title: CYB5D2 displays tumor suppression activities towards cervical cancer.
abstract: Cervical cancer is caused by infections with human papillomaviruses (HPV) and genetic alternations in the cervical epithelium. While the former is well studied, the latter remains unclear. We report here that CYB5D2/Neuferricin possesses tumor suppressing activity towards cervical tumorigenesis. Ectopic expression of CYB5D2 did not affect HeLa cell proliferation and the cell's ability to form xenograft tumors, but significantly inhibited HeLa cell invasion in vitro and the cell-produced lung metastasis in NOD/SCID mice. Knockdown of CYB5D2 enhanced HeLa cell invasion. Two mutations in CYB5D2, the substitutions of arginine (R) 7 with either proline (P) or glycine (G), were reported in colon cancer. Both CYB5D2(R7P) and CYB5D2(R7G) were incapable of inhibiting HeLa cell invasion. CYB5D2 binds heme, in which aspartate (D) 86 is required. While CYB5D2(D86G) is heme-binding defective, it inhibited HeLa cell invasion. On the other hand, CYB5D2(R7P) and CYB5D2(R7G) bound heme but did not inhibit HeLa cell invasion. Collectively, CYB5D2 inhibits HeLa cell invasion independently of its heme binding. Furthermore, immunohistochemistry examination of CYB5D2 expression in 20 normal cervical tissues and 40 cervical squamous cell carcinomas (SCC) revealed a CYB5D2 reduction in 87.5% (35/40) of SCC. Analysis of CYB5D2 gene expression and genomic alteration data available from Oncomeine™ detected significant reductions of CYB5D2 mRNA in 40 SCCs and CYB5D2 gene copy number in 107 SCCs. Collectively, we provide evidence that CYB5D2 is a candidate tumor suppressor of cervical tumorigenesis.
authors.affiliation: Division of Nephrology, Department of Medicine, Xiangya Hospital, Central South University, Changsha, Hunan, PR China; Division of Nephrology, Department of Medicine, McMaster University, Canada; Father Sean O'Sullivan Research Institute, Canada; The Hamilton Center for Kidney Research, St. Joseph's Hospital, Canada.
authors.forename: Yanyun
authors.initials: Y
authors.lastname: Xie
authors.affiliation: Division of Nephrology, Department of Medicine, McMaster University, Canada; Father Sean O'Sullivan Research Institute, Canada; The Hamilton Center for Kidney Research, St. Joseph's Hospital, Canada.
authors.forename: Yen Ting
authors.initials: YT
authors.lastname: Shen
authors.affiliation: Father Sean O'Sullivan Research Institute, Canada; Department of Surgery, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Anil
authors.initials: A
authors.lastname: Kapoor
authors.affiliation: Division of Nephrology, Department of Medicine, McMaster University, Canada; Father Sean O'Sullivan Research Institute, Canada; The Hamilton Center for Kidney Research, St. Joseph's Hospital, Canada.
authors.forename: Diane
authors.initials: D
authors.lastname: Ojo
authors.affiliation: The Genetics Laboratory, Institute of Women and Children's Health, Longgang District, Shenzhen, Guangdong, PR China; ZhunYi Medical University, Zhunyi, Guizhou, PR China.
authors.forename: Fengxiang
authors.initials: F
authors.lastname: Wei
authors.affiliation: Division of Nephrology, Department of Medicine, McMaster University, Canada; Father Sean O'Sullivan Research Institute, Canada; The Hamilton Center for Kidney Research, St. Joseph's Hospital, Canada.
authors.forename: Jason
authors.initials: J
authors.lastname: De Melo
authors.affiliation: Division of Nephrology, Department of Medicine, McMaster University, Canada; Father Sean O'Sullivan Research Institute, Canada; The Hamilton Center for Kidney Research, St. Joseph's Hospital, Canada.
authors.forename: Xiaozeng
authors.initials: X
authors.lastname: Lin
authors.affiliation: Division of Nephrology, Department of Medicine, McMaster University, Canada; Father Sean O'Sullivan Research Institute, Canada; The Hamilton Center for Kidney Research, St. Joseph's Hospital, Canada.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Wong
authors.affiliation: Division of Nephrology, Department of Medicine, McMaster University, Canada; Father Sean O'Sullivan Research Institute, Canada; The Hamilton Center for Kidney Research, St. Joseph's Hospital, Canada.
authors.forename: Judy
authors.initials: J
authors.lastname: Yan
authors.affiliation: Division of Nephrology, Department of Medicine, Xiangya Hospital, Central South University, Changsha, Hunan, PR China.
authors.forename: Lijian
authors.initials: L
authors.lastname: Tao
authors.affiliation: Division of Medical Oncology, Department of Oncology, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Pierre
authors.initials: P
authors.lastname: Major
authors.affiliation: Division of Nephrology, Department of Medicine, McMaster University, Canada; Father Sean O'Sullivan Research Institute, Canada; The Hamilton Center for Kidney Research, St. Joseph's Hospital, Canada. Electronic address: damut@mcmaster.ca.
authors.forename: Damu
authors.initials: D
authors.lastname: Tang
mesh_terms: D000818:Animals; D015786:Cytochromes b5 / Q000096:biosynthesis* / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009154:Mutation; D009361:Neoplasm Invasiveness; D025521:Tumor Suppressor Proteins / Q000096:biosynthesis* / Q000235:genetics; D002583:Uterine Cervical Neoplasms / Q000201:enzymology* / Q000235:genetics
chemical_list: C000592776:CYB5D2 protein, human; D025521:Tumor Suppressor Proteins; D015786:Cytochromes b5
keywords: CYB5D2; Cervical cancer; Metastasis; Tumor suppressor; Xenograft tumors