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SOX17 Increases the Cisplatin Sensitivity of an Endometrial Cancer

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SOX17 Increases the Cisplatin Sensitivity of an Endometrial Cancer Zhang et al. Cancer Cell Int (2016) 16:29 DOI 10.1186/s12935-016-0304-7 Cancer Cell International PRIMARY RESEARCH Open Access SOX17 increases the cisplatin sensitivity of an endometrial cancer cell line Yongli Zhang1,3, FeiZhou Jiang1, Wei Bao2, Huilin Zhang1, XiaoYing He2, Huihui Wang1 and Xiaoping Wan3* Abstract Background: Endometrial cancer (EC) is the most common form of malignant gynecological tumor. Treatment with cisplatin (CDDP) is the mainstay of EC chemotherapy. The apoptotic machinery is regarded as an important etiologi- cal factor in chemoresistance. Recent evidence has suggested that overexpression of the transcription factor SOX17 prevented apoptosis in tumor cell lines. The effect of SOX17 on apoptosis in EC cisplatin chemoresistance remains unclear. Methods: Immunohistochemistry and the reverse transcription-polymerase chain reaction were employed to detect gene expression in paraffin-embedded EC tissues and blood samples. The anti-proliferative ability of SOX17 on EC cells was assessed by MTT. Flow cytometric analysis was used to detect cell apoptosis by annexin V/PI double- staining. The expression of apoptosis-related proteins was analyzed by western blot. In the in vivo study, nude mice were subcutaneously injected with EC cells, and received cisplatin treatment through intraperitoneal chemotherapy. Apoptosis of in vivo samples was analyzed by TUNEL assay. Results: SOX17 expression decreased the chemical resistance of EC cells to CDDP. HEC-1B cells with an elevated expression of SOX17 had a lower cell viability and higher apoptosis rate after cisplatin exposure. Overexpression SOX17 up-regulated wild type p53 after being exposed to cisplatin, while the expression of BCL2-associated X protein and cleaved caspase-3 simultaneously increased. Caspase-9 inhibitor reduced the efficacy of SOX17 in HEC-1B cells after cisplatin treatment. In the in vivo study, SOX17 overexpression clearly restrained the tumor growth and increased the cisplatin toxicity and apoptosis of tumor cells. Conclusions: SOX17 is involved in the p53-mediated apoptosis pathway, and increases the sensitivity of HEC-1B cells to cisplatin. Keywords: SOX17, Endometrial cancer, Cisplatin, Chemoresistance, Apoptosis Background tumor cell apoptosis by creating inter- and intra-strand Endometrial cancer (EC) is the most common form of DNA adducts through irreversible intercalation, thereby gynecological malignancy, with an estimated 47,130 new inducing both DNA damage and apoptotic responses cases and 8010 deaths occurring in 2014 [1]. Chemo- [3]. CDDP induces apoptosis only in sensitive cells, not therapy combined with whole pelvic external beam radi- in their resistant counterparts [4]. CDDP resistance is a otherapy is the key procedure in improving the survival common phenomenon in EC impeding successful can- rate of patients with clinical II/III stage disease [2]. CDDP cer treatment, the underlying molecular mechanism of is the first-line chemotherapeutic agent for EC treat- which is not well understood. ment. The pharmacological action of CDDP is to induce The importance of the transcription factor SOX17 (SRY-box containing gene 17) in EC cell biology has recently aroused great interest. SOX17 belongs to the *Correspondence: [email protected] 3 Department of Obstetrics and Gynecology, Shanghai First Maternity high mobility group (HMG) box transcription factor and Infant Hospital, Tongji University School of Medicine, No. 2699 superfamily, which is homologous to the sex-deter- Gaokexi Road, Shanghai 201204, China mining gene SRY [5]. SOX17 has been recognized as Full list of author information is available at the end of the article © 2016 Zhang et al. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/ publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Zhang et al. Cancer Cell Int (2016) 16:29 Page 2 of 9 an important antagonist and inhibitor of the canonical samples from chemo-resistant patients was significantly Wnt signaling pathway [6]. Human SOX17 was found to decreased compared with that from chemo-sensitive encode a 414-amino-acid protein containing a HMG box, patients (Fig. 1c). which has been implicated in embryogenesis [7]. Apoptotic disorders are among the many mechanisms Generation and identification of transiently transfected significant in carcinogenesis [8]. An earlier study has cells shown that SOX17 overexpression prevents apoptosis in Western blot analyses were performed to assay the oligodendroglioma (HOG) cells [3]. Moreover, the apop- expression of SOX17 in the EC cell lines. SOX17 protein totic machinery has been considered to be an impor- was expressed in all the EC cell lines (Fig. 2a). However, tant etiological factor in chemoresistance. The effect of only HEC-1B