KLF8 is activated by TGF‐β1 via Smad2 and contributes to ovarian cancer progression

Abstract

Krüppel-like factor 8 (KLF8) is a transcription factor expressed abnormally in various cancer types and promotes oncogenic transformation. However, the role of KLF8 in ovarian cancer (OC) progression remains unclear. This study reports that transforming growth factor-β1 (TGF-β1)/Smad2/KLF8 axis regulates epithelial-mesenchymal transition (EMT) and contributes to OC progression. We analyzed the KLF8 expression in OC cells and tissues, wherein a significant overexpression of KLF8 was observed. Increased KLF8 expressions were correlated with higher cell proliferation, EMT, migration, and invasion and conferred poor clinical outcomes in OC patients. Overexpressed KLF8 increases F-actin polymerization and induces cytoskeleton remodeling of OC cells. Furthermore, a dissection of the molecular mechanism defined that TGF-β1 triggers KLF8 through the Smad2 pathway and regulates EMT. Pharmacological and genetic inhibition of Smad2 followed by TGF-β1 treatment failed to activate KLF8 expression and induction of EMT.Using promoter-luciferase reporter assays, we defined that upon TGF-β1 activation, phosphorylated Smad2 binds and promotes the KLF8 promoter activity, and knockdown of Smad2 inhibits KLF8 promoter activation. Together, these results demonstrate that TGF-β1 activates KLF8 expression by the Smad2 pathway, and KLF8 contributes to OC progression and may serve as a potential therapeutic strategy for treating OC patients.

FBXO28 promotes cell proliferation, migration and invasion via upregulation of the TGF-beta1/SMAD2/3 signaling pathway in ovarian cancer

“…The TGF-b1 signaling pathway involves binding of mainly TGF-b1 ligands to their receptors, and the phosphorylated TGF-b1 receptor can activate various signaling pathways, including the Smad2/3, Ras and PI3K pathways [ 38 ]. Several studies have shown that TGF-b1 signaling can be associated with the cause and development of cancer by regulating cell migration, the tumor microenvironment and metastatic capacity [ 39 – 43 ]. In ovarian cancer, TGF-b1 has been shown to regulate proliferation, the EMT, the stem cell phenotype, and metastasis [ 44 – 46 ].…”

Transgenerational Transmission of 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) Effects in Human Granulosa Cells: The Role of MicroRNAs

“…KLF expression is often altered in tumors, and this is essential for tumor development. For instance, KLF8 is activated by transforming growth factor-β1 (TGF-β1) via SMAD2 and contributes to ovarian cancer progression [65,66]. Cherukunnath et al reported that the TGF-β1/SMAD2/KLF8 axis regulates epithelial-mesenchymal transition and contributes to ovarian cancer progression [66].…”

Circ‐ILF2 in oral squamous cell carcinoma promotes cisplatin resistance and induces M2 polarization of macrophages

“…KLF8 regulates the transcription of genes involved in diverse biological processes, such as proliferation, inflammation, migration and invasion 43 . KLF8 is widely expressed in various tissues, and abnormal expression of KLF8 is manifested in several cancers, including lung, gastric and ovarian cancers 44,45 . Previous studies have reported that KLF8 plays important roles in DNA repair and apoptosis resistance 43 .…”

“… 43 KLF8 is widely expressed in various tissues, and abnormal expression of KLF8 is manifested in several cancers, including lung, gastric and ovarian cancers. 44 , 45 Previous studies have reported that KLF8 plays important roles in DNA repair and apoptosis resistance. 43 In our study, we found that KLF8 is a downstream target of miR‐1252 and that miR‐1252 is responsible for circ‐ILF2 induced KLF8 upregulation.…”