title: Inhibition of KPNA4 attenuates prostate cancer metastasis.
abstract: Prostate cancer (PCa) is a common cancer in men. Although current treatments effectively palliate symptoms and prolong life, the metastatic PCa remains incurable. It is important to find biomarkers and targets to improve metastatic PCa diagnosis and treatment. Here we report a novel correlation between karyopherin α4 (KPNA4) and PCa pathological stages. KPNA4 mediates the cytoplasm-to-nucleus translocation of transcription factors, including nuclear factor kappa B, although its role in PCa was largely unknown. We find that knockdown of KPNA4 reduces cell migration in multiple PCa cell lines, suggesting a role of KPNA4 in PCa progression. Indeed, stable knockdown of KPNA4 significantly reduces PCa invasion and distant metastasis in mouse models. Functionally, KPNA4 alters tumor microenvironment in terms of macrophage polarization and osteoclastogenesis by modulating tumor necrosis factor (TNF)-α and -β. Further, KPNA4 is proved as a direct target of miR-708, a tumor-suppressive microRNA. We disclose the role of miR-708-KPNA4-TNF axes in PCa metastasis and KPNA4's potential as a novel biomarker for PCa metastasis.
authors.affiliation: Department of Basic Science and Craniofacial Biology, New York University College of Dentistry, New York, NY, USA.
authors.forename: J
authors.initials: J
authors.lastname: Yang
authors.affiliation: Department of Basic Science and Craniofacial Biology, New York University College of Dentistry, New York, NY, USA.
authors.forename: C
authors.initials: C
authors.lastname: Lu
authors.affiliation: Department of Obstetrics and Gynaecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China.
authors.forename: J
authors.initials: J
authors.lastname: Wei
authors.affiliation: Department of Basic Science and Craniofacial Biology, New York University College of Dentistry, New York, NY, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Guo
authors.affiliation: Department of Basic Science and Craniofacial Biology, New York University College of Dentistry, New York, NY, USA.
authors.forename: W
authors.initials: W
authors.lastname: Liu
authors.affiliation: Department of Basic Science and Craniofacial Biology, New York University College of Dentistry, New York, NY, USA.
authors.forename: L
authors.initials: L
authors.lastname: Luo
authors.affiliation: Department of Statistics and Computer Information Systems, Baruch College, The City University of New York, New York, NY, USA.
authors.forename: G
authors.initials: G
authors.lastname: Fisch
authors.affiliation: Department of Basic Science and Craniofacial Biology, New York University College of Dentistry, New York, NY, USA.|Department of Urology, New York University Langone Medical Center, New York, NY, USA.
authors.forename: X
authors.initials: X
authors.lastname: Li
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D049109:Cell Proliferation; D018450:Disease Progression; D015870:Gene Expression; D055785:Gene Knockdown Techniques; D020868:Gene Silencing; D006801:Humans; D008233:Lymphotoxin-alpha / Q000378:metabolism; D008297:Male; D051379:Mice; D035683:MicroRNAs / Q000235:genetics; D008954:Models, Biological; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D034622:RNA Interference; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D028901:alpha Karyopherins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism
chemical_list: C106259:KPNA4 protein, human; D008233:Lymphotoxin-alpha; C568528:MIRN708 microRNA, human; D035683:MicroRNAs; D014409:Tumor Necrosis Factor-alpha; D028901:alpha Karyopherins