Nur77 deficiency in mice accelerates tumor invasion and metastasis by facilitating TNFα secretion and lowering CSF-1R expression.
Nur77, an orphan member of the nuclear receptor superfamily, plays critical roles in inflammation and immunity. However, the role of Nur77 in tumor microenvironment remains elusive. Results showed that deletion of Nur77 strikingly enhanced tumor metastasis compared to WT mice. Additionally, compared to the conditioned media derived from Nur77+/+ peritoneal macrophages (CM1), the conditioned media derived from Nur77-/- peritoneal macrophages (CM2) significantly promoted the EMT of cancer cells, and greatly enhanced the migratory and invasive abilities of cancer cells. Moreover, studies using TNF-α blocking antibody demonstrated that pro-inflammatory cytokine TNF-α was indispensable in supporting CM2-induced EMT to drive cancer cells migration and invasion. Furthermore, we found that Nur77 promoted the expression of CSF-1R, a novel downstream target gene of Nur77, and subsequently enhanced the migration of inflammatory cells. Notably, infiltration of inflammatory cells in the tumors of Nur77-/- mice was markedly abrogated compared to Nur77+/+ mice. Collectively, these results revealed that host Nur77 expression was pivotal in antitumor immune response, and in inhibiting tumor metastasis.
Pathology Center and Department of Pathology, Soochow University, Suzhou, China.
Xiu-Ming
XM
Li
Pathology Center and Department of Pathology, Soochow University, Suzhou, China.
Jing-Ru
JR
Wang
Pathology Center and Department of Pathology, Soochow University, Suzhou, China.
Tong
T
Shen
Pathology Center and Department of Pathology, Soochow University, Suzhou, China.
Shang-Shang
SS
Gao
Department of Pathology, The First Affiliated Hospital of Soochow University, Suzhou, China.
Xiao-Shun
XS
He
Pathology Center and Department of Pathology, Soochow University, Suzhou, China.
Jiang-Nan
JN
Li
Pathology Center and Department of Pathology, Soochow University, Suzhou, China.
Tian-Yu
TY
Yang
Pathology Center and Department of Pathology, Soochow University, Suzhou, China.
Shen
S
Zhang
Department of Pathology, The First Affiliated Hospital of Soochow University, Suzhou, China.
Wen-Juan
WJ
Gan
Department of Pathology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China.
Jian-Ming
JM
Li
Pathology Center and Department of Pathology, Soochow University, Suzhou, China.
Hua
0000-0002-5392-3234
H
Wu