Oncogenic HPV infection interrupts the expression of tumor-suppressive miR-34a through viral oncoprotein E6

Xiaohong Wang, Hsu Kun Wang, J. Philip Mccoy, Nilam S. Banerjee, Janet S. Rader, Thomas R. Broker, Craig Meyers, Louise T. Chow, Zhi Ming Zheng

Research output: Contribution to journalArticle

162 Citations (Scopus)

Abstract

MicroRNAs (miRNA) play pivotal roles in controlling cell proliferation and differentiation. Aberrant miRNA expression in human is becoming recognized as a new molecular mechanism of carcinogenesis. However, the causes for alterations in miRNA expression remain largely unknown. Infection with oncogenic human papillomavirus types 16 (HPV16) and 18 (HPV18) can lead to cervical and other ano-genital cancers. Here, we have demonstrated that cervical cancer tissues and cervical cancer- derived cell lines containing oncogenic HPVs display reduced expression of tumor-suppressive miR-34a. The reduction of miR-34a expression in organotypic tissues derived from HPV-containing primary human keratinocytes correlates with the early productive phase and is attributed to the expression of viral E6, which destabilizes the tumor suppressor p53, a known miR-34a transactivator. Knockdown of viral E6 expression in HPV16+ and HPV18+ cervical cancer cell lines by siRNAs leads to an increased expression of p53 and miR-34a and accumulation of miR-34a in G 0/G1 phase cells. Ectopic expression of miR-34a in HPV18+ HeLa cells and HPV- HCT116 cells results in a substantial induction of cell growth retardation and a moderate cell apoptosis. Together, this is the first time a viral oncoprotein has been shown to regulate cellular miRNA expression. Our data have provided new insights into mechanisms by which high-risk HPVs contribute to the development of cervical cancer.

Original languageEnglish (US)
Pages (from-to)637-647
Number of pages11
JournalRNA
Volume15
Issue number4
DOIs
StatePublished - Apr 1 2009

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Oncogene Proteins
MicroRNAs
Uterine Cervical Neoplasms
Human papillomavirus 18
Human papillomavirus 16
Infection
Neoplasms
HCT116 Cells
Cell Line
Trans-Activators
G1 Phase
Keratinocytes
HeLa Cells
Cell Differentiation
Carcinogenesis
Cell Proliferation
Apoptosis
Growth

All Science Journal Classification (ASJC) codes

  • Molecular Biology

Cite this

Wang, X., Wang, H. K., Mccoy, J. P., Banerjee, N. S., Rader, J. S., Broker, T. R., ... Zheng, Z. M. (2009). Oncogenic HPV infection interrupts the expression of tumor-suppressive miR-34a through viral oncoprotein E6. RNA, 15(4), 637-647. https://doi.org/10.1261/rna.1442309
Wang, Xiaohong ; Wang, Hsu Kun ; Mccoy, J. Philip ; Banerjee, Nilam S. ; Rader, Janet S. ; Broker, Thomas R. ; Meyers, Craig ; Chow, Louise T. ; Zheng, Zhi Ming. / Oncogenic HPV infection interrupts the expression of tumor-suppressive miR-34a through viral oncoprotein E6. In: RNA. 2009 ; Vol. 15, No. 4. pp. 637-647.
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abstract = "MicroRNAs (miRNA) play pivotal roles in controlling cell proliferation and differentiation. Aberrant miRNA expression in human is becoming recognized as a new molecular mechanism of carcinogenesis. However, the causes for alterations in miRNA expression remain largely unknown. Infection with oncogenic human papillomavirus types 16 (HPV16) and 18 (HPV18) can lead to cervical and other ano-genital cancers. Here, we have demonstrated that cervical cancer tissues and cervical cancer- derived cell lines containing oncogenic HPVs display reduced expression of tumor-suppressive miR-34a. The reduction of miR-34a expression in organotypic tissues derived from HPV-containing primary human keratinocytes correlates with the early productive phase and is attributed to the expression of viral E6, which destabilizes the tumor suppressor p53, a known miR-34a transactivator. Knockdown of viral E6 expression in HPV16+ and HPV18+ cervical cancer cell lines by siRNAs leads to an increased expression of p53 and miR-34a and accumulation of miR-34a in G 0/G1 phase cells. Ectopic expression of miR-34a in HPV18+ HeLa cells and HPV- HCT116 cells results in a substantial induction of cell growth retardation and a moderate cell apoptosis. Together, this is the first time a viral oncoprotein has been shown to regulate cellular miRNA expression. Our data have provided new insights into mechanisms by which high-risk HPVs contribute to the development of cervical cancer.",
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Wang, X, Wang, HK, Mccoy, JP, Banerjee, NS, Rader, JS, Broker, TR, Meyers, C, Chow, LT & Zheng, ZM 2009, 'Oncogenic HPV infection interrupts the expression of tumor-suppressive miR-34a through viral oncoprotein E6', RNA, vol. 15, no. 4, pp. 637-647. https://doi.org/10.1261/rna.1442309

Oncogenic HPV infection interrupts the expression of tumor-suppressive miR-34a through viral oncoprotein E6. / Wang, Xiaohong; Wang, Hsu Kun; Mccoy, J. Philip; Banerjee, Nilam S.; Rader, Janet S.; Broker, Thomas R.; Meyers, Craig; Chow, Louise T.; Zheng, Zhi Ming.

In: RNA, Vol. 15, No. 4, 01.04.2009, p. 637-647.

Research output: Contribution to journalArticle

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Wang X, Wang HK, Mccoy JP, Banerjee NS, Rader JS, Broker TR et al. Oncogenic HPV infection interrupts the expression of tumor-suppressive miR-34a through viral oncoprotein E6. RNA. 2009 Apr 1;15(4):637-647. https://doi.org/10.1261/rna.1442309