Aminopeptidase A initiates tumorigenesis and enhances tumor cell stemness via TWIST1 upregulation in colorectal cancer

被引:21
作者
Chuang, Hui-Yu [1 ]
Jiang, Jeng-Kae [3 ,4 ]
Yang, Muh-Hwa [5 ,6 ,7 ,9 ,10 ]
Wang, Hsei-Wei [2 ,7 ,8 ]
Li, Ming-Chun [11 ]
Tsai, Chan-Yen [2 ]
Jhang, Yau-Yun [1 ]
Huang, Jason C. [1 ,12 ]
机构
[1] Natl Yang Ming Univ, Dept Biotechnol & Lab Sci Med, Taipei, Taiwan
[2] Natl Yang Ming Univ, Inst Microbiol & Immunol, Taipei, Taiwan
[3] Natl Yang Ming Univ, Sch Med, Dept Surg, Taipei, Taiwan
[4] Taipei Vet Gen Hosp, Div Colorectal Surg, Dept Surg, Taipei, Taiwan
[5] Natl Yang Ming Univ, Inst Clin Med, Taipei, Taiwan
[6] Taipei Vet Gen Hosp, Dept Med, Div Hematol Oncol, Taipei, Taiwan
[7] Natl Yang Ming Univ, Canc Res Ctr, Taipei, Taiwan
[8] Taipei City Hosp, Dept Educ & Res, Taipei, Taiwan
[9] Natl Yang Ming Univ, Immun & Inflammat Res Ctr, Taipei, Taiwan
[10] Acad Sinica, Genom Res Ctr, Taipei, Taiwan
[11] Taipei City Hosp, Yang Ming Branch, Div Pediat, Taipei, Taiwan
[12] Natl Yang Ming Univ, AIDS Prevent & Res Ctr, Taipei, Taiwan
关键词
colorectal cancer; aminopeptidase A; metastasis; TWIST1; cancer stem cell; NF-KAPPA-B; EPITHELIAL-MESENCHYMAL TRANSITION; RENIN-ANGIOTENSIN SYSTEM; MAIN EFFECTOR PEPTIDES; CLINICAL-SIGNIFICANCE; PERIPHERAL-BLOOD; E-CADHERIN; KEY ROLE; EXPRESSION; ALPHA;
D O I
10.18632/oncotarget.15072
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Metastasis accounts for the high mortality rate associated with colorectal cancer (CRC), but metastasis regulators are not fully understood. To identify a novel gene involved in tumor metastasis, we used oligonucleotide microarrays, transcriptome distance analyses, and machine learning algorithms to determine links between primary and metastatic colorectal cancers. Aminopeptidase A (APA; also known as ENPEP) was selected as our focus because its relationship with colorectal cancer requires clarification. Higher APA mRNA levels were observed in patients in advanced stages of cancer, suggesting a correlation between ENPEP and degree of malignancy. Our data also indicate that APA overexpression in CRC cells induced cell migration, invasion, anchorage-independent capability, and mesenchyme-like characteristics (e.g., EMT markers). We also observed TWIST induction in APA-overexpressing SW480 cells and TWIST down-regulation in HT29 cells knocked down with APA. Both APA silencing and impaired APA activity were found to reduce migratory capacity, cancer anchorage, stemness properties, and drug resistance in vitro and in vivo. We therefore suggest that APA enzymatic activity affects tumor initiation and cancer malignancy in a TWIST-dependent manner. Results from RT-qPCR and the immunohistochemical staining of specimens taken from CRC patients indicate a significant correlation between APA and TWIST. According to data from SurvExpress analyses of TWIST1 and APA mRNA expression profiles, high APA and TWIST expression are positively correlated with poor CRC prognosis. APA may act as a prognostic factor and/or therapeutic target for CRC metastasis and recurrence.
引用
收藏
页码:21266 / 21280
页数:15
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