Proinflammatory cytokine TNFα promotes HPV-associated oral carcinogenesis by increasing cancer stemness

Abstract

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.

Prevalence of anogenital infection by Human Papillomavirus (HPV) in users of immunobiological therapy

“…A recent study showed that exposure to chronic inflammation induced by TNF-α contributes to the persistence of HPV-infected keratinocytes and their transformation into immortalized cells with greater mutagenic potential. It has been suggested that HPV alone is insufficient for oncogenic conversion and that TNF-α acts as a cofactor for this transformation (Hong et al, 2020). Therefore, it is assumed that blockade of TNF-α with immunobiologicals can play a protective role against malignancies involving HPV.…”

Intrinsic and Extrinsic Factors Impacting Cancer Stemness and Tumor Progression

“…It was also found that IL-1β can increase the formation of colon cancer spheres, which show an up-regulation of stemness factor genes and increased drug resistance [ 134 ]. Finally, tumor necrosis factor (TNF)-α promotes HPV-associated oral carcinogenesis by increasing stemness [ 135 ].…”

Transitional dynamics of cancer stem cells in invasion and metastasis

“…Despite targeted therapeutic approaches in the treatment of chronic myeloid leukemia (CML), BCR-ABL-independent mechanisms seem to exist which sustain the survival of leukemic stem cells (LSCs) as minimal residual disease or persister cells with increased stem cell characteristics and quiescence [60] . Chronic inflammation and tumor necrosis factor α (TNFα), the major proinflammatory cytokine was found to induce malignant growth and stemness phenotype in HPV-infected oral cancer cells [61] . TIC population in pancreatic ductal adenocarcinoma (PDAC) was marked by high cell surface levels of the tetraspanin CD9 correlated with poorer survival, showed pronounced epithelial and mesenchymal cancer cell populations, re-initiated tumor formation and recapitulated the cellular heterogeneity of primary PDAC.…”