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Intratumoral localization and activity of 17?-hydroxysteroid dehydrogenase type 1 in non-small cell lung cancer: a potent prognostic factor.

ABSTRACT:

Background

Estrogens were recently demonstrated to be synthesized in non-small cell lung carcinomas (NSCLCs) via aromatase activity and aromatase inhibitor (AI) did suppressed estrogen receptor (ER) positive NSCLC growth. However, other enzymes involved in intratumoral production and metabolism of estrogens, i.e. 17?-hydroxysteroid dehydrogenases (i.e. 17?HSD1 and 17?HSD2) and others have not been studied. Therefore, in this study, we examined the clinical/ biological significance of 17?-hydroxysteroid dehydrogenases in NSCLCs.

Methodology

Archival materials obtained from 103 NSCLC patients were immunohistochemically evaluated using anti-17?HSD1 and anti-17?HSD2 antibodies. The findings of immunohistochemistry were then correlated with intratumoral estrone (E1) and estradiol (E2) concentration, clinicopathological factors and overall survival of the patients. We further employed NSCLC cell lines, A549 and LK87 to study the functional significance of 17?HSD1, in vitro.

Results

A higher 17?HSD1 immunoreactivity tended to be positively associated with aromatase (p=0.057) and tumor stage (p=0.055) whereas a higher 17?HSD2 immunoreactivity was positively associated with a squamous cell and adenosquamous cell carcinomas subtypes (p=0.031), tumor stage (p=0.004), T factor of TNM classification (p=0.010), maximum tumor diameter (p=0.002) and tended to be associated with N factor of TMN classification (p=0.065). A higher 17?HSD1 immunoreactivity was also significantly associated with lower intratumoral E1 concentration (p=0.040) and a higher intratumoral E2/E1 concentration ratio (p=0.028). On the other hand a higher 17?HSD2 immunoreactivity was significantly associated with higher intratumoral E1 concentration (p=0.035). Results of multivariate regression analysis demonstrated an increased 17?HSD1 immunoreactivity in tumor cells as an independent negative prognostic factor (HR= 2.83, p=0.007). E1 treatment in 17?HSD1 positive NSCLC cells, A549 and LK87, resulted in E2 production (p<0.0001) and enhanced cell proliferation, which was abrogated effectively by 17?HSD1 siRNA knockdown (p<0.0001). In addition, aromatase inhibitor treatment resulted in 17?HSD1 up regulation in both A549 and LK87 cells.

Conclusion

Results of our present study suggest that 17?HSD1 may be considered an important prognostic factor in NSCLC patients and targeting 17?HSD1 activity may further improve the clinical response in estrogen responsive NSCLC patients.

SUBMITTER: Verma MK

PROVIDER: S-EPMC3724709 | biostudies-literature | 2013 Jul

REPOSITORIES: biostudies-literature

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Intratumoral localization and activity of 17β-hydroxysteroid dehydrogenase type 1 in non-small cell lung cancer: a potent prognostic factor.

Verma Mohit K MK Miki Yasuhiro Y Abe Keiko K Suzuki Takashi T Niikawa Hiromichi H Suzuki Satoshi S Kondo Takashi T Sasano Hironobu H

Journal of translational medicine 20130709

<h4>Background</h4>Estrogens were recently demonstrated to be synthesized in non-small cell lung carcinomas (NSCLCs) via aromatase activity and aromatase inhibitor (AI) did suppressed estrogen receptor (ER) positive NSCLC growth. However, other enzymes involved in intratumoral production and metabolism of estrogens, i.e. 17β-hydroxysteroid dehydrogenases (i.e. 17βHSD1 and 17βHSD2) and others have not been studied. Therefore, in this study, we examined the clinical/ biological significance of 17β ...[more]

PMID: 23837683

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Project description:Numerous studies have reported that oestrogens may contribute to the development of non‑small cell lung cancer (NSCLC). Although different steroidogenic enzymes have been detected in the lung, the precise mechanism leading to an exaggerated accumulation of active oestrogens in NSCLC remains unexplained. 17‑β‑Hydroxysteroid dehydrogenase type 2 (HSD17B2) is an enzyme involved in oestrogen and androgen inactivation by converting 17‑β‑oestradiol into oestrone, and testosterone into 4‑androstenedione. Therefore, the enzyme serves an important role in regulation of the intracellular availability of active sex steroids. This study aimed to determine the expression levels of HSD17B2 in lung cancer (LC) and adjacent histopathologically unchanged tissues obtained from 161 patients with NSCLC, and to analyse the association of HSD17B2 with clinicopathological features. For that purpose, reverse transcription‑quantitative PCR, western blotting and immunohistochemistry were conducted. The results revealed that the mRNA and protein expression levels of HSD17B2 were significantly decreased in LC tissues compared with matched controls (P<10‑6). Conversely, strong cytoplasmic staining of HSD17B2 was detected in the unchanged respiratory epithelium and in glandular cells. Notably, a strong association was detected between reduced HSD17B2 expression and advanced tumour stage, grade and size. Furthermore, it was revealed that HSD17B2 may have potential prognostic significance in NSCLC. A log‑rank test revealed the benefit of high HSD17B2 protein expression for the overall survival (OS) of patients (P=0.0017), and multivariate analysis confirmed this finding (hazard ratio=0.21; 95% confidence interval=0.07‑0.63; P=0.0043). Stratified analysis in the Kaplan‑Meier Plotter database indicated that patients with higher HSD17B2 expression presented better OS and post‑progression survival. This beneficial effect was particularly evident in patients with adenocarcinoma and during the early stages of NSCLC. Decreased expression of HSD17B2 appears to be a frequent feature in NSCLC. Retrospective analysis suggests that the HSD17B2 mRNA and protein status might be independent prognostic factors in NSCLC and should be further investigated.