title: HPV positive neuroendocrine cervical cancer cells are dependent on Myc but not E6/E7 viral oncogenes.
abstract: Using conditional cell reprogramming, we generated a stable cell culture of an extremely rare and aggressive neuroendocrine cervical cancer. The cultured cells contained HPV-16, formed colonies in soft agar and rapidly produced tumors in immunodeficient mice. The HPV-16 genome was integrated adjacent to the Myc gene, both of which were amplified 40-fold. Analysis of RNA transcripts detected fusion of the HPV/Myc genes, arising from apparent microhomologous recombination. Spectral karyotyping (SKY) and fluorescent-in-situ hybridization (FISH) demonstrated coordinate localization and translocation of the amplified Myc and HPV genes on chromosomes 8 and 21. Similar to the primary tumor, tumor cell cultures expressed very high levels of the Myc protein and, in contrast to all other HPV-positive cervical cancer cell lines, they harbored a gain-of-function mutation in p53 (R273C). Unexpectedly, viral oncogene knockdown had no effect on the growth of the cells, but it did inhibit the proliferation of a conventional HPV-16 positive cervical cancer cell line. Knockdown of Myc, but not the mutant p53, significantly inhibited tumor cell proliferation. On the basis of these data, we propose that the primary driver of transformation in this aggressive cervical cancer is not HPV oncogene expression but rather the overexpression of Myc.
authors.affiliation: Department of Pathology, Georgetown University Medical School, Washington DC, 20057, USA.
authors.forename: Hang
authors.initials: H
authors.lastname: Yuan
authors.affiliation: Department of Pathology, Georgetown University Medical School, Washington DC, 20057, USA.
authors.forename: Ewa
authors.initials: E
authors.lastname: Krawczyk
authors.affiliation: Department of Pathology, Georgetown University Medical School, Washington DC, 20057, USA.
authors.forename: Jan
authors.initials: J
authors.lastname: Blancato
authors.affiliation: Department of Pathology, Georgetown University Medical School, Washington DC, 20057, USA.|Department of Oncology, Georgetown University Medical School, Washington DC, 20057, USA.
authors.forename: Christopher
authors.initials: C
authors.lastname: Albanese
authors.affiliation: Department of Pathology, Georgetown University Medical School, Washington DC, 20057, USA.
authors.forename: Dan
authors.initials: D
authors.lastname: Zhou
authors.affiliation: Department of Pathology, Georgetown University Medical School, Washington DC, 20057, USA.
authors.forename: Naidong
authors.initials: N
authors.lastname: Wang
authors.affiliation: Department of Pathology, Georgetown University Medical School, Washington DC, 20057, USA.
authors.forename: Siddartha
authors.initials: S
authors.lastname: Paul
authors.affiliation: Department of Pathology, Georgetown University Medical School, Washington DC, 20057, USA.|College of Pharmacy, King Abulaziz University, Jeddah, Saudi Arabia.
authors.forename: Faris
authors.initials: F
authors.lastname: Alkhilaiwi
authors.affiliation: Department of Pathology, Georgetown University Medical School, Washington DC, 20057, USA.
authors.forename: Nancy
authors.initials: N
authors.lastname: Palechor-Ceron
authors.affiliation: Department of Pathology, Georgetown University Medical School, Washington DC, 20057, USA.
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Dakic
authors.affiliation: Department of Pathology, Georgetown University Medical School, Washington DC, 20057, USA.
authors.forename: Shuang
authors.initials: S
authors.lastname: Fang
authors.affiliation: Department of Pathology, Georgetown University Medical School, Washington DC, 20057, USA.
authors.forename: Sujata
authors.initials: S
authors.lastname: Choudhary
authors.affiliation: Department of Pathology, Georgetown University Medical School, Washington DC, 20057, USA.
authors.forename: Tung-Wei
authors.initials: TW
authors.lastname: Hou
authors.affiliation: Department of Oncology, Georgetown University Medical School, Washington DC, 20057, USA.
authors.forename: Yun-Ling
authors.initials: YL
authors.lastname: Zheng
authors.affiliation: Department of Oncology, Georgetown University Medical School, Washington DC, 20057, USA.
authors.forename: Bassem R
authors.initials: BR
authors.lastname: Haddad
authors.affiliation: Department of Pathology, Georgetown University Medical School, Washington DC, 20057, USA.
authors.forename: Yukari
authors.initials: Y
authors.lastname: Usuda
authors.affiliation: Department of Pathology, Georgetown University Medical School, Washington DC, 20057, USA.
authors.forename: Dan
authors.initials: D
authors.lastname: Hartmann
authors.affiliation: Human Cancer Genetics Program and Dept. of Molecular Virology, Immunology and Medical Genetics, Ohio State University Comprehensive Cancer Center, USA.
authors.forename: David
authors.initials: D
authors.lastname: Symer
authors.affiliation: Dept. of Internal Medicine, Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA.
authors.forename: Maura
authors.initials: M
authors.lastname: Gillison
authors.affiliation: Department of Pathology, Georgetown University Medical School, Washington DC, 20057, USA.
authors.forename: Seema
authors.initials: S
authors.lastname: Agarwal
authors.affiliation: Cancer Genomics Section, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA.
authors.forename: Danny
authors.initials: D
authors.lastname: Wangsa
authors.affiliation: Cancer Genomics Section, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA.
authors.forename: Thomas
authors.initials: T
authors.lastname: Ried
authors.affiliation: Department of Pathology, Georgetown University Medical School, Washington DC, 20057, USA.
authors.forename: Xuefeng
authors.initials: X
authors.lastname: Liu
authors.affiliation: Department of Pathology, Georgetown University Medical School, Washington DC, 20057, USA.
authors.forename: Richard
authors.initials: R
authors.lastname: Schlegel
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic; D005260:Female; D050939:Gene Fusion; D052162:Human papillomavirus 16 / Q000235:genetics*; D017404:In Situ Hybridization, Fluorescence; D007621:Karyotyping; D051379:Mice; D008954:Models, Biological; D009856:Oncogene Proteins, Viral / Q000235:genetics / Q000378:metabolism*; D050725:Papillomavirus E7 Proteins / Q000235:genetics / Q000378:metabolism*; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism*; D011995:Recombination, Genetic; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D002583:Uterine Cervical Neoplasms / Q000503:physiopathology*
chemical_list: C068651:E6 protein, Human papillomavirus type 16; C489428:Myc protein, mouse; D009856:Oncogene Proteins, Viral; D050725:Papillomavirus E7 Proteins; D016271:Proto-Oncogene Proteins c-myc; D012097:Repressor Proteins; C059731:oncogene protein E7, Human papillomavirus type 16