TY - JOUR
T1 - HPV positive neuroendocrine cervical cancer cells are dependent on Myc but not E6/E7 viral oncogenes
AU - Yuan, Hang
AU - Krawczyk, Ewa
AU - Blancato, Jan
AU - Albanese, Christopher
AU - Zhou, Dan
AU - Wang, Naidong
AU - Paul, Siddartha
AU - Alkhilaiwi, Faris
AU - Palechor-Ceron, Nancy
AU - Dakic, Aleksandra
AU - Fang, Shuang
AU - Choudhary, Sujata
AU - Hou, Tung Wei
AU - Zheng, Yun Ling
AU - Haddad, Bassem R.
AU - Usuda, Yukari
AU - Hartmann, Dan
AU - Symer, David
AU - Gillison, Maura
AU - Agarwal, Seema
AU - Wangsa, Danny
AU - Ried, Thomas
AU - Liu, Xuefeng
AU - Schlegel, Richard
N1 - Funding Information:
This work was funded by National Institutes of Health/National Cancer Institute grants R33CA177466 (RS), R01RR032315 (RS), R21CA180524 (XL), internal grant support (HY and EK) from the Center for Cell Reprogramming at GUMC, and the Intramural Research Program of the NIH (TR), National Cancer Institute, Center for Cancer Research. The authors would like to thank Dr. Steven Rosenberg (NCI) for providing the patient's tumor sample, Darawalee Wangsa Zong for providing the spectral karyotyping probes, and the Histopathology & Tissue Shared Resource at GUMC for histology and immunochemistry study.
Publisher Copyright:
© 2017 The Author(s).
PY - 2017/4/5
Y1 - 2017/4/5
N2 - 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.
AB - 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.
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U2 - 10.1038/srep45617
DO - 10.1038/srep45617
M3 - Article
C2 - 28378747
AN - SCOPUS:85016980270
SN - 2045-2322
VL - 7
JO - Scientific reports
JF - Scientific reports
M1 - 45617
ER -