GNA14 Stimulation of KLF7 Promotes Malignant Growth of Endometrial Cancer Through Upregulation of HAS2

Background: Endometrial cancer (UCEC) is one of the most common gynecological malignancies. We previously found that G protein α subunit 14 (GNA14) was highly expressed in UCEC tissues and functioned as oncogene. Krüppel-like factors (KLFs) are transcription factors and play important roles in cancer development. However, the connection between GNA14 and KLF7 in UCEC are unclear. We herein explored the role of GNA14/KLF7 in UCEC development. Methods: : Clinical relevance of GNA14, KLF7 and HAS2 in UCEC was analyzed from TCGA. siRNAs were used to knock down indicated genes. Lentivirus was used to perform overexpression. 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 determined dys-regulated genes. Results: : We demonstrated that GNA14 upregulation of KLF7 promoted UCEC carcinogenesis through activation of hyaluronan synthase 2 (HAS2). Firstly, GNA14 promoted the expression KLF7 in UCEC cells. GNA14 was positively correlated with KLF7 in normal and UCEC tissues based on TCGA database. Then, loss-of-function and gain-of-function assays showed that KLF7 promoted cell proliferation, colony formation, cell cycle progression, and migration of UCEC cells. Apoptosis was inhibited by KLF7. KLF7 knockdown also reduced xenografted tumor growth of UCEC cells. Furthermore, RNA sequence results showed that KLF7 regulated thousands of genes, among which 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 and migration. Conclusion: Taken together, we reveal that GNA14/KLF7/HAS2 signaling cascade is a novel contributor to UCEC development.