Involvement of Cellular Prion Protein in Invasion and Metastasis of Lung Cancer by Inducing Treg Cell Development

Abstract

The cellular prion protein (PrPC) is a cell surface glycoprotein expressed in many cell types that plays an important role in normal cellular processes. However, an increase in PrPC expression has been associated with a variety of human cancers, where it may be involved in resistance to the proliferation and metastasis of cancer cells. PrP-deficient (Prnp0/0) and PrP-overexpressing (Tga20) mice were studied to evaluate the role of PrPC in the invasion and metastasis of cancer. Tga20 mice, with increased PrPC, died more quickly from lung cancer than did the Prnp0/0 mice, and this effect was associated with increased transforming growth factor-beta (TGF-β) and programmed death ligand-1 (PD-L1), which are important for the development and function of regulatory T (Treg) cells. The number of FoxP3+CD25+ Treg cells was increased in Tga20 mice compared to Prnp0/0 mice, but there was no significant difference in either natural killer or cytotoxic T cell numbers. In addition, mice infected with the ME7 scrapie strain had decreased numbers of Treg cells and decreased expression of TGF-β and PD-L1. These results suggest that PrPC plays an important role in invasion and metastasis of cancer cells by inducing Treg cells through upregulation of TGF-β and PD-L1 expression.

Deletion of mdig enhances H3K36me3 and metastatic potential of the triple negative breast cancer cells

“…The IQSEC2 and its family members are Arf-nucleotide exchange factors and have been implicated in angiogenesis and tumor metastasis ( D'Souza and Casanova, 2016 ). Several other genes among them, including NMNAT1 ( Yaku et al., 2018 ), MAGED2 ( Jia et al., 2019 ), SLC12A7 ( Brown et al., 2018 ), IGFBP7 ( Paulitschke et al., 2019 ), HUWE1 ( Vaughan et al., 2015 ), PLS3 ( Ueo et al., 2015 ), PRNP ( Cha et al., 2021 ), HMGB2 ( Cui et al., 2019 ), LAMP2 ( Damaghi et al., 2015 ), CTSD ( Ketterer et al., 2020 ), etc., have also been linked to the glycolysis, EMT, stemness, and metastasis of the cancer cells. Thus, enhancement of H3K36me3 may preferentially favor the expression of genes contributing to EMT and cancer cell metastasis.…”

TGF-β as Predictive Marker and Pharmacological Target in Lung Cancer Approach

“…Moreover, it has been shown, by transplanting cell tumors into nude mice, that the lysine-specific histone demethylase 1 (LSD1) demethylates the SEPT6 promoter, thus positively regulating Septin 6 (SEPT6), which, through the TGF-β/Smad pathway, accelerates metastasis in NSCLC [ 62 ]. In addition, it was investigated in in vivo experiments that the overexpression of cellular prion proteins drives the invasion and metastasis of the LC, an effect linked to TGF-β and PD-L1, which is important for the role of regulatory T cells in LC and immunotherapeutic approach [ 63 ]. Furthermore, TGF-β is the major driver of pleural dissemination in metastatic LC; in particular, pleural mesothelial cells that co-cultured with A549 cells expressed high levels of TGF-β and underwent apoptosis and senescence [ 64 ].…”

The Role of Cellular Prion Protein in Cancer Biology: A Potential Therapeutic Target

“…Regulatory T cells (Tregs), which have immunosuppressive activity ( 50 ), are one of the main targets of cancer immunotherapy ( 51 ). By constructing a lung metastatic model of melanoma in Prnp0/0 and Tga20 mice, it was demonstrated that the increased expression of PrP C induces the development of Tregs by upregulating transforming growth factor-beta (TGF-β) and programmed death ligand-1(PD-L1), thereby promoting tumor progression ( 52 ).…”