The prognosis of patients with high‐grade or advanced‐stage endometrial cancer remains poor. As cancer stem‐like cells (CSCs) are thought to be associated with endometrial cancers, it is essential to investigate the molecular mechanisms that regulate endometrial CSCs. Dual‐specificity phosphatase 6 (DUSP6) functions as a negative‐feedback regulator of MAPK–ERK1/2 signaling, but its role in endometrial cancer remains unknown. We investigated whether DUSP6 is involved in cancer cell stemness using endometrial cancer cell lines and specimens from endometrial cancer patients. DUSP6 induced the expression of CSC‐related genes including ALDH1, Nanog, SOX2 and Oct4A, increased the population of cells in the G0/G1 phase, and promoted sphere formation ability. DUSP6 knockdown resulted in reduced cell invasion and metastasis, whereas DUSP6 overexpression inhibited apoptosis under serum‐free conditions. Moreover, DUSP6 decreased phosphorylated ERK1/2 and increased phosphorylated Akt levels, which potentially induces CSC features. In patients with endometrial cancers, DUSP6 expression was determined using immunohistochemistry, and based on the results, the patients were dichotomized into high‐ and low‐DUSP6‐expression groups. Progression‐free survival and overall survival were significantly shorter in the high‐DUSP6‐expression group. These results suggest that DUSP6 has potential value as a biomarker of CSCs and as a target of therapies designed to eliminate CSCs in endometrial cancer.

中文翻译：

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双重特异性磷酸酶6在维持人类子宫内膜癌的癌干样细胞表型中起着至关重要的作用。

患有高级或晚期子宫内膜癌的患者的预后仍然很差。由于人们认为癌干样细胞（CSC）与子宫内膜癌有关，因此研究调节子宫内膜CSC的分子机制至关重要。双重特异性磷酸酶6（DUSP6）作为MAPK–ERK1 / 2信号的负反馈调节剂，但在子宫内膜癌中的作用仍然未知。我们使用子宫内膜癌细胞系和来自子宫内膜癌患者的标本调查了DUSP6是否参与癌细胞干细胞的研究。DUSP6诱导了CSC相关基因的表达，包括ALDH1，Nanog，SOX2和Oct4A，增加了G0 / G1期的细胞数量，并增强了球的形成能力。DUSP6敲低导致细胞侵袭和转移减少，而DUSP6的过表达在无血清条件下抑制细胞凋亡。此外，DUSP6降低了磷酸化的ERK1 / 2，并增加了磷酸化的Akt水平，这可能诱发CSC功能。在子宫内膜癌患者中，采用免疫组织化学方法确定了DUSP6的表达，并根据结果将患者分为高表达组和低表达组。高DUSP6表达组的无进展生存期和总生存期明显缩短。这些结果表明，DUSP6作为CSCs的生物标志物和作为旨在消除子宫内膜癌中CSCs的治疗靶标具有潜在价值。在子宫内膜癌患者中，采用免疫组织化学方法确定了DUSP6的表达，并根据结果将患者分为高表达组和低表达组。高DUSP6表达组的无进展生存期和总生存期明显缩短。这些结果表明，DUSP6作为CSCs的生物标志物和作为旨在消除子宫内膜癌中CSCs的治疗靶标具有潜在价值。在子宫内膜癌患者中，采用免疫组织化学方法确定了DUSP6的表达，并根据结果将患者分为高表达组和低表达组。高DUSP6表达组的无进展生存期和总生存期明显缩短。这些结果表明，DUSP6作为CSCs的生物标志物和作为旨在消除子宫内膜癌中CSCs的治疗靶标具有潜在价值。