Kynurenine 3-monooxygenase upregulates pluripotent genes through β-catenin and promotes triple-negative breast cancer progression
| Autor: | Tzu Ting Huang, Ming-Shen Dai, Pei-Yi Chu, Mei-Fang Tseng, Chunyu Liu, Ling-Ming Tseng, Ji-Lin Chen, Hsin Chen Lee, Chia-Han Lee, Yune-Fang Ueng, Yuan-Ya Chang, Ka-Yi Lau, Chun Teng Huang, Wan-Lun Wang, Tzu-Yi Chiang |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Homeobox protein NANOG Research paper Mice Nude lcsh:Medicine Triple Negative Breast Neoplasms medicine.disease_cause General Biochemistry Genetics and Molecular Biology Metastasis 03 medical and health sciences Mice 0302 clinical medicine Kynurenine 3-Monooxygenase Cell Line Tumor Neoplasms medicine Animals Humans Triple negative breast cancer Triple-negative breast cancer Cells Cultured beta Catenin Kynurenine KMO Gene knockdown Mice Inbred BALB C lcsh:R5-920 biology Cell growth CD44 lcsh:R Mammary Neoplasms Experimental General Medicine Nanog Homeobox Protein β-catenin medicine.disease Up-Regulation Gene Expression Regulation Neoplastic 030104 developmental biology Hyaluronan Receptors 030220 oncology & carcinogenesis Catenin Cancer research biology.protein Commentary Female Carcinogenesis lcsh:Medicine (General) Signal Transduction |
| Zdroj: | EBioMedicine EBioMedicine, Vol 54, Iss, Pp-(2020) |
| ISSN: | 2352-3964 |
| Popis: | Background: Triple-negative breast cancer (TNBC) is aggressive and has a poor prognosis. Kynurenine 3-monooxygenase (KMO), a crucial kynurenine metabolic enzyme, is involved in inflammation, immune response and tumorigenesis. We aimed to study the role of KMO in TNBC. Methods: KMO alteration and expression data from public databases were analyzed. KMO expression levels in TNBC samples were analyzed using immunohistochemistry. Knockdown of KMO in TNBC cells was achieved by RNAi and CRISPR/Cas9. KMO functions were examined by MTT, colony-forming, transwell migration/invasion, and mammosphere assays. The molecular events were analyzed by cDNA microarrays, Western blot, quantitative real-time PCR and luciferase reporter assays. Tumor growth and metastasis were detected by orthotopic xenograft and tail vein metastasis mouse models, respectively. Findings: KMO was amplified and associated with worse survival in breast cancer patients. KMO expression levels were higher in TNBC tumors compared to adjacent normal mammary tissues. In vitro ectopic KMO expression increased cell growth, colony and mammosphere formation, migration, invasion as well as mesenchymal marker expression levels in TNBC cells. In addition, KMO increased pluripotent gene expression levels and promoter activities in vitro. Mechanistically, KMO was associated with β-catenin and prevented β-catenin degradation, thereby enhancing the transcription of pluripotent genes. KMO knockdown suppressed tumor growth and the expression levels of β-catenin, CD44 and Nanog. Furthermore, mutant KMO (known with suppressed enzymatic activity) could still promote TNBC cell migration/invasion. Importantly, mice bearing CRISPR KMO-knockdown TNBC tumors showed decreased lung metastasis and prolonged survival. Interpretation: KMO regulates pluripotent genes via β-catenin and plays an oncogenic role in TNBC progression. Keywords: KMO, Triple negative breast cancer, β-catenin |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|