Downregulation of MTAP promotes Tumor Growth and Metastasis by regulating ODC Activity in Breast Cancer

Zhang, Ying1,2; Zhang, Tian-Tian1,2; Gao, Lin3,4; Tan, Ya-Nan5; Li, Yu-Ting1,2; Tan, Xiang-Yu1,2; Huang, Tu-Xiong3,4; Li, Hua-Hui1,2; Bai, Feng6; Zou, Chang3,4; Pei, Xin-Hai7; Tan, Bin-Bin1,2; Fu, Li1,2

2022

10.7150/ijbs.67149

International Journal of Biological Sciences   影响因子和分区

1449-2288

5'-Methylthioadenosine phosphorylase (MTAP) is a key enzyme in the methionine salvage pathway and has been reported to suppress tumorigenesis. The MTAP gene is located at 9p21, a chromosome region often deleted in breast cancer (BC). However, the clinical and biological significance of MTAP in BC is still unclear. Here, we reported that MTAP was frequently downregulated in 41% (35/85) of primary BCs and 89% (8/9) of BC cell lines. Low expression of MTAP was significantly correlated with a poor survival of BC patients (P=0.0334). Functional studies showed that MTAP was able to suppress both in vitro and in vivo tumorigenic ability of BC cells, including migration, invasion, angiogenesis, tumor growth and metastasis in nude mice with orthotopic xenograft tumor of BC. Mechanistically, we found that downregulation of MTAP could increase the polyamine levels by activating ornithine decarboxylase (ODC). By treating the MTAP-repressing BC cells with specific ODC inhibitor Difluoromethylornithine (DFMO) or treating the MTAP-overexpressing BC cells with additional putrescine, metastasis-promoting or-suppressing phenotype of these MTAP-manipulated cells was significantly reversed, respectively. Taken together, our data suggested that MTAP has a critical metastasis-suppressive role by tightly regulating ODC activity in BC cells, which may serve as a prominent novel therapeutic target for advanced breast cancer treatment.

ODC MTAP Polyamine biosynthesis Breast cancer Metastasis

SCI

英语

其他

National Natural Science Foundation of China (NSFC)[81772957,81702104] ; Industry and Information Technology Foundation of Shenzhen[20180309100135860] ; Science and Technology Program of Guangdong Province in China[2019B030301009]

Biochemistry & Molecular Biology ; Life Sciences & Biomedicine - Other Topics

Biochemistry & Molecular Biology ; Biology

WOS:000795855800002

IVYSPRING INT PUBL

Web of Science

1.Shenzhen Univ, Dept Pharmacol, Guangdong Prov Key Lab Reg Immun & Dis, Hlth Sci Ctr, Shenzhen 518060, Guangdong, Peoples R China
2.Shenzhen Univ, Int Canc Ctr, Hlth Sci Ctr, Shenzhen 518060, Guangdong, Peoples R China
3.Jinan Univ, Clin Med Coll 2, Shenzhen Peoples Hosp, Shenzhen 518020, Guangdong, Peoples R China
4.Southern Univ Sci & Technol, Affiliated Hosp 1, Shenzhen 518020, Guangdong, Peoples R China
5.Univ Hong Kong, Dept Clin Oncol, Shenzhen Hosp, Shenzhen 518053, Peoples R China
6.Shenzhen Univ, Dept Pathol, Hlth Sci Ctr, Shenzhen 518060, Guangdong, Peoples R China
7.Shenzhen Univ, Dept Anat & Histol, Hlth Sci Ctr, Shenzhen 518060, Guangdong, Peoples R China

Zhang, Ying,Zhang, Tian-Tian,Gao, Lin,et al. Downregulation of MTAP promotes Tumor Growth and Metastasis by regulating ODC Activity in Breast Cancer[J]. International Journal of Biological Sciences,2022,18(7).

Zhang, Ying.,Zhang, Tian-Tian.,Gao, Lin.,Tan, Ya-Nan.,Li, Yu-Ting.,...&Fu, Li.(2022).Downregulation of MTAP promotes Tumor Growth and Metastasis by regulating ODC Activity in Breast Cancer.International Journal of Biological Sciences,18(7).

Zhang, Ying,et al."Downregulation of MTAP promotes Tumor Growth and Metastasis by regulating ODC Activity in Breast Cancer".International Journal of Biological Sciences 18.7(2022).