006801:Humans; D007328:Insulin / Q000009:adverse effects*; D017258:Medroxyprogesterone Acetate / Q000494:pharmacology / Q000627:therapeutic use; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D009419:Nerve Tissue Proteins / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D044925:Oxidoreductases Acting on CH-CH Group Donors / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D011379:Prognosis; D011980:Receptors, Progesterone / Q000235:genetics / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics*; D014591:Uterine Diseases / Q000201:enzymology* / Q000235:genetics / Q000473:pathology
chemical_list: D007328:Insulin; D009419:Nerve Tissue Proteins; D011980:Receptors, Progesterone; D050796:STAT3 Transcription Factor; D017258:Medroxyprogesterone Acetate; D044925:Oxidoreductases Acting on CH-CH Group Donors; C499055:DHCR24 protein, human