Up‐regulation of interleukin‐17 expression by human papillomavirus type 16 E6 in nonsmall cell lung cancer

Abstract

BACKGROUND: Human papillomavirus (HPV) 16/18 infection is associated with nonsmoking lung cancer. In this study, the authors investigated a putative correlation between interleukin (IL)-17 expression and HPV infection in clinical nonsmall cell lung cancer (NSCLC) tissues and examined the effects of HPV infection on a human NSCLC cell line. METHODS: IL-17 expression was investigated in 79 NSCLC tumor tissues by immunohistochemistry. Growth rate, IL-17 mRNA, and secreting protein levels were also examined in HPV 16/18 E6-transfected H1299 human NSCLC cells. RESULTS: Immunohistochemical data showed that 48.1% of lung tumors had IL-17 staining, which was significantly associated with patients' sex (P ¼.03), HPV infection (P ¼.002), and tumor stage (P ¼.03). Significant correlations of IL-17 with IL-6 (P < .001) and IL-17 with Mcl-1 (P < .001) expression were also observed. Cell growth rate was increased, and IL-17/Mcl-1 expression levels were elevated in HPV 16 E6-transfected H1299 cells. The transfected E6 oncoproteins can significantly up-regulate expression levels of IL-17 and antiapoptotic protein Mcl-1. CONCLUSIONS: The study suggests that HPV infection-induced IL-17 levels can stimulate Mcl-1 expression through the PI3K pathway and promote lung tumor cell progression through a p53-and IL-6-independent pathway. Cancer 2010;116:4800-9.

Effect of human papillomavirus 16 oncoproteins on oncostatin M upregulation in oral squamous cell carcinoma

“…Moreover, HPV infection is known to modulate the host immune response [3][4][5]. Therefore, we hypothesized that HPV could modulate production of OSM, leading to OSCC development/progression.…”

“…For example, HPV16E5 inhibits major histocompatibility complex (MHC) and human leukocyte antigen (HLA)-molecule trafficking, with downstream effects on the antigen-presentation process [2]. HPV16E6/E7 potently downregulates E-cadherin, inhibiting antigen presentation to Langerhans cells by infected cells [3], and modulate the host immune response by induction of cytokines, especially oncogenic and immunosuppressive cytokines such as IL-6 and IL-17, leading to cancer development/progression [4,5]. However, knowledge concerning the role of HPVassociated OSCC on cytokine modulation is still limited.…”

Human Papillomavirus Type 16/18 Oncoproteins: Potential Therapeutic Targets in Non-smoking Associated Lung Cancer

“…These findings indicate that E6 can up-regulate Mcl-1 through p53-PI3K/Akt-(IL-6)-(IL-17) pathway. Intriguingly, the IL-6 level in HPV18 E6-transfected cells was significantly higher than that in HPV16 E6 counterparts, but the IL-6 level in HPV 16 E7 was similar to that in HPV 18 E7 transfectants (Chang et al, 2010). Our previous studies found that over-expression of HPV-16 E6 and E7 oncoproteins led to HIF-1α-dependent increase of IL-8 in NSCLC cells .…”

“…Further, the up-regulated IL-17 levels lead to the increased Mcl-1 expression through the PI3K pathway and promote lung tumor cell progression through p53-and IL-6-independent mechanisms . Similarly, Cheng et al has shown that IL-6 and Mcl-1 protein levels were also elevated in HPV 16/18 E6-and E7-transfected A549 cells and HPV-16-infected TL-1 cells, mainly via PI3K/ Akt pathway, while a positive IL-6 expression was the prerequisite of Mcl-1 expression in lung tumor (Chang et al, 2010). These findings indicate that E6 can up-regulate Mcl-1 through p53-PI3K/Akt-(IL-6)-(IL-17) pathway.…”

“…In addition, IL-17 was reported to enhance the angiogenesis and growth of NSCLC in the severe combined immunodeficiency mouse model (Numasaki et al, 2005). Chang et al found that IL-17/Mcl-1 levels were elevated by HPV16 E6 (Chang et al, 2010). They also identified that there were significant correlations between IL-17 and IL-6 (P<0.001) or between IL-17 and Mcl-1 (P<0.001) .…”