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

Abstract

BackgroundEstrogens 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-hydroxysteroid dehydrogenases in NSCLCs.MethodologyArchival materials obtained from 103 NSCLC patients were immunohistochemically evaluated using anti-17βHSD1 and anti-17βHSD2 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 17βHSD1, in vitro.ResultsA higher 17βHSD1 immunoreactivity tended to be positively associated with aromatase (p=0.057) and tumor stage (p=0.055) whereas a higher 17βHSD2 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 17βHSD1 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 17βHSD2 immunoreactivity was significantly associated with higher intratumoral E1 concentration (p=0.035). Results of multivariate regression analysis demonstrated an increased 17βHSD1 immunoreactivity in tumor cells as an independent negative prognostic factor (HR= 2.83, p=0.007). E1 treatment in 17βHSD1 positive NSCLC cells, A549 and LK87, resulted in E2 production (p<0.0001) and enhanced cell proliferation, which was abrogated effectively by 17βHSD1 siRNA knockdown (p<0.0001). In addition, aromatase inhibitor treatment resulted in 17βHSD1 up regulation in both A549 and LK87 cells.ConclusionResults of our present study suggest that 17βHSD1 may be considered an important prognostic factor in NSCLC patients and targeting 17βHSD1 activity may further improve the clinical response in estrogen responsive NSCLC patients.

Increased expression of 17-beta-hydroxysteroid dehydrogenase type 1 in non-small cell lung cancer

“…However, no association between the intratumoral E2 concentration and the expression of HSD17B1 was found in mentioned study. Nonetheless, Verma et al have recently examined the significance of HSD17B1 enzyme in NSCLC using immunohistochemical staining of patients' tissue sections [50]. A higher HSD17B1 immunoreactivity in investigated cancerous specimens was positively correlated with the presence of CYP19A1, tumor stage and with a high intratumoral E2/E1 ratio.…”

“…Indeed, results of retrospective analyses revealed that postmenopausal women diagnosed with NSCLC had significantly better survival rates than premenopausal women and men [57]. High levels of E2 detected in serum were connected with poorer clinical outcome for NSCLC male patients and increased intratumoral level of HSD17B1 was associated with their worse overall survival [17,50].…”

The role of the androgen receptor and hydroxysteroid 17β dehydrogenase in breast cancer : Impact on tamoxifen treatment

“…The downregulation of HSD17B1 in response to E2 stimulation is relatively rapid, occurring after 24 hours and becoming more prominent after prolonged exposure. In breast cancer patients, E2 depletion was accompanied by an increase in HSD17B1 expression (90), and similar observations were made in lung cancer (91). In regard to HSD17B2, there appears to be a timesensitive response in response to E2.…”

“…It was hypothesized that this upregulation of HSD17B1 could be a response to estrogen depletion where the tissue attempts to restore estrogen signaling by alternative pathways (90). Supporting findings were made using lung cancer cell lines A549 and LK87, in which aromatase inhibitor treatment resulted in increased HSD17B1 expression (91). In ERα-and AR-positive breast cancer cell line T-47D, aromatase inhibitor treatment resulted in increased HSD17B2 and DHT expression.…”

RNA-Seq analysis for the potential targets and molecular mechanisms of 17 β-estradiol in squamous cell lung carcinoma

“…Coincidentally, estrogen receptors are also reported to play a key role in the progression of various types of NSCLC including adenocarcinoma (ADCA), SCLC, and large-cell carcinoma [10]. Moreover, the clinical and biological significances of estrogen metabolisms has been studied in NSCLCs and they might play critical roles in regulating lung cancer biology [11]. However, effects of E2 on the progression of NSCLC, especially for SCLC, have not been adequately studied and whether E2 could be a candidate treatment for SCLC was rarely studied.…”