Abstract
BackgroundProgestin is effective to promote endometrial cancer (EC) cells apoptosis, however, continuous progestin administration causes low level of progestin receptor B (PRB), further resulting in progestin resistance. Here, we performed microarray analysis on Ishikawa cells (PRB+) treated with medroxyprogesterone acetate (MPA) to explore the molecular mechanism underlying the inhibitory influence of MPA on PRB+ EC cells.MethodsMicroarray analysis was performed by using Ishikawa cells (PRB+) treated with MPA. Differentially expressed mRNA and long noncoding RNAs (lncRNAs) were identified. Furthermore, the functions of these mRNAs and lncRNAs were predicted by functional enrichment analysis. QRT-PCR was further performed to verify the microarray data.ResultsA total of 358 differentially expressed genes and 292 lncRNAs were identified in Ishikawa cells (PRB+) treated with MPA. QRT-PCR verified these data. Functional enrichment analysis identified endoplasmic reticulum (ER) stress as the key pathway involved in the inhibitory effect of MPA on EC cells. And the ER stress apoptotic molecule CHOP and ER stress related molecule HERPUD1 were both highly expressed in Ishikawa cells (PRB+) treated with MPA. Co-expression analysis showed lnc-CETP-3 was highly correlated with CHOP and HERPUD1, suggesting it might participate in ER stress pathway-related EC cell apoptosis caused by MPA. In addition, compared with untreated cells, lnc-CETP-3, CHOP and HERPUD1 were significantly up-regulated in Ishikawa cells (PRB+) treated with MPA, whereas they have no statistical significance in KLE cells (PRB-).ConclusionsMPA may activate ER stress by progesterone-PRB pathway to up-regulate CHOP expression, which may be one of the molecular mechanisms underlying the inhibitory effect of MPA on EC cells with PRB+. Lnc-CETP-3 might be involved in this process. These findings may provide therapeutic targets for EC patients with PRB-, and resistance-related targets to increase the sensitivity of MPA on EC cells.
Highlights
Progestin is effective to promote endometrial cancer (EC) cells apoptosis, continuous progestin administration causes low level of progestin receptor B (PRB), further resulting in progestin resistance
Identification of differentially expressed mRNAs and long noncoding RNAs (lncRNAs) We identified the differentially expressed mRNAs and lncRNAs by comparing the expression data between Ishikawa cells treated with medroxyprogesterone acetate (MPA) and untreated cells. |Log2(Fold change)| > 1 and P < 0.05 were set as threshold
Among the top 500 significant Gene Ontology (GO) terms, we found that in Ishikawa cells treated with MPA most of the lncRNAs were associated with cell nucleus and mitochondrion in cellular component terms (Fig. 3a); in biological process terms most of the lncRNAs were involved in DNA transcription, protein ubiquitination, endoplasmic reticulum unfolded protein response, small molecule metabolic process, and protein ubiquitination (Fig. 3b); in molecular function most of the lncRNAs were involved in DNA binding, protein binding, RNA binding, and metal ion binding (Fig. 3c)
Summary
Progestin is effective to promote endometrial cancer (EC) cells apoptosis, continuous progestin administration causes low level of progestin receptor B (PRB), further resulting in progestin resistance. We performed microarray analysis on Ishikawa cells (PRB+) treated with medroxyprogesterone acetate (MPA) to explore the molecular mechanism underlying the inhibitory influence of MPA on PRB+ EC cells. Medroxyprogesterone acetate (MPA), a steroidal progestin, has been used as a conservative treatment for young patients with clinical stage I, grade I EC for a long time, which is desirable in patients hoping to preserve fertility [2]. Most patients with EC develop progestin-resistance though they initially respond to progestin treatment, which further causes tumor progression [2]. A study has reported that 62% of patients with EC have an initial response to progestin, and 23% of initial responders later have developed recurrent disease [5]. > 30% of young patients have no response to progestin due to de novo or acquired progestin resistance during treatment [6].
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