Department of obstetrics and gynecology, the First Hospital of Lanzhou University, Key Laboratory for Gynecologic Oncology Gansu Province, NO.1 Donggang West Road, Chengguan District, Lanzhou, Gansu, 730000, P. R. China.
BMC Cancer. 2021 Apr 23;21(1):456. doi: 10.1186/s12885-021-08202-y.
Endometrial cancer (UCEC) is one of the most common gynecological malignancies. We previously found that overexpression of G protein α subunit 14 (GNA14) promoted UCEC growth. Krüppel-like factor 7 (KLF7) acts as an oncogene in various cancer types, whereas the connection between GNA14 and KLF7 in UCEC is unclear. We herein explored the involvement of GNA14/KLF7 in UCEC development.
Clinical relevance of GNA14, KLF7 and HAS2 in UCEC was analyzed from TCGA and by immunohistochemical staining. Knockdown and overexpression of indicated genes were conducted by transfecting the cells with siRNAs and lentivirus, respectively. mRNA and protein expression was detected by qRT-PCR and Western blot. CCK8, colony formation, cell cycle, apoptosis, transwell and wound healing were performed to check cell biology function in vitro. Tumor growth in nude mice was conducted to check in vivo function. RNA sequencing was used to determine dys-regulated genes.
We demonstrated that GNA14 stimulated the expression of KLF7 in UCEC cells. There was a positive correlation between GNA14 and KLF7 in normal and UCEC tissues. In vitro, KLF7 promoted cell proliferation, colony formation, cell cycle progression, and migration of UCEC cells. Apoptosis was inhibited by KLF7. Xenografted tumorigenesis of UCEC cells was suppressed by KLF7 knockdown. Furthermore, RNA sequencing results showed that KLF7 regulated the expression of a large amount of genes, among which hyaluronan synthase 2 (HAS2) was downregulated in KLF7 knockdown cells. Based on TCGA database and immunoblotting assays, KLF7 positively regulated HAS2 in UCEC cells and tissues. Lastly, knockdown of HAS2 reversed the oncogenic role of KLF7 on UCEC cell proliferation, migration, and xenografted tumor development.
Taken together, we reveal that GNA14/KLF7/HAS2 signaling cascade exerts tumor promoting function during UCEC development.
子宫内膜癌（UCEC）是最常见的妇科恶性肿瘤之一。我们之前发现 G 蛋白α亚基 14（GNA14）的过表达促进了 UCEC 的生长。Krüppel 样因子 7（KLF7）在多种癌症类型中充当癌基因，而 GNA14 和 KLF7 在 UCEC 中的联系尚不清楚。我们在此探讨了 GNA14/KLF7 在 UCEC 发展中的作用。
从 TCGA 和免疫组织化学染色中分析 GNA14、KLF7 和 HAS2 在 UCEC 中的临床相关性。通过转染 siRNA 和慢病毒分别对指示基因进行敲低和过表达。通过 qRT-PCR 和 Western blot 检测 mRNA 和蛋白表达。通过 CCK8、集落形成、细胞周期、凋亡、Transwell 和划痕愈合实验检测细胞体外生物学功能。通过裸鼠肿瘤生长实验检测体内功能。通过 RNA 测序确定失调基因。
我们证明 GNA14 刺激 UCEC 细胞中 KLF7 的表达。在正常和 UCEC 组织中，GNA14 与 KLF7 之间存在正相关。在体外，KLF7 促进 UCEC 细胞的增殖、集落形成、细胞周期进程和迁移。凋亡被 KLF7 抑制。KLF7 敲低抑制 UCEC 细胞的异种移植肿瘤发生。此外，RNA 测序结果表明，KLF7 调控大量基因的表达，其中在 KLF7 敲低细胞中透明质酸合酶 2（HAS2）下调。基于 TCGA 数据库和免疫印迹分析，KLF7 在 UCEC 细胞和组织中正向调节 HAS2。最后，HAS2 的敲低逆转了 KLF7 对 UCEC 细胞增殖、迁移和异种移植肿瘤发展的致癌作用。
综上所述，我们揭示了 GNA14/KLF7/HAS2 信号级联在 UCEC 发展过程中发挥肿瘤促进作用。
