Figure 11.

Mechanism of action of COX-2 in creating immunosuppressive tumor microenvironment The upregulated COX-2 expression creates an inflammatory microenvironment in WTs which is may be mediated by enhanced p-ERK signaling leading to activation of HIF-1α target genes via p-STAT3. In another way, COX-2 can also activate the expression of HIF-1α through its enzymatic product prostaglandin E2. HIF-1α can also directly upregulate expression of COX-2 during hypoxia and thus form a feedback loop to continually activate the COX-2 pathway. Hence, it may be assumed that COX-2 affects the inflammation, hyperproliferation, and angiogenesis and immunosuppression (Tregs,PDCs) in WTs by IGF2 induced COX-2 mediated p-ERK1/2 pathway.