High-risk human papillomaviruses (HPVs) are involved in the development of several human cancers, including oropharyngeal squamous cell carcinomas. However, many studies have demonstrated that HPV alone is not sufficient for the oncogenic transformation of normal human epithelial cells, indicating that additional cofactors are required for the oncogenic conversion of HPV-infected cells. Inasmuch as chronic inflammation is also closely associated with carcinogenesis, we investigated the effect of chronic exposure to tumor necrosis factor α (TNFα), the major proinflammatory cytokine, on oncogenesis in two immortalized oral keratinocyte cell lines, namely, HPV16-immortalized and human telomerase reverse transcriptase (hTERT)-immortalized cells. TNFα treatment led to the acquisition of malignant growth properties in HPV16-immortalized cells, such as (1) calcium resistance, (2) anchorage independence, and (3) increased cell proliferation in vivo. Moreover, TNFα increased the cancer stem cell-like population and stemness phenotype in HPV16-immortalized cells. However, such transforming effects were not observed in hTERTimmortalized cells, suggesting an HPV-specific role in TNFα-promoted oncogenesis. We also generated hTERT-immortalized cells that express HPV16 E6 and E7. Chronic TNFα exposure successfully induced the malignant growth and stemness phenotype in the E6-expressing cells but not in the control and E7-expressing cells. We further demonstrated that HPV16 E6 played a key role in TNFα-induced cancer stemness via suppression of the stemness-inhibiting microRNAs miR-203 and miR-200c. Overexpression of miR-203 and miR-200c suppressed cancer stemness in TNFα-treated HPV16-immortalized cells. Overall, our study suggests that chronic inflammation promotes cancer stemness in HPV-infected cells, thereby promoting HPV-associated oral carcinogenesis.
While acute inflammation is a part of the defense response, there have been emerging lines of evidence that suggest a strong link between chronic inflammation and cancer. Human papillomaviruses (HPV) infection is one of key factors in cervical cancer development, and possible link between HPV and oral carcinogenesis have been proposed. However, mechanisms by which HPV and chronic inflammation contribute to oral carcinogenesis have not been fully understood. The objective of this study was to determine the effect of chronic inflammation on malignant progression of HPV-associated oral carcinogenesis. We treated HPV-immortalized oral keratinocytes (HOK-16B) with a major pro-inflammatory cytokine, TNF-α for 4 months and examined the effect of chronic TNF-α treatment on malignant behavior of HOK-16B. Chronic treatment of TNF-α resulted in reduction in differentiation potential, and induction in proliferation potential and in migration ability of the HPV-immortalized oral keratinocytes. cDNA microarray analysis revealed that a subset of genes was significantly downregulated in long-term TNF-α treated cells, and the genes that were involved in differentiation, tumor suppression, and cell-cell junction functions supported the three increased malignant phenotypes, respectively. Our results indicate that chronic inflammation promotes malignant behavior of HPV-immortalized oral keratinocytes, suggesting that chronic inflammation is an important co-carcinogenic factor for HPV-associated oral carcinogenesis. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5542. doi:10.1158/1538-7445.AM2011-5542
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