DLX1 acts as a crucial target of FOXM1 to promote ovarian cancer aggressiveness by enhancing TGF-β/SMAD4 signaling

被引：49

作者：

Chan, D. W. ^{[1
]}

Hui, W. W. Y. ^{[1
]}

Wang, J. J. ^{[2
,3
]}

Yung, M. M. H. ^{[1
]}

Hui, L. M. N. ^{[1
]}

Qin, Y. ^{[3
]}

Liang, R. R. ^{[1
]}

Leung, T. H. Y. ^{[1
]}

Xu, D. ^{[4
,5
]}

Chan, K. K. L. ^{[1
]}

Yao, K-M ^{[2
]}

Tsang, B. K. ^{[6
,7
,8
,9
]}

Ngan, H. Y. S. ^{[1
]}

机构：

[1] Univ Hong Kong, Dept Obstet & Gynaecol, Hong Kong, Hong Kong, Peoples R China

[2] Univ Hong Kong, Sch Biomed Sci, Hong Kong, Hong Kong, Peoples R China

[3] Univ Hong Kong, Ctr Genom Sci, LKS Fac Med, Hong Kong, Hong Kong, Peoples R China

[4] Shanghai Jiao Tong Univ, Dept Med Lab Sci, Sch Med, Shanghai, Peoples R China

[5] Hudson Inst Med Res, Clayton, Vic, Australia

[6] Macau Univ Sci & Technol, Macau Inst Appl Res Med & Hlth, State Key Lab Qual Res Chinese Med, Macau, Peoples R China

[7] Univ Ottawa, Dept Obstet & Gynaecol, Interdisciplinary Sch Hlth Sci, Ottawa, ON, Canada

[8] Univ Ottawa, Dept Cellular & Mol Med, Interdisciplinary Sch Hlth Sci, Ottawa, ON, Canada

[9] Ottawa Hosp Res Inst, Chron Dis Program, Ottawa, ON, Canada

来源：

ONCOGENE | 2017年 / 36卷 / 10期

关键词：

FORKHEAD BOX M1; ENDOTHELIAL GROWTH-FACTOR; TRANSCRIPTION FACTOR; TGF-BETA; MESENCHYMAL TRANSITION; CELL-PROLIFERATION; GENE-EXPRESSION; POOR-PROGNOSIS; INVASION; MIGRATION;

D O I：

10.1038/onc.2016.307

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Recent evidence from a comprehensive genome analysis and functional studies have revealed that FOXM1 is a crucial metastatic regulator that drives cancer progression. However, the regulatory mechanism by which FOXM1 exerts its metastatic functions in cancer cells remains obscure. Here, we report that DLX1 acts as a FOXM1 downstream target, exerting pro-metastatic function in ovarian cancers. Both FOXM1 isoforms (FOXM1B or FOXM1C) could transcriptionally upregulate DLX1 through two conserved binding sites, located at + 61 to + 69bp downstream (TFBS1) and -675 to -667bp upstream (TFBS2) of the DLX1 promoter, respectively. This regulation was further accentuated by the significant correlation between the nuclear expression of FOXM1 and DLX1 in high-grade serous ovarian cancers. Functionally, the ectopic expression of DLX1 promoted ovarian cancer cell growth, cell migration/ invasion and intraperitoneal dissemination of ovarian cancer in mice, whereas small interfering RNA-mediated DLX1 knockdown in FOXM1-overexpressing ovarian cancer cells abrogated these oncogenic capacities. In contrast, depletion of FOXM1 by shRNAi only partially attenuated tumor growth and exerted almost no effect on cell migration/invasion and the intraperitoneal dissemination of DLX1-overexpressing ovarian cancer cells. Furthermore, the mechanistic studies showed that DLX1 positively modulates transforming growth factor-beta (TGF-beta) signaling by upregulating PAI-1 and JUNB through direct interaction with SMAD4 in the nucleus upon TGF-beta 1 induction. Taken together, these data strongly suggest that DLX1 has a pivotal role in FOXM1 signaling to promote cancer aggressiveness through intensifying TGF-beta/SMAD4 signaling in high-grade serous ovarian cancer cells.

引用

页码：1404 / 1416

页数：13

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