Effects and Mechanisms of Innate Immune Molecules on Inhibiting Nasopharyngeal Carcinoma

Effects and Mechanisms of Innate