title: Osteopontin facilitates tumor metastasis by regulating epithelial-mesenchymal plasticity.
abstract: Tumor metastasis leads to high mortality; therefore, understanding the mechanisms that underlie tumor metastasis is crucial. Generally seen as a secretory protein, osteopontin (OPN) is involved in multifarious pathophysiological events. Here, we present a novel pro-metastatic role of OPN during metastatic colonization. Unlike secretory OPN (sOPN), which triggers the epithelial-mesenchymal transition (EMT) to initiate cancer metastasis, intracellular/nuclear OPN (iOPN) induces the mesenchymal-epithelial transition (MET) to facilitate the formation of metastases. Nuclear OPN is found to interact with HIF2α and impact the subsequent AKT1/miR-429/ZEB cascade. In vivo assays confirm that the progression of metastatic colonization is accompanied by the nuclear accumulation of OPN and the MET process. Furthermore, evidence of nuclear OPN in the lung metastases is exhibited in clinical specimens. Finally, VEGF in the microenvironment was shown to induce the translocation of OPN into the nucleus through a KDR/PLCγ/PKC-dependent pathway. Taken together, our results describe the pleiotropic roles of OPN in the tumor metastasis cascade, which indicate its potential as an effective target for both early and advanced tumors.
authors.affiliation: International Joint Cancer Institute, The Second Military Medical University, 800 Xiangyin Road, Library Building 9-11th Floor, Shanghai 200433, China.|The 305 Hospital of PLA, A13 Wenjin Street, Beijing 100017, China.
authors.forename: Rongjie
authors.initials: R
authors.lastname: Jia
authors.affiliation: International Joint Cancer Institute, The Second Military Medical University, 800 Xiangyin Road, Library Building 9-11th Floor, Shanghai 200433, China.|Department of Radiation Oncology, Yantai Yuhuangding Hospital, 20 East Yuhuangding Road, Yantai, Shandong 264000, China.
authors.forename: Yingchao
authors.initials: Y
authors.lastname: Liang
authors.affiliation: International Joint Cancer Institute, The Second Military Medical University, 800 Xiangyin Road, Library Building 9-11th Floor, Shanghai 200433, China.
authors.forename: Rui
authors.initials: R
authors.lastname: Chen
authors.affiliation: International Joint Cancer Institute, The Second Military Medical University, 800 Xiangyin Road, Library Building 9-11th Floor, Shanghai 200433, China.
authors.forename: Guoke
authors.initials: G
authors.lastname: Liu
authors.affiliation: International Joint Cancer Institute, The Second Military Medical University, 800 Xiangyin Road, Library Building 9-11th Floor, Shanghai 200433, China.
authors.forename: Hao
authors.initials: H
authors.lastname: Wang
authors.affiliation: International Joint Cancer Institute, The Second Military Medical University, 800 Xiangyin Road, Library Building 9-11th Floor, Shanghai 200433, China.
authors.forename: Min
authors.initials: M
authors.lastname: Tang
authors.affiliation: Changhai Hospital, The Second Military Medical University, 168 Changhai Road, Shanghai 200433, China.
authors.forename: Xuyu
authors.initials: X
authors.lastname: Zhou
authors.affiliation: International Joint Cancer Institute, The Second Military Medical University, 800 Xiangyin Road, Library Building 9-11th Floor, Shanghai 200433, China.
authors.forename: Huajing
authors.initials: H
authors.lastname: Wang
authors.affiliation: International Joint Cancer Institute, The Second Military Medical University, 800 Xiangyin Road, Library Building 9-11th Floor, Shanghai 200433, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Yang
authors.affiliation: PLA General Hospital Cancer Center Key Lab, PLA Postgraduate School of Medicine, 28 Fuxing Road, Beijing 100853, China.
authors.forename: Huafeng
authors.initials: H
authors.lastname: Wei
authors.affiliation: International Joint Cancer Institute, The Second Military Medical University, 800 Xiangyin Road, Library Building 9-11th Floor, Shanghai 200433, China.
authors.forename: Bohua
authors.initials: B
authors.lastname: Li
authors.affiliation: Department of Radiation Oncology, Yantai Yuhuangding Hospital, 20 East Yuhuangding Road, Yantai, Shandong 264000, China.
authors.forename: Yipeng
authors.initials: Y
authors.lastname: Song
authors.affiliation: International Joint Cancer Institute, The Second Military Medical University, 800 Xiangyin Road, Library Building 9-11th Floor, Shanghai 200433, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Zhao
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D000066670:Cell Plasticity; D058750:Epithelial-Mesenchymal Transition; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D035683:MicroRNAs / Q000378:metabolism; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000378:metabolism* / Q000473:pathology*; D053495:Osteopontin / Q000172:deficiency / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D059016:Tumor Microenvironment; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D035683:MicroRNAs; D053495:Osteopontin; D051057:Proto-Oncogene Proteins c-akt; D042461:Vascular Endothelial Growth Factor A; D000099162:Endothelial PAS Domain-Containing Protein 1; C546363:MIRN429 microRNA, human; C494918:AKT1 protein, human