Soluble B7-H3 promotes the invasion and metastasis of pancreatic carcinoma cells through the TLR4/NF-κB pathway

Pancreatic carcinoma (PCa) is a highly invasive and lethal malignant disease. It is the fourth leading cause of cancer deaths in the United States, and the overall 5-year survival rate for this disease from 2004 to 2010 was 7%1. Due to the aggressive nature of PCa, more than 80% of patients are already at an advanced stage when diagnosed with pancreatic cancer, present with local invasion or distant metastasis and are not eligible for surgical removal2. Even when complete surgical excision can be performed, the overall 5-year survival rate after surgery remains below 20%3,4. B7-H3, a newly discovered member of the B7 family, including its soluble form, sB7-H3, was discovered by Zhang et al.5 and plays a crucial role in the T-cell-mediated immune response6. It is widely expressed in many human organs and cells in the human body at the RNA level, whereas its protein expression is relatively limited. In recent decades, research on membrane-bound B7-H3 (mB7-H3), has revealed an abnormally high expression of mB7-H3 in a wide variety of human tumor tissues, which is closely correlated with an unfavorable progression and a poor prognosis for cancer patients, implying that the mB7-H3 expression level can be used as a tumor biomarker7,8. However, although the mechanism by which B7-H3 affects tumor progression is not clear, some studies have discovered B7-H3-mediated mechanisms of resistance to anti-cancer drugs, such as paclitaxel and gemcitabine, that act partly through the Jak2/Stat3 pathway and involve increased levels of Mcl-1 and survivin proteins9,10. Other studies have shown that B7-H3 promotes the expression of IL-8, VEGF and matrix metalloproteinases (MMPs) in the tumoral microenvironment11,12,13. However, the exact nature of the interaction between B7-H3 and cytokines is not understood. NF-κB is a crucial transcription factor that plays a key role in innate and adaptive immunity. Recent research has documented that the constitutive activation of NF-κB is associated with tumorigenesis, invasion and metastasis in human carcinomas14,15. A pro-tumorigenic relationship between NF-κB and stat316 has been demonstrated, in which stat3 induces constitutive NF-κB activity in tumors to promote chemoresistance and tumorigenesis. In addition, NF-κB signaling increases the expression of IL-8, VEGF and MMPs in the tumor microenvironment17,18. Whether a correlation also exists between B7-H3 and NF-κB that facilitates cancer progression requires further investigation. In the present study, we provide evidence that sB7-H3 increases the activity of NF-κB in a TLR4-dependent manner, which promotes PCa cell invasion and metastasis in vitro and in vivo.