KLF16 Downregulates the Expression of Tumor Suppressor Gene TGFBR3 to Promote Bladder Cancer Proliferation and Migration

Abstract

Krüppel-like factors (KLFs), which comprise 17 family members, exert important functions during the development of cancer. The role of KLF16 seems controversial in carcinogenesis because both tumor suppressive and promoting effects have been reported. Methods:The expression level of KLF16 was analyzed based on public data sets from The Cancer Genome Atlas (TCGA) and evaluated by immunohistochemical (IHC) staining. CCK8 assay, colony formation analysis, transwell assays and the PI/Annexin V-APC assay kit were performed to detect cell growth, colony formation, cell migration and apoptosis of BC cells. Xenograft tumorigenesis assay was performed to detect the KLF16 expression on BC growth in vivo. Dual-luciferase reporter assay and chromatin immunoprecipitation (ChIP)-qPCR assay were performed to analyze the interaction between KLF16 and its target. Results: In this study, we explored the role of KLF16 in bladder cancer (BC). We demonstrated that KLF16 was overexpressed in human BC tissues. The high expression of KLF16 was a potential predictor of a poor prognosis in patients with BC. Interference with KLF16 expression in 563 cells, having relatively higher levels of KLF16, repressed cell proliferation and migration. In contrast, upregulation of KLF16 in T24 cells enhanced cellular function, including cell growth and migration. KLF16 also suppressed the apoptosis of BC cells. Additionally, KLF16 inhibited the expression of the TGF-type III receptor (TGFBR3) by binding to its promoter sequence and reducing transcriptional activity. There was a negative correlation between KLF16 and TGFBR3 in human BC tissues. Furthermore, TGFBR3 was revealed to be a negative regulator of BC cell proliferation and migration. KLF16 also supported BC tumorigenesis by downregulating TGFBR3 expression in vivo. Discussion: These results suggested that KLF16 acts as an oncogene in BC through transcriptional inactivation of TGFBR3. This study provides evidence that targeting the KLF16/TGFBR3 axis may be beneficial for BC patients.

Identification and verification of anoikis-related gene markers to predict the prognosis of patients with bladder cancer and assist in the diagnosis and treatment of bladder cancer

“…TGFBR3 inhibits the development of tumors such as renal cancer, lung cancer, and liver cancer, and has been considered a tumor-inhibiting factor ( 48 - 50 ). Encouragingly, Chen et al discovered in 2022 that TGFBR3 was negatively correlated with the progression and metastasis of bladder cancer ( 51 ). The results of our study confirmed this conclusion.…”

Machine learning to comprehensively reveal signature genes and regulatory mechanisms in pituitary tumors

“…Studies have also shown that LHX3 is a biomarker for predicting prognosis in patients with advanced hepatocellular carcinoma [11]. All these phenomena suggest the importance of LHX3 in regulating the development of malignant diseases.TGFBR3 acts as a co-receptor for TGF-β and undergoes lysogenic cleavage under the action of metalloproteinases, the soluble TGFBR3 produced after shedding of the extracellular functional region can competitively bind to tumor autocrine TGF-B and inhibit human tumor progression by blocking the pro-oncogenic effect of TGF-β [5]. TGFBR3 acts as a co-receptor for inhibin A but not inhibin B in mouse gonadotropin cells in vivo [17], and bioinformatic results suggest that TGFBR3 can act as an invasive pituitary tumor [28].…”

Krüppel-like factors in tumors: Key regulators and therapeutic avenues

“…KLF8 is activated by TGF-β1 through SMAD2 and promotes ovarian cancer progression ( 96 ). KLF16 is an oncogene in bladder cancer due to its inhibition of TGF-β receptor 3, which inhibits tumor proliferation by a non-canonical TGF-β pathway ( 97 , 98 ). KLF17 is a crucial regulator of TGF-β signaling, which forms a positive feedback loop with SMAD3, and the expression of both is often positively correlated in cancer tissues.…”