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CD44s is a crucial ATG7 downstream regulator for stem-like property, invasion, and lung metastasis of human bladder cancer (BC) cells.

ABSTRACT: Over half a million US residents are suffering with bladder cancer (BC), which costs a total $4 billion in treatment annually. Although recent studies report that autophagy-related gene 7 (ATG7) is overexpressed in BCs, the regulatory effects of ATG7 on cancer stem-like phenotypes and invasion have not been explored yet. Current studies demonstrated that the deficiency of ATG7 by its shRNA dramatically reduced sphere formation and invasion in vitro, as well as lung metastasis in vivo in human invasive BC cells. Further studies indicated that the knockdown of ATG7 attenuated the expression of CD44 standard (CD44s), while ectopic introduction of CD44s, was capable of completely restoring sphere formation, invasion, and lung metastasis in T24T(shATG7) cells. Mechanistic studies revealed that ATG7 overexpression stabilized CD44s proteins accompanied with upregulating USP28 proteins. Upregulated USP28 was able to bind to CD44s and remove the ubiquitin group from CD44s' protein, resulting in the stabilization of CD44s protein. Moreover, ATG7 inhibition stabilized AUF1 protein and thereby reduced tet1 mRNA stability and expression, which was able to demethylate usp28 promoter, reduced USP28 expression, finally promoting CD44s degradation. In addition, CD44s was defined to inhibit degradation of RhoGDI?, which in turn promotes BC invasion. Our results demonstrate that CD44s is a key ATG7 downstream regulator of the sphere formation, invasion, and lung metastasis of BCs, providing significant insight into understanding the BC invasions, metastasis, and stem-like properties.

SUBMITTER: Zhu J

PROVIDER: S-EPMC7112719 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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CD44s is a crucial ATG7 downstream regulator for stem-like property, invasion, and lung metastasis of human bladder cancer (BC) cells.

Zhu Junlan J Huang Grace G Hua Xiaohui X Li Yang Y Yan Huiying H Che Xun X Tian Zhongxian Z Liufu Huating H Huang Chao C Li Jingxia J Xu Jiheng J Dai Wei W Huang Haishan H Huang Chuanshu C

Oncogene 20190111 17

Over half a million US residents are suffering with bladder cancer (BC), which costs a total $4 billion in treatment annually. Although recent studies report that autophagy-related gene 7 (ATG7) is overexpressed in BCs, the regulatory effects of ATG7 on cancer stem-like phenotypes and invasion have not been explored yet. Current studies demonstrated that the deficiency of ATG7 by its shRNA dramatically reduced sphere formation and invasion in vitro, as well as lung metastasis in vivo in human in ...[more]

PMID: 30635654

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Project description:Tumour-associated macrophages (TAMs) are associated with both the progression and poor prognosis of a variety of solid tumours. This study aimed to investigate and clarify the tumour-promoting role of CXCL8 secreted by TAMs in the urothelial carcinoma microenvironment of the bladder. Immunohistochemistry (n = 55) was used to detect Chemokine (C-X-C motif) ligand 8 (CXCL8), CD163 (a TAM marker), Matrixmetalloproteinase-9 (MMP-9), vascular endothelial growth factor (VEGF), and E-cadherin in cancerous and adjacent tissues of bladder cancer patients. TAMs-like PBM (peripheral blood mononuclear)-derived macrophages were developed using in vitro experiments. T24, 5637, and UM-UC-3 were treated with conditioned medium (CM) for the experimental intervention group, without CM for the blank control group, and with CM and an anti-CXCL8 neutralizing antibody for the experimental control group, respectively. The immunohistochemical study showed that the expression of CXCL8 was significantly upregulated as the number of infiltrating TAMs increased in the tumour tissues. A high expression of CXCL8 significantly correlated with an increase in the expression of MMP-9 and VEGF and a decrease in expression of E-cadherin in the microenvironment. This revealed that TAM-derived CXCL8 is highly associated with bladder cancer migration, invasion, and angiogenesis. The concentration of CXCL8 was significantly higher in CM collected from TAM-like PBM-derived macrophages than that from THP-1 cells. In subsequent in vitro experiments, we found that CM derived from TAM-like PBM-derived macrophages can also increase the migration rate, invasiveness, and pro-angiogenic properties of tumour cells. Additionally, the effect of CXCL8 was significantly diminished by the addition of an anti-CXCL8 neutralizing antibody to CM. The infiltration of TAMs in the tumour microenvironment leads to the elevation of CXCL8, which in turn promotes the secretion of MMP-9, VEGF, and E-cadherin by bladder cancer cells. This alters the migration, invasion, and pro-angiogenic capacity of bladder cancer cells and accelerates cancer progression.

Dataset Information

CD44s is a crucial ATG7 downstream regulator for stem-like property, invasion, and lung metastasis of human bladder cancer (BC) cells.

Publications

CD44s is a crucial ATG7 downstream regulator for stem-like property, invasion, and lung metastasis of human bladder cancer (BC) cells.

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