Differential regulation of the JE gene encoding the monocyte chemoattractant protein (MCP-1) in cervical carcinoma cells and derived hybrids

Abstract

Malignant human papillomavirus type 18 (HPV18)-positive cervical carcinoma cells can be reverted to a nonmalignant phenotype by generation of somatic cell hybrids with normal human fibroblasts. Although nontumorigenic hybrids, their tumorigenic segregants, and the parental HeLa cells have similar in vitro properties, inoculation only of nontumorigenic cells into nude mice results in a selective suppression of HPV18 transcription which precedes cessation of cellular growth. Our present study, aimed at understanding the differential regulation in vitro and in vivo, shows that the JE gene, encoding the monocyte chemoattractant protein (MCP-1), is expressed only in nontumorigenic hybrids. Although the gene, including its regulatory region, is intact, no JE (MCP-1) mRNA is detected in the tumorigenic segregants and in other malignant HPV-positive cervical carcinoma cell lines. Tests of several monocyte-derived cytokines showed that only tumor necrosis factor alpha strongly induces the JE (MCP-1) gene in nontumorigenic cells and that this is accompanied by a dose-dependent reduction of HPV transcription. The JE (MCP-1) up-regulation occurs within 2 h and does not require de novo protein synthesis. The response to tumor necrosis factor alpha seems to be mediated by an NF-KB-related mechanism, since the induction can be completely abrogated by pretreating the cells with an antioxidant such as pyrrolidine dithiocarbamate. Interestingly, cocultivation of nonmalignant hybrids with monocyte-enriched fractions from human peripheral blood also results in an induction of the JE (MCP-1) gene and a concomitant suppression of HPV18 transcription. Neither effect is observed in malignant cells. These data suggest that JE (MCP-1) may play a pivotal role in the intercellular communication by triggering an intracellular pathway which negatively interferes with viral transcription in HPV-positive nontumorigenic cells.

Selective suppression of monocyte chemoattractant protein‐1 expression by human papillomavirus E6 and E7 oncoproteins in human cervical epithelial and epidermal cells

“…18 However, even though MCP-1 expression is induced after infection by a variety of RNA and DNA viruses, MCP-1 expression is suppressed after epithelial cell infection by HPV in vitro. 19 This parallels the situation in vivo, where advancing cervical intraepithelial neoplasia is associated with loss of MCP-1 expression. 20 The mechanisms responsible for HPV-mediated suppression of MCP-1 expression are unclear.…”

“…MCP-1 expression by HeLa cells in our study contradicts earlier reports. 19 Although the lineage history of the HeLa culture we examined may differ from that used in the earlier study, the HPV genome is still present in the cells we tested (data not shown) and their ability to secrete MCP-1 is unexplained. Nonetheless, in primary epithelial cells, the correlation between E6/E7 expression and suppression of MCP-1 is complete.…”

The oncogenic potential of human papillomaviruses: a review on the role of host genetics and environmental cofactors

“…56 Further evidence comes from nonmalignant cells shown to contain an inhibitory chemokine. Rosl et al 59 documented that macrophage chemoattractant protein 1 (MCP-1), a chemokine derived from activated macrophages, represses HPV E6 ⁄E7 transcription. This finding was supported by a study in which the introduction of the JE (MCP-1) gene into malignant cells resulted in cell growth retardation.…”

“…Multiple HPV types have been implicated in the promotion of cervical SCC development. The HPV types found in cervical neoplastic cells were classified by Muñoz et al into those associated with low (6, 11, 13, 40, 42-44, 54, 61, 62, 70, 72, 74, 81) and high (16,18,31,33,35,39,45,51,52,56,58,59,68,73,82) risk of progression to malignancy. In addition, the authors concluded that HPV types 26, 53 and 66 should be considered probably carcinogenic due to the extremely small number of affected patients.…”

Performance of proex c and pretect hpv‐proofer e6/e7 mrna tests in comparison with the hybrid capture 2 hpv dna test for triaging ascus and lsil cytology

“…[11][12][13] The cervical oncogenic process is initiated by persistent infection with high-risk HPV and mediated by the upregulation of HPV E6/E7 oncoproteins. 14,15 As the overexpression of these oncoproteins is associated with increased risk of lesion progression, the detection of E6/E7 oncoprotein activity should be more specific and a better predictor of cervical cancer risk than HPV DNA detection methods that cannot differentiate between persistent and transient infections. [16][17][18][19][20] Detection of E6/E7 oncoproteins activity can be achieved by testing for E6/E7 mRNA transcripts.…”