title: O-linked-N-acetylglucosamine transferase is associated with metastatic spread of human papillomavirus E6 and E7 oncoproteins to the lungs of mice.
abstract: High-risk human papilloma virus (HPV) 16/18 infections are often found in lung cancer. The cellular mechanisms involved in the metastatic spread of HPV-infected cervical cancer cells remain largely elusive. High O-linked-N-acetylglucosamine (O-GlcNAc) modification has also been observed in lung cancer. In the present study, we assessed the relationship between O-GlcNAc transferase (OGT) and HPV 16/18 E6/E7, or C-X-C chemokine receptor type 4 (CXCR4), in HeLa cells and in lungs of xenografted mice. Depleting OGT with an OGT-specific shRNA significantly decreased levels of E6 and E7 oncoproteins in HeLa cells and xenograft tumors, and reduced tumor formation in vivo. Western blotting and immunofluorescence analysis showed significantly decreased expression levels of E6, E7, and HCF-1 in the lungs of xenografted mice treated with an OGT-specific shRNA compared to those treated with non-targeting shRNA. Additionally, levels of E7 or OGT co-localized with Ki-67 were significantly decreased in the lungs of xenografted mice treated with OGT-specific shRNA compared to those treated with non-targeting shRNA. Moreover, levels of CXCR4 were significantly decreased in HeLa cells and in the lungs of xenografted mice treated with OGT-specific shRNA compared to those treated with non-targeting shRNA; this may be related to reduced adhesion or invasion of circulating HPV-positive tumor cells. These findings provide novel evidence that OGT functions in metastatic spread of HPV E6/E7-positive tumor cells to the lungs through E6/E7, HCF-1 and CXCR4, suggesting OGT might be a therapeutic target for HPV-positive lung cancer.
authors.affiliation: Department of Thoracic and Cardiovascular Surgery, Gyeongsang National University School of Medicine, Jinju, Gyeongnam, Republic of Korea.
authors.forename: Sung Hwan
authors.initials: SH
authors.lastname: Kim
authors.affiliation: Department of Anatomy and Convergence Medical Science, Institute of Health Sciences, Gyeongsang National University School of Medicine, Jinju, Gyeongnam, Republic of Korea.
authors.forename: Yoon Sook
authors.initials: YS
authors.lastname: Kim
authors.affiliation: Department of Anatomy and Convergence Medical Science, Institute of Health Sciences, Gyeongsang National University School of Medicine, Jinju, Gyeongnam, Republic of Korea.
authors.forename: Mee Young
authors.initials: MY
authors.lastname: Choi
authors.affiliation: Department of Anatomy and Convergence Medical Science, Institute of Health Sciences, Gyeongsang National University School of Medicine, Jinju, Gyeongnam, Republic of Korea.
authors.forename: Minjun
authors.initials: M
authors.lastname: Kim
authors.affiliation: Department of Thoracic and Cardiovascular Surgery, Gyeongsang National University School of Medicine, Jinju, Gyeongnam, Republic of Korea.
authors.forename: Jun Ho
authors.initials: JH
authors.lastname: Yang
authors.affiliation: Department of Thoracic and Cardiovascular Surgery, Gyeongsang National University School of Medicine, Jinju, Gyeongnam, Republic of Korea.
authors.forename: Hyun Oh
authors.initials: HO
authors.lastname: Park
authors.affiliation: Department of Thoracic and Cardiovascular Surgery, Gyeongsang National University School of Medicine, Jinju, Gyeongnam, Republic of Korea.
authors.forename: In Seok
authors.initials: IS
authors.lastname: Jang
authors.affiliation: Department of Thoracic and Cardiovascular Surgery, Gyeongsang National University School of Medicine, Jinju, Gyeongnam, Republic of Korea.
authors.forename: Sung Ho
authors.initials: SH
authors.lastname: Moon
authors.affiliation: Department of Internal Medicine, Gyeongsang National University School of Medicine, Jinju, Gyeongnam, Republic of Korea.
