Kynurenine 3-monooxygenase upregulates pluripotent genes through β-catenin and promotes triple-negative breast cancer progression
Tzu-Ting Huang,
Ling-Ming Tseng,
Ji-Lin Chen,
Pei-Yi Chu,
Chia-Han Lee,
Chun-Teng Huang,
Wan-Lun Wang,
Ka-Yi Lau,
Mei-Fang Tseng,
Yuan-Ya Chang,
Tzu-Yi Chiang,
Yune-Fang Ueng,
Hsin-Chen Lee,
Ming-Shen Dai,
Chun-Yu Liu
Affiliations
Tzu-Ting Huang
Comprehensive Breast Health Center, Taipei Veterans General Hospital, Taipei, Taiwan
Ling-Ming Tseng
Comprehensive Breast Health Center, Taipei Veterans General Hospital, Taipei, Taiwan; School of Medicine, National Yang-Ming University, Taipei, Taiwan; Division of Experimental Surgery, Department of Surgery, Taipei Veterans General Hospital, Taipei, Taiwan
Ji-Lin Chen
Comprehensive Breast Health Center, Taipei Veterans General Hospital, Taipei, Taiwan
Pei-Yi Chu
Department of Pathology, Show Chwan Memorial Hospital, Changhua City, Taiwan; School of Medicine, Fu Jen Catholic University, New Taipei City, Taiwan
Chia-Han Lee
Comprehensive Breast Health Center, Taipei Veterans General Hospital, Taipei, Taiwan
Chun-Teng Huang
School of Medicine, National Yang-Ming University, Taipei, Taiwan; Division of Hematology & Oncology, Department of Medicine, Yang-Ming Branch of Taipei City Hospital, Centre, Taipei, Taiwan
Wan-Lun Wang
Comprehensive Breast Health Center, Taipei Veterans General Hospital, Taipei, Taiwan; School of Medicine, National Yang-Ming University, Taipei, Taiwan
Ka-Yi Lau
Comprehensive Breast Health Center, Taipei Veterans General Hospital, Taipei, Taiwan
Mei-Fang Tseng
Comprehensive Breast Health Center, Taipei Veterans General Hospital, Taipei, Taiwan
Yuan-Ya Chang
Comprehensive Breast Health Center, Taipei Veterans General Hospital, Taipei, Taiwan
Tzu-Yi Chiang
Institute of Biopharmaceutical Sciences, School of Pharmacy, National Yang-Ming University, Taipei 112, Taiwan
Yune-Fang Ueng
Institute of Biopharmaceutical Sciences, School of Pharmacy, National Yang-Ming University, Taipei 112, Taiwan; Division of Basic Chinese Medicine, National Research Institute of Chinese Medicine, Taipei 112, Taiwan; Institute of Medical Sciences, Taipei Medical University, Taipei 101, Taiwan
Hsin-Chen Lee
Institute of Pharmacology, School of Medicine, National Yang-Ming University, Taiwan
Ming-Shen Dai
Hematology/Oncology, Tri-Service General Hospital, National Defense Medical, Taiwan
Chun-Yu Liu
Comprehensive Breast Health Center, Taipei Veterans General Hospital, Taipei, Taiwan; School of Medicine, National Yang-Ming University, Taipei, Taiwan; Division of Transfusion Medicine, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan; Division of Medical Oncology, Center for Immuno-Oncology, Department of Oncology, Taipei Veterans General Hospital, Taipei, Taiwan; Corresponding author at: Division of Transfusion Medicine, Department of Medicine, Taipei Veterans General Hospital, No. 201, Sec. 2, Shih-Pai Road, Taipei 112, Taiwan.
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
