title: Increased expression of 17-beta-hydroxysteroid dehydrogenase type 1 in non-small cell lung cancer.
abstract: OBJECTIVE
  Recent studies indicated that estrogens may influence the development of non-small cell lung cancer (NSCLC). The 17-beta-hydroxysteroid dehydrogenase type 1 (HSD17B1) catalyzes the reduction of estrone (E1) to the highly potent E2. Although the significance of aromatase in an intratumoral E2 production in NSCLC is well established, the role of HSD17B1 remains largely unknown. Therefore, we investigated the expression of HSD17B1 in lung cancerous and corresponding histopathologically unchanged tissues from NSCLC patients and the association between HSD17B1 expression and clinicopathological features. Than, we examined the biological significance of HSD17B1 in NSCLC cells in vitro. We tested the impact of 5-Aza-2'-deoxycytidine (5-dAzaC) on HSD17B1 expression and activity.
  
  
  METHODS
  We used Real Time quantitative PCR (RT-qPCR), Western blotting and immunohistochemistry to evaluate HSD17B1 expression in tissues obtained from 48 patients with NSCLC. The methylation status of the promoter region of HSD17B1 in A549 and Calu-1 cells was evaluated by bisulfite sequencing. We investigated the effect of 5-dAzaC on HSD17B1 transcript levels (by RT-qPCR) and on HSD17B1 enzyme activity by measuring the conversion of E1 to E2. The xCELLigence System was used for monitoring of cell proliferation.
  
  
  RESULTS
  We found a substantial increase of HSD17B1 mRNA and protein amount in NSCLC tissues compared with histopathologically unchanged tissues in the group of male patients. An overexpression of HSD17B1 was associated with squamous cell carcinoma and with lung cancer stage 3A. We showed that 5-dAzaC induces DNA demethylation of HSD17B1 promoter, leading to increased HSD17B1 mRNA levels and protein activity in NSCLC cells. It resulted in enhanced E2 production in both cell lines and supported the proliferation of Calu-1 cells but not A549 cells.
  
  
  CONCLUSIONS
  Increased expression of HSD17B1 in NSCLC may contribute to an elevated intratissue level of E2 and consequently may support the development and spread of cancer.
authors.affiliation: Department of Biochemistry and Molecular Biology, Poznan University of Medical Sciences, Święcickiego 6 Street, 60-781 Poznan, Poland. Electronic address: hdrzewiecka@ump.edu.pl.
authors.forename: Hanna
authors.initials: H
authors.lastname: Drzewiecka
authors.affiliation: Department of Thoracic Surgery, Poznan University of Medical Sciences, Szamarzewskiego 62 Street, 60-569 Poznan, Poland.
authors.forename: Bartłomiej
authors.initials: B
authors.lastname: Gałęcki
authors.affiliation: Department of Clinical Pathomorphology, Poznan University of Medical Sciences, Przybyszewskiego 49 Street, 60-355 Poznan, Poland.
authors.forename: Donata
authors.initials: D
authors.lastname: Jarmołowska-Jurczyszyn
authors.affiliation: Department of Clinical Pathomorphology, Poznan University of Medical Sciences, Przybyszewskiego 49 Street, 60-355 Poznan, Poland.
authors.forename: Andrzej
authors.initials: A
authors.lastname: Kluk
authors.affiliation: Department of Thoracic Surgery, Poznan University of Medical Sciences, Szamarzewskiego 62 Street, 60-569 Poznan, Poland.
authors.forename: Wojciech
authors.initials: W
authors.lastname: Dyszkiewicz
authors.affiliation: Department of Biochemistry and Molecular Biology, Poznan University of Medical Sciences, Święcickiego 6 Street, 60-781 Poznan, Poland.
authors.forename: Paweł P
authors.initials: PP
authors.lastname: Jagodziński
mesh_terms: D000328:Adult; D000368:Aged; D001374:Azacitidine / Q000494:pharmacology; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D019175:DNA Methylation; D004960:Estradiol Dehydrogenases / Q000235:genetics* / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007150:Immunohistochemistry; D008175:Lung Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic; D047368:Tumor Burden
chemical_list: D012333:RNA, Messenger; D004960:Estradiol Dehydrogenases; C513331:HSD17B1 protein, human; D001374:Azacitidine
keywords: 17-Beta-estradiol; 17-Beta-hydroxysteroid dehydrogenase type 1 (HSD17B1); Clinicopathological features; Estrogens; Gender; Non-small cell lung cancer (NSCLC)