title: Ubiquilin 2 enhances osteosarcoma progression through resistance to hypoxic stress.
abstract: Ubiquilin 2 (UBQLN2), a member of the ubiquitin-like protein family (ubiquilins), maintains protein homeostasis. Although UBQLN2 has been implicated in the pathogenesis of neurodegenerative diseases, it is also associated with malignant tumors. Therefore, we examined whether UBQLN2 plays a role in human osteosarcoma. The human osteosarcoma cell line MG63 was transfected with UBQLN2 siRNA and cultured under hypoxic conditions. The rat osteosarcoma cell line COS1NR was inoculated into Fischer 344 rats, followed by injection of UBQLN2 siRNA with atelocollagen. An immunohistochemical analysis of UBQLN2 was performed using 34 cases of human high-grade osteosarcomas, and metastasis-free survival was estimated by the Kaplan-Meier method. Silencing of UBQLN2 by siRNA transfection under hypoxia led to activation of JNK and p38, resulting in induction of apoptosis in the osteosarcoma cell line MG63. Injection of UBQLN2 siRNA suppressed tumor growth in the rat osteosarcoma model, followed by apoptosis induction. The immunohistochemical examination revealed that high UBQLN2 expression was significantly associated with the unfavorable metastasis-free survival of osteosarcoma patients. UBQLN2 plays an important role in resistance to hypoxic stress and enhances tumor progression in osteosarcoma. UBQLN2 may be a new molecular target for chemotherapeutics and a useful clinicopathological marker in human osteosarcoma.
authors: Department of Orthopaedic Surgery, Nara Medical University, Kashihara, Nara 634-8521, Japan.
authors: Shinji
authors: S
authors: Tsukamoto
authors: Department of Pathology, Nara Medical University, Kashihara, Nara 634-8521, Japan.
authors: Keiji
authors: K
authors: Shimada
authors: Department of Orthopaedic Surgery, Nara Medical University, Kashihara, Nara 634-8521, Japan.
authors: Kanya
authors: K
authors: Honoki
authors: Department of Orthopaedic Surgery, Nara Medical University, Kashihara, Nara 634-8521, Japan.
authors: Akira
authors: A
authors: Kido
authors: Department of Public Health, Health Management and Policy, Nara Medical University, Kashihara, Nara 634-8521, Japan.
authors: Manabu
authors: M
authors: Akahane
authors: Department of Orthopaedic Surgery, Nara Medical University, Kashihara, Nara 634-8521, Japan.
authors: Yasuhito
authors: Y
authors: Tanaka
authors: Department of Pathology, Nara Medical University, Kashihara, Nara 634-8521, Japan.
authors: Noboru
authors: N
authors: Konishi
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D017209:Apoptosis; D000071183:Autophagy-Related Proteins; D015153:Blotting, Western; D001859:Bone Neoplasms / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D018797:Cell Cycle Proteins / Q000502:physiology*; D045744:Cell Line, Tumor; D018450:Disease Progression; D000860:Hypoxia / Q000378:metabolism*; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D012516:Osteosarcoma / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D034741:RNA, Small Interfering / Q000235:genetics; D051381:Rats; D011916:Rats, Inbred F344; D060888:Real-Time Polymerase Chain Reaction; D014162:Transfection / Q000379:methods; D014452:Ubiquitins / Q000502:physiology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000071183:Autophagy-Related Proteins; D018797:Cell Cycle Proteins; D034741:RNA, Small Interfering; C405662:UBQLN2 protein, human; D014452:Ubiquitins; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases