Role of NLRP7 in Normal and Malignant Trophoblast Cells

Abstract

Gestational choriocarcinoma (CC) is an aggressive cancer that develops upon the occurrence of abnormal pregnancies such as Hydatidiform moles (HMs) or upon non-molar pregnancies. CC cells often metastasize in multiple organs and can cause maternal death. Recent studies have established an association between recurrent HMs and mutations in the Nlrp7 gene. NLRP7 is a member of a new family of proteins that contributes to innate immune processes. Depending on its level of expression, NLRP7 can function in an inflammasome-dependent or independent pathway. To date, the role of NLRP7 in normal and in malignant human placentation remains to be elucidated. We have recently demonstrated that NLRP7 is overexpressed in CC trophoblast cells and may contribute to their acquisition of immune tolerance via the regulation of key immune tolerance-associated factors, namely HLA family, βCG and PD-L1. We have also demonstrated that NLRP7 increases trophoblast proliferation and decreases their differentiation, both in normal and tumor conditions. Actual findings suggest that NLRP7 expression may ensure a strong tolerance of the trophoblast by the maternal immune system during normal pregnancy and may directly affect the behavior and aggressiveness of malignant trophoblast cells. The proposed review summarizes recent advances in the understanding of the significance of NLRP7 overexpression in CC and discusses its multifaceted roles, including its function in an inflammasome-dependent or independent pathways.

Keywords: NLRP7; choriocarcinoma; inflammasome; maternal immune tolerance; pregnancy; tumor microenvironment.

Figure 1

Illustration of the domains that comprise the NLRP7 inflammasome. NLRP7 inflammasome is composed of the NLRP7 receptor, the ASC adaptor protein and procaspase 1. PYD: pyrin domain; NATCH: nucleotide binding domain (allows the ATP-dependent oligomerization of the NLRs); LRR: leucine-rich repeats.

Figure 2

Proposed model for the role of NLRP7 protein in the development of gestational choriocarcinoma.

Figure 3

Representation of the mode of function of NLRP7 in normal and tumor trophoblast cells. (A): NLRP7 is normally expressed in trophoblast cells and functions in an inflammasome-dependent manner to allow maturation of pro-IL-1β to IL1β. The transcription of pro-IL-1β depends on the activation of NF-κB that translocates into the nucleus and increases the transcription of pro-IL-1β. NLRP7 also regulates the expression of HLA-G and PD-L1 to allow normal tolerance of the trophoblast by the maternal immune system and favors the polarization of macrophages to M1 subtype. All these processes allow the protection of the fetus and ensure the progress of the pregnancy. (B): In malignant trophoblast cells, NLRP7 is overexpressed and functions in an inflammasome-independent manner. NLRP7 in turn mediates the increase in HLA-G and PD-L1 expression. This exacerbates maternal immune tolerance and camouflage of the tumor cells, creating a favorable, ant—inflammatory environment for tumor growth. NLRP7 overexpression mediates the excessive proliferation of trophoblast cells and suppresses their differentiation, allowing for further migration and invasion that ultimately leads to metastasis of distinct maternal organs.