In the Model Cell Lines of Moderately and Poorly Differentiated Endometrial Carcinoma, Estrogens Can Be Formed via the Sulfatase Pathway.

Renata Pavlič,Stefan Poschner,Maša Sinreih,Marija Gjorgoska,Eva Hafner,Tea Lanišnik Rižner,Walter Jäger,Kristina Gajser

doi:10.3389/fmolb.2021.743403

Renata Pavlič, Stefan Poschner + Show 6 more

Open Access

https://doi.org/10.3389/fmolb.2021.743403

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Abstract

Endometrial cancer (EC) is the most common gynecological malignancy in resource-abundant countries. The majority of EC cases are estrogen dependent but the mechanisms of estrogen biosynthesis and oxidative metabolism and estrogen action are not completely understood. Here, we evaluated formation of estrogens in models of moderately and poorly differentiated EC: RL95-2 and KLE cells, respectively. Results revealed high expression of estrone-sulfate (E1-S) transporters (SLCO1A2, SLCO1B3, SLCO1C1, SLCO3A1, SLC10A6, SLC22A9), and increased E1-S uptake in KLE vs RL95-2 cells. In RL95-2 cells, higher levels of sulfatase and better metabolism of E1-S to E1 were confirmed compared to KLE cells. In KLE cells, disturbed balance in expression of HSD17B genes led to enhanced activation of E1 to E2, compared to RL95-2 cells. Additionally, increased CYP1B1 expression and down-regulation of genes encoding phase II metabolic enzymes: COMT, NQO1, NQO2, and GSTP1 suggested decreased detoxification of carcinogenic metabolites in KLE cells. Results indicate that in model cell lines of moderately and poorly differentiated EC, estrogens can be formed via the sulfatase pathway.

Highlights

Endometrial cancer (EC) is the most frequent gynecological cancer in the developed world (Bray et al, 2018), with a continuing trend for increased incidence over recent decades due to pandemic obesity and increased life expectancy (Lindemann et al, 2010)
We carried out gene expression analysis supported by E1-S uptake, metabolism studies for dehydroepiandrosterone sulfate (DHEA-S), DHEA, E1-S, and E1, and quantification of metabolites by LC-HRMS and LC-MS/MS
These analyses have revealed that the RL95-2 and KLE model cell lines of moderately and poorly differentiated EC, respectively, differ significantly

Summary

Introduction

Endometrial cancer (EC) is the most frequent gynecological cancer in the developed world (Bray et al, 2018), with a continuing trend for increased incidence over recent decades due to pandemic obesity and increased life expectancy (Lindemann et al, 2010). In contrast type II, includes clear-cell, serous, or squamous histology, or endometrioid tumors with poorly differentiated histology (grade 3) (Amant et al, 2005; Chiang and Soslow, 2014; Murali et al, 2014; Morice et al, 2016), which comprises 20% of all cases. Tumors that show combined morphological and molecular characteristics of types I and II are common (Yeramian et al, 2013). In addition to these sporadic cases, about 10% of ECs are hereditary and are associated with Lynch syndrome (Amant et al, 2005). Transcriptomic, and proteomic data, EC is classified into four molecular subtypes (Kandoth et al, 2013)

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