Masonic Cancer Center and Department of Obstetrics, Gynecology and Women's Health, University of Minnesota Twin Cities, Room 490, 420 Delaware Street S.E., Minneapolis, MN, 55455, USA.
Department of Women's Health, University of Minnesota, Minneapolis, MN, USA.
Horm Cancer. 2018 Oct;9(5):326-337. doi: 10.1007/s12672-018-0337-6. Epub 2018 Jun 27.
Despite advances in surgical technique and adjuvant treatment, endometrial cancer has recently seen an increase in incidence and mortality in the USA. The majority of endometrial cancers can be cured by surgery alone or in combination with adjuvant chemo- or radiotherapy; however, a subset of patients experience recurrence for reasons that remain unclear. Recurrence is associated with chemoresistance to carboplatin and paclitaxel and consequentially, high mortality. Understanding the pathways involved in endometrial cancer chemoresistance is paramount for the identification of biomarkers and novel molecular targets for this disease. Here, we generated the first matched pairs of carboplatin-sensitive/carboplatin-resistant and paclitaxel-sensitive/paclitaxel-resistant endometrial cancer cells and subjected them to bulk RNA sequencing analysis. We found that 45 genes are commonly upregulated in carboplatin- and paclitaxel-resistant cells as compared to controls. Of these, the leukemia inhibitory factor, (LIF), the protein tyrosine phosphatase type IVA, member 3 (PTP4A3), and the transforming growth factor beta 1 (TGFB1) showed a highly significant correlation between expression level and endometrial cancer overall survival (OS) and can stratify the 545 endometrial cancer patients in the TCGA cohort into a high-risk and low-risk-cohorts. Additionally, four genes within the 45 upregulated chemoresistance-associated genes are ADAMTS5, MICAL2, STAT5A, and PTP4A3 codes for proteins for which small-molecule inhibitors already exist. We identified these proteins as molecular targets for chemoresistant endometrial cancer and showed that treatment with their correspondent inhibitors effectively killed otherwise chemoresistant cells. Collectively, these findings underline the utility of matched pair of chemosensitive and chemoresistant cancer cells to identify markers for endometrial cancer risk stratification and to serve as a pharmacogenomics model for identification of alternative chemotherapy approaches for treatment of patients with recurrent disease.
尽管手术技术和辅助治疗有所进步，但子宫内膜癌最近在美国的发病率和死亡率有所上升。大多数子宫内膜癌可以通过手术单独或联合辅助化疗或放疗治愈；然而，一部分患者由于原因不明而复发。复发与顺铂和紫杉醇的化疗耐药有关，因此死亡率很高。了解子宫内膜癌化疗耐药相关的途径对于鉴定该疾病的生物标志物和新的分子靶点至关重要。在这里，我们生成了第一对顺铂敏感/顺铂耐药和紫杉醇敏感/紫杉醇耐药的配对子宫内膜癌细胞，并对其进行了批量 RNA 测序分析。我们发现，与对照组相比，45 个基因在顺铂和紫杉醇耐药细胞中普遍上调。在这些基因中，白血病抑制因子 (LIF)、蛋白酪氨酸磷酸酶 IVA 型成员 3 (PTP4A3) 和转化生长因子β1 (TGFB1) 的表达水平与子宫内膜癌总生存期 (OS) 之间存在高度显著相关性，并且可以将 TCGA 队列中的 545 名子宫内膜癌患者分为高危和低危队列。此外，在 45 个上调的耐药相关基因中，有 4 个基因 ADAMTS5、MICAL2、STAT5A 和 PTP4A3 编码的蛋白质已经存在小分子抑制剂。我们将这些蛋白质鉴定为耐药性子宫内膜癌的分子靶标，并表明用它们对应的抑制剂治疗可以有效地杀死原本耐药的细胞。总之，这些发现强调了使用配对的化疗敏感和耐药癌细胞来鉴定子宫内膜癌风险分层的标志物以及作为鉴定复发性疾病患者替代化疗方法的药物基因组学模型的实用性。