authors.forename: Hyun Ok
authors.initials: HO
authors.lastname: Kim
authors.affiliation: Department of Pathology, Gyeongsang National University School of Medicine, Jinju, Gyeongnam, Republic of Korea.
authors.forename: Dae Hyun
authors.initials: DH
authors.lastname: Song
authors.affiliation: Department of Anatomy and Convergence Medical Science, Institute of Health Sciences, Gyeongsang National University School of Medicine, Jinju, Gyeongnam, Republic of Korea.
authors.forename: Dong Hoon
authors.initials: DH
authors.lastname: Lee
authors.affiliation: Department of Anatomy and Convergence Medical Science, Institute of Health Sciences, Gyeongsang National University School of Medicine, Jinju, Gyeongnam, Republic of Korea.
authors.forename: Gu Seob
authors.initials: GS
authors.lastname: Roh
authors.affiliation: Department of Anatomy and Convergence Medical Science, Institute of Health Sciences, Gyeongsang National University School of Medicine, Jinju, Gyeongnam, Republic of Korea.
authors.forename: Hyun Joon
authors.initials: HJ
authors.lastname: Kim
authors.affiliation: Department of Anatomy and Convergence Medical Science, Institute of Health Sciences, Gyeongsang National University School of Medicine, Jinju, Gyeongnam, Republic of Korea.
authors.forename: Sang Soo
authors.initials: SS
authors.lastname: Kang
authors.affiliation: Department of Anatomy and Convergence Medical Science, Institute of Health Sciences, Gyeongsang National University School of Medicine, Jinju, Gyeongnam, Republic of Korea.
authors.forename: Gyeong Jae
authors.initials: GJ
authors.lastname: Cho
authors.affiliation: Department of Thoracic and Cardiovascular Surgery, Gyeongsang National University School of Medicine, Jinju, Gyeongnam, Republic of Korea.
authors.forename: Jun Young
authors.initials: JY
authors.lastname: Choi
authors.affiliation: Department of Anatomy and Convergence Medical Science, Institute of Health Sciences, Gyeongsang National University School of Medicine, Jinju, Gyeongnam, Republic of Korea. Electronic address: choiws@gnu.ac.kr.
authors.forename: Wan Sung
authors.initials: WS
authors.lastname: Choi
mesh_terms: D000818:Animals; D004268:DNA-Binding Proteins / Q000378:metabolism; D006367:HeLa Cells; D064593:Heterografts; D051863:Host Cell Factor C1 / Q000378:metabolism; D052162:Human papillomavirus 16 / Q000472:pathogenicity*; D052161:Human papillomavirus 18 / Q000472:pathogenicity*; D006801:Humans; D008168:Lung / Q000378:metabolism / Q000821:virology; D008175:Lung Neoplasms / Q000209:etiology* / Q000378:metabolism / Q000556:secondary; D051379:Mice; D008819:Mice, Nude; D017351:N-Acetylglucosaminyltransferases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D009856:Oncogene Proteins, Viral / Q000378:metabolism; D050725:Papillomavirus E7 Proteins / Q000378:metabolism; D030361:Papillomavirus Infections / Q000209:etiology* / Q000378:metabolism / Q000821:virology; D034741:RNA, Small Interfering / Q000235:genetics; D019718:Receptors, CXCR4 / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism
chemical_list: C527276:CXCR4 protein, human; C514936:CXCR4 protein, mouse; D004268:DNA-Binding Proteins; C068651:E6 protein, Human papillomavirus type 16; C052603:E6 protein, Human papillomavirus type 18; C052633:E7 protein, Human papillomavirus type 18; C497693:Hcfc1 protein, mouse; D051863:Host Cell Factor C1; D009856:Oncogene Proteins, Viral; D050725:Papillomavirus E7 Proteins; D034741:RNA, Small Interfering; D019718:Receptors, CXCR4; D012097:Repressor Proteins; C059731:oncogene protein E7, Human papillomavirus type 16; D017351:N-Acetylglucosaminyltransferases; C449880:O-GlcNAc transferase
keywords: CXCR4; E6; E7; HPV-positive lung cancer; Metastasis; OGT