Intracellular Osteopontin inhibits toll-like receptor signaling and impedes liver carcinogenesis.
Osteopontin (OPN) has been implicated widely in tumor growth and metastasis, but the range of its contributions is not yet fully understood. In this study, we show that genetic ablation of Opn in mice sensitizes them to diethylnitrosamine (DEN)-induced hepatocarcinogenesis. Opn-deficient mice (Opn(-/-) mice) exhibited enhanced production of proinflammatory cytokines and compensatory proliferation. Administering OPN antibody or recombinant OPN protein to wild-type or Opn(-/-) mice-derived macrophages, respectively, had little effect on cytokine production. In contrast, overexpression of intracellular OPN (iOPN) in Opn-deficient macrophages strongly suppressed production of proinflammatory cytokines. In addition, we found that iOPN was able to interact with the pivotal Toll-like receptor (TLR) signaling protein MyD88 in macrophages after stimulation with cellular debris, thereby disrupting TLR signaling in macrophages. Our results indicated that iOPN was capable of functioning as an endogenous negative regulator of TLR-mediated immune responses, acting to ameliorate production of proinflammatory cytokines and curtail DEN-induced hepatocarcinogenesis. Together, our results expand the important role of OPN in inflammation-associated cancers and deepen its relevance for novel treatment strategies in liver cancer.
International Joint Cancer Institute, The Second Military Medical University, Shanghai, China. School of Pharmacy, Liaocheng University, Liaocheng, Shandong, China.
Xiaoyu
X
Fan
International Joint Cancer Institute, The Second Military Medical University, Shanghai, China.
Chunyan
C
He
Changhai Hospital, The Second Military Medical University, Shanghai, China.
Wei
W
Jing
Changhai Hospital, The Second Military Medical University, Shanghai, China.
Xuyu
X
Zhou
International Joint Cancer Institute, The Second Military Medical University, Shanghai, China. School of Pharmacy, Liaocheng University, Liaocheng, Shandong, China.
Rui
R
Chen
International Joint Cancer Institute, The Second Military Medical University, Shanghai, China.
Lei
L
Cao
Changhai Hospital, The Second Military Medical University, Shanghai, China.
Minhui
M
Zhu
International Joint Cancer Institute, The Second Military Medical University, Shanghai, China. School of Pharmacy, Liaocheng University, Liaocheng, Shandong, China.
Rongjie
R
Jia
International Joint Cancer Institute, The Second Military Medical University, Shanghai, China. School of Pharmacy, Liaocheng University, Liaocheng, Shandong, China.
Hao
H
Wang
International Joint Cancer Institute, The Second Military Medical University, Shanghai, China. School of Pharmacy, Liaocheng University, Liaocheng, Shandong, China. PLA General Hospital Cancer Center, PLA Postgraduate School of Medicine, Beijing, China. yjguo@smmu.edu.cn zhaojian@smmu.edu.cn.
Yajun
Y
Guo
International Joint Cancer Institute, The Second Military Medical University, Shanghai, China. School of Pharmacy, Liaocheng University, Liaocheng, Shandong, China. PLA General Hospital Cancer Center, PLA Postgraduate School of Medicine, Beijing, China. yjguo@smmu.edu.cn zhaojian@smmu.edu.cn.
Jian
J
Zhao
D000818:Animals; D063646:Carcinogenesis / Q000235:genetics / Q000378:metabolism*; D002470:Cell Survival / Q000502:physiology; D057809:HEK293 Cells; D006801:Humans; D008114:Liver Neoplasms, Experimental / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D053495:Osteopontin / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D051193:Toll-Like Receptors / Q000037:antagonists & inhibitors* / Q000378:metabolism
D051193:Toll-Like Receptors; D053495:Osteopontin