KLF15 suppresses tumor growth and metastasis in Triple-Negative Breast Cancer by downregulating CCL2 and CCL7

Abstract

Kruppel like factor 15 (KLF15), a transcriptional factor belonging to the Kruppel-like factor (KLF) family of genes, has recently been reported as a tumor suppressor gene in breast cancer. However, the specific mechanisms by which KLF15 inhibits BrCa have not been elucidated. Here we investigated the role and mechanism of KLF15 in triple-negative breast cancer (TNBC). KLF15 expression and methylation were detected by RT-qPCR, RT-PCR and methylation-specific PCR in breast cancer cell lines and tissues. The effects of KLF15 on TNBC cell functions were examined via various cellular function assays. The specific anti-tumor mechanisms of KLF15 were further investigated by RNA sequence, RT-qPCR, Western blotting, luciferase assay, ChIP, and bioinformatics analysis. As the results showed that KLF15 is significantly downregulated in breast cancer cell lines and tissues, which promoter methylation of KLF15 partially contributes to. Exogenous expression of KLF15 induced apoptosis and G2/M phase cell cycle arrest, suppressed cell proliferation, metastasis and in vivo tumorigenesis of TNBC cells. Mechanism studies revealed that KLF15 targeted and downregulated C–C motif chemokine ligand 2 (CCL2) and CCL7. Moreover, transcriptome and metabolome analysis revealed that KLF15 is involved in key anti-tumor regulatory and metabolic pathways in TNBC. In conclusion, KLF15 suppresses cell growth and metastasis in TNBC by downregulating CCL2 and CCL7. KLF15 may be a prognostic biomarker in TNBC.

Mitochondrial Calcium Signaling Regulates Branched-Chain Amino Acid Catabolism in Fibrolamellar Carcinoma

“…We observe a significant, uniporter-dependent reduction in KLF15 protein levels in DP-expressing cells. Reduction in KLF15 levels has been correlated with tumor growth and poor prognosis in several types of cancer 61-66 , but to our knowledge, this is the first time KLF15 expression changes have been implicated in liver cancer. KLF15 also regulates genes associated with gluconeogenesis, lipogenesis, metabolism of non-BCAA amino acids, and the urea cycle 31,67,68 .…”

TREM1+ tumor-associated macrophages secrete CCL7 to promote hepatocellular carcinoma metastasis

“…For example, a study reported that tumor-associated macrophages secrete TGF-β1 to promote cancer stem cells and EMT in hepatocellular carcinoma(Fan et al 2014 ). Multiple studies have shown that CCL7 plays an important role in cancer metastasis, such as promoting the metastasis of breast cancer(Kanyomse et al 2022 ), colorectal cancer(Xu et al 2022a , b ), gastric cancer(Chen et al 2020 ) and other tumors. In particular, cancer-associated fibroblasts in HCC tumor tissue can secrete CCL7 to promote HCC metastasis(Liu et al 2016 ).…”

maGENEgerZ: An Efficient Artificial Intelligence-Based Framework Can Extract More Expressed Genes and Biological Insights Underlying Breast Cancer Drug Response Mechanism

“…Figure 4b reports the following 12 genes obtained from the PPI network: ACTG2, PRKAR2B, ALDH2, PRKACB, KRT19, KRT18, WASF3, DLG5, TRIM37, GSTM3, GSTA1, and CYP2A6. Four genes (KRT18, KRT19, PLCB4, and PRKACB) were related to the estrogen signaling pathway, which is reported to play a key role in breast cancer progression and treatment [66][67][68]. Three genes (CYP2A6, GSTA1, and GSTM3) were linked to chemical carcinogenesis-the DNA adduct pathway-involved in cancer development [69,70].…”