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

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 cancerderived cell lines containing oncogenic HPVs display reduced expression of tumor-suppressive miR-34a. The reduction of miR34a 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 /G 1 phase cells. Ectopic expression of miR-34a in HPV18+ HeLa cells and HPV À 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.

Viral epigenomes in human tumorigenesis

“…Several recent studies have shown that E6 and E7 bind to different cell proteins involved in the processes of adhesion, apoptosis, cell cycle, DNA repair, metabolism, signal transduction, transcription and other functions (Horikawa and Barrett, 2003;Whiteside et al, 2008;Howie et al, 2009;McLaughlin-Drubin and Mu¨nger, 2009). In addition, deregulation of the expression of several miRNAs in the host cells associated with HPV infection induced by some of its oncoproteins has been noted by several authors (Martinez et al, 2008;Reshmi and Pillai, 2008;Wang et al, 2008Wang et al, , 2009.…”

miR-375 Is Down-Regulated in Squamous Cervical Cancer and Inhibits Cell Migration and Invasion via Targeting Transcription Factor SP1

“…Viral oncoprotein E6 or E7 can induce alteration of cellular miRNA expression in different ways during the development and progression of cervical cancer. HPV 16 infection reduced miR-218 expression, resulting in increased expression of LAMB3 (which encodes laminin-5 ␤3), 36 and HPV 16 E6 induced a reduction of miR-34a 14,37 and miR23b, 38 due to the degradation of p53 in cervical cancer cell lines. To determine whether the reduction of miR-375 expression is regulated by HR-HPV oncoproteins, we examined the expression of miR-375 in normal cervical tissues with or without HR-HPV infection.…”

microRNA Portraits in Human Vulvar Carcinoma

“…Various miRNA genes are downstream targets of transcription factors such as c-Myc, p53, and E2F and their expression can be modulated by oncogenic HPV E6 and E7 (6). HPV infection in tumor cells can negatively regulate the levels of a specific miRNA (miR-34a) through the inhibition of p53 by the E6 viral protein (7). E6 and E7 HPV viral proteins cause decreased miR-218, a tumor suppressor microRNA (8); miR-125b can directly reduce proliferation of HPV in vitro models.…”