cells expressed high levels of p53 protein SOX17 on apoptosis in EC chemoresistance has not been under basal conditions. To further investigate the func- investigated. tion of SOX17 in EC cells, SOX17 overexpression and The TP53 gene, a guardian of cell genome stability, is SOX17 knockdown plasmids were constructed and were one of the most extensively researched genes involved in used to transfect HEC-1B cells. The cells were used for apoptosis. Abnormal p53 protein production leads to an further study at 72 h post transfection, and the expres- inability to repair damaged DNA as well as uncontrol- sion levels of SOX17 were confirmed using western blot lable cancer cell growth [9–11]. One of the mechanisms analysis (Fig. 2b, c). underlying CDDP resistance is the inhibition of cell apoptosis through the increase in p53 protein levels. SOX17 increased the sensitivity of HEC‑1B cells to CDDP In the cytosol, p53 induces cell death by forming inhib- Cytotoxicity tests were performed to study the influ- itory complexes with Bcl-XL and Bcl-2, which leads to ence of SOX17 on the cytotoxicity of CDDP to HEC-1B the permeabilization of the mitochondrial membrane cells. After transfected for 72 h, the cells were treated and the release of cytochrome C [12]. Mutation of p53 with CDDP (20 μg/ml) for 24, 48, 72, 96 h. Cells overex- has been strongly associated with chemoresistance of pressing SOX17 displayed a higher sensitivity to CDDP lung [13], ovarian [14] and gastric [15] cancers. In breast and a lower cell viability than the control (Fig. 2d), cancer, tumors containing p53 mutants are enriched for whereas cells with a reduced expression of SOX17 had a the SOX17 gene [16]. lower sensitivity to CDDP and an enhanced cell viability However, the role of SOX17 in EC chemoresistance is (Fig. 2e). These data suggested that SOX17 increased the not completely understood. Based on these findings, we CDDP sensitivity of EC cells. investigated whether SOX17 regulates chemosensitiv- To further assay the effect of SOX17 on the sensitiv- ity in EC. Here we found that up-regulation of SOX17 ity of HEC-1B cells to CDDP, we used flow cytometry to improved p53 expression, which in turn sensitized EC examine the apoptosis rate of HEC-1B cells after treat- cells to CDDP. ment with CDDP (20 μg/ml) for 48 h. The apoptosis rate of HEC-1B cells over-expressing SOX17 was higher Results than that of the control group (P < 0.05). Meanwhile, SOX17 expression is decreased in chemo‑resistant under-expression of SOX17 decreased the apoptosis rate endometrial cancer (P < 0.05). The apoptosis rate after treatment with CDDP Patients with EC who have received comprehensive stag- was 55.1 ± 2.47 and 2.36 ± 0.47 % in SOX17 up-regu- ing surgery and suffered disease relapse within 6 months lated and down-regulated groups, respectively (P < 0.05) after regular platinum containing therapy are consid- (Fig. 3a–d). These results further suggested that SOX17 ered to be platinum resistant [17]. We selected a group increased the CDDP sensitivity of HEC-1B cells. of 21 chemo-resistant and another of 21 chemo-sensitive patients. To confirm the expression levels of SOX17, we SOX17 overexpression sensitizes EC cell to cisplatin assayed SOX17 expression in paraffin-embedded tis- by increasing apoptosis sues obtained from all 42 EC patients. SOX17 levels were SOX17 overexpression increased the levels of apopto- lower in the chemo-resistant tissues (Fig. 1a, b; Addi- sis in EC cells. We next investigated the role of SOX17 tional file 1: Table S1). There were no significant differ- in regulating cell apoptosis after treatment with CDDP ences between the clinical features of the patients of the (20 μg/ml) for 48 h. Cleaved caspase-9, the marker of two groups (Additional file 1: Table S2). To clarify the mitochondrial apoptosis activation, increased with molecular mechanisms underlying CDDP resistance in higher SOX17 expression. As a result, cleaved caspase-3 EC cells, SOX17 expression levels in 29 EC patients were (cc-3), the executor of apoptosis, increased, whereas the assayed after cisplatin-based combination chemother- level of survivin, an inhibitor of apoptosis, decreased apy. The results showed that SOX17 expression in blood (Fig. 4a). Similarly, pretreatment with inhibitors of Zhang et al. Cancer Cell Int (2016) 16:29 Page 3 of 9 Fig. 1 SOX17 down-regulated expression in chemo-resistant endometrial cancer. a, b IHC analysis of the expression of SOX17 in EC tissues. The levels of SOX17 proteins are higher in chemo-sensitive EC tissues. Original magnification: 200 (left), 400 (right). c The analyses of the SOX17 × × expression levels were performed on blood samples from cisplatin-sensitive patients (n 17) and cisplatin-resistant patients (n 12). All data were = = Ct expressed as fold change relative to the expression of GAPDH in the tissue (control, expression 1). The results were expressed as Log 10 (2−△△ ) = (*P < 0.05) Fig.
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