Highly expressed STAT1 contributes to the suppression of stemness properties in human paclitaxel-resistant ovarian cancer cells.

Fanchen Wang,Jiao Liu,Guoxiong Xu,Jinguo Zhang,Lingyun Zhang

doi:10.18632/aging.103317

Abstract

Signal transducer and activator of transcription-1 (STAT1) is an important factor in various cellular processes. The cancer stem cell (CSC) is considered as a tumor-initiating cell that drives the inner hierarchy in many cancers including epithelial ovarian cancer (EOC). Here, we explored for the first time the regulation of STAT1 on stemness properties in chemoresistant EOC cells. The paclitaxel (PTX)-resistant EOC cell line (OV3R-PTX) was derived from PTX-sensitive OVCAR-3 cells treated by the PTX regimen. A single cell clone OV3R-PTX-B4 was selected by fluorescence-activated cell sorting. PTX-resistant cells grew slowly in conventional 2D and 3D cultures, but tumor xenograft with PTX-resistant cells grew fast in nude mice. Interestingly, OV3R-PTX-B4 cells shared the characteristics of CSCs and stemness properties were found to be increased in the non-adherent spheroid culture system. The PTX-resistant cells had a high expression of CSC-related markers and low expression of STAT1 that had a high methylation level of CpG in its promoter region. Overexpressed STAT1 suppressed stemness properties, cell proliferation, and colony formation and favored the overall survival of patients with EOC. In summary, these data indicate a regulatory mechanism of STAT1 underlying drug resistance and provide a potential therapeutic application for EOC patients with PTX resistance.

Highlights

Epithelial ovarian cancer (EOC) is the most common ovarian cancer (OC) accounting for more than 90% of all cases and the age distribution shows that the highest incidence occurs at age 75-85 [1]
Since the multicellular 3D culture model is the most commonly used in cancer research, both OVCAR-3 and OV3R-PTX cells were cultured in Gravity plates for
Malignant tumors consist of a mixed cell population in which cancer stem cell (CSC) represent a small number of tumor cells in the subpopulation that are often observed and related to metastasis, relapse, and chemoresistance

Summary

Introduction

Epithelial ovarian cancer (EOC) is the most common ovarian cancer (OC) accounting for more than 90% of all cases and the age distribution shows that the highest incidence occurs at age 75-85 [1]. The standard first-line treatment of EOC is debulking surgery followed by platinum combined with paclitaxel (PTX) chemotherapy. These therapies are often effective initially, but patients later face recurrence due in part to the development of multidrug resistance, which contributes to poor prognosis [4, 5]. A small subset of CSCs is deemed to be the real driving force of tumor development [8] and to share some common features with normal stem cells as they have the self-renewal capacity and proliferation potential [9, 10]. CSCs are often observed in tumors of patients with relapse and drug resistance, which have a self-renew property and are able to differentiate into heterogeneous lineages of cancer cells [6]. The chemoresistance arisen in recurrent EOC may be a result of the stem cell transformation, which drivers cancer cell heterogeneity [11]

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