Potential role of the HOXD8 transcription factor in cisplatin resistance and tumour metastasis in advanced epithelial ovarian cancer

Pengming Sun,Guifen Liu,Binhua Dong,Xiaodan Mao,Elena Ioana Braicu,Yiyi Song,Dabin Liu,Jalid Sehouli

doi:10.1038/s41598-018-31030-3

Abstract

Few studies have examined the potential transcription factor (TF) simultaneously associated with cisplatin resistance and metastasis in ovarian cancer. To assess a related mechanism, a 345-channel protein/DNA array and transcriptional activity ELISA were performed to compare the TF activities in the cisplatin-sensitive SKOV3 and cisplatin-resistant SKOV3-DDP cells and in HO-8910 and the homologous highly metastatic HO-8910PM cells. In SKOV3-DDP vs. SKOV3 cells, 43 TFs were up-regulated, while 31 were down-regulated. In HO-8910PM vs. HO-8910 cells, 13 TFs were up-regulated, while 18 were down-regulated. In these two models, 4 TFs (HOXD8(1), HOXD8(2), RB, RFX1/2/3) were simultaneously up-regulated, and 9 TFs (SRE, FKHR, Angiotensinogen ANG-IRE, Pax2, CD28RC/NF-IL2B, HLF, CPE, CBFB and c-Ets-1) were down-regulated. HOXD8 mRNA and protein expression levels measured by reverse transcription polymerase chain reaction and ELISA, respectively, were significantly higher in SKOV3-DDP and HO-8910PM than in their corresponding cell lines (both p < 0.05). In 52 cases of different ovarian disease, the patients with recurrent and cisplatin-resistant ovarian cancer had higher expression levels of HOXD8 than patients with primary malignant tumours (p = 0.018, p = 0.001) or benign tumours (p = 0.001, p < 0.001). Taken together, these results suggest that HOXD8 is potentially associated with both cisplatin resistance and metastasis in advanced ovarian cancer.

Highlights

Ovarian cancer is a deadly disease that affects women globally
Eukaryotic gene expression is regulated by proteins called transcription factors, which bind to the promoter region of a gene[11]
13 transcription factors associated with ovarian cancer cisplatin-resistance and metastasis were identified, of which four were up-regulated (HOXD8(1), HOXD8(2), RB, RFX1/2/3) and nine down-regulated (SRE, FKHR, Angiotensinogen ANG-insulin-response element (IRE), Pax[2], CD28RC/NF-IL2B, HLF, CPE, CBFB and c-Ets-1) (Fig. 3C–E)

Summary

Introduction

Ovarian cancer is a deadly disease that affects women globally. The worldwide incidence of ovarian cancer is currently at 225,500 new diagnoses each year[1,2]. The majority of ovarian cancers are diagnosed at an advanced stage when they have already metastasized to other organs outside the pelvis, mostly because of a lack of characteristic symptoms, a lack of effective early-screening strategies, and their aggressive tumour behaviour[3,4]. These factors lead to the high mortality rate of ovarian cancer. Study of chemotherapy resistance mechanisms is critical for improving the clinical outcomes of patients with advanced ovarian cancer. Analysing transcription factor activity is critical in developing a thorough understanding of how gene expression is regulated. HOX gene expression could be important in diagnosis and therapy

Methods

Results

Conclusion