Abstract
Early metastasis of pancreatic cancer (PC) leads to high mortality, and the underlying mechanism of metastasis remains unclear. Tumor necrosis factor superfamily member 9 (TNFSF9) is associated with poor prognosis in PC. Here, we investigated the effect of TNFSF9 on PC proliferation and apoptosis, and focused on the effect of TNFSF9 on PC metastasis and its potential mechanism. We found that TNFSF9 promotes PC metastasis in vivo and in vitro, and may be partially dependent on the Wnt/Snail signaling pathway. In addition, TNFSF9 also regulates the release of cytokines IL-10 and transforming growth factor-β (TGF-β) in pancreatic cancer cells through Wnt signaling to induce the M2 polarization of macrophages and promote the migration of PC cells. Overall, our study found that TNFSF9 may directly promote PC metastasis or indirectly promote PC metastasis through macrophage M2 polarization. Our study provides a new costimulatory target for the treatment of PC.
Highlights
Pancreatic cancer is one of the most deadly and incurable cancer types, and its 5-year survival rate is less than 10% [1]
At the mRNA and protein levels, the expression of Tumor necrosis factor superfamily member 9 (TNFSF9) in pancreatic cancer cells ASPC-1, PANC-1 and BXPC-3 was significantly higher than that of normal pancreatic epithelial cells HPDE6-C7 (P < 0.05), while the expression of COLO357 was not different from HPDE6-C7 (Figure 1D–1F). These results indicated that the expression of TNFSF9 in PC is significantly increased, and may be related to the metastasis of PC
We found that the expression of TNFSF9 in PC was significantly higher than that of normal tissues adjacent to the cancer, and through in vitro cell experiments found that TNFSF9 promotes the proliferation of pancreatic cancer cells and inhibits the apoptosis of pancreatic cancer cells
Summary
Pancreatic cancer is one of the most deadly and incurable cancer types, and its 5-year survival rate is less than 10% [1]. Among the most common malignant tumors diagnosed in men and women in 2021, their incidence is the 10th and 8th respectively. Their mortality rates are ranked 4th [2]. TNFSF9 was originally found to be expressed on antigen-presenting cells such as macrophages. TNFSF9 expression is highly upregulated in early to late stage tumors and is significantly associated with the occurrence of distant metastases and shortened survival in late disease [8]. TNFSF9 is cross-linked with TNFRSF9, which promotes monocyte/macrophage migration to the tumor microenvironment and osteoclast generation by upregulation of FRA1 expression, thereby promoting breast cancer metastasis [12]. The role of TNFSF9 in the development of PC has not been studied
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