期刊
CANCER LETTERS
卷 453, 期 -, 页码 21-33出版社
ELSEVIER IRELAND LTD
DOI: 10.1016/j.canlet.2019.03.013
关键词
Tumor growth; Metastasis; Chemosensitivity; Apoptosis
类别
资金
- FIS [PI16/01352, PI17/00411]
- CIBERONC [CB16/12/00443 ISC-III]
- Juan Serrano Foundation
- AECC Foundation
- Ramon Areces Foundation
- Spanish Ministry of Economy and Competitiveness (MINECO) [SAF2013-46423-R, SAF2017-89944-R]
- European Commission (FP7-PEOPLE-2013-CIG)
- WWCR [16-0224]
- Fundacion La Caixa-FIMA agreement
- ANOC
- Asociacion de Amigos de la Universidad de Navarra
- La Caixa Banking Foundation
- FPU, Spanish Ministry of Education
High mortality rates caused by NSCLC show the need for the identification of novel therapeutic targets. In this study we have investigated the biological effects and molecular mechanisms elicited by TMPRSS4 in NSCLC. Overexpression of TMPRSS4 in LKR13 cells increased malignancy, subcutaneous tumor growth and multiorganic metastasis. In conditional knock-down (KD) experiments, abrogation of TMPRSS4 in H358 and H2170 cells altered proliferation, clonogenicity, tumor engraftment and tumor growth. Reduction in S and G2/M phases of the cell cycle, decreased BrdU incorporation and increased apoptosis was also found. Transcriptomic analysis in KD cells revealed downregulation of genes involved in DNA replication, such as MCM6, TYMS and CDKN1A (p21). In patients, expression of a signature of MCM6/TYMS/TMPRSS4 genes was highly associated with poor prognosis. Downregulation of TMPRSS4 significantly increased sensitivity to chemotherapy agents. In experiments using cisplatin, apoptosis and expression of the DNA-damage marker gamma-H2A was higher in cells lacking TMPRSS4. Moreover, in vivo assays demonstrated that tumors with no TMPRSS4 were significantly more sensitive to cisplatin than controls. These results show that TMPRSS4 can be considered as a novel target in NSCLC, whose inhibition increases chemosensitivity.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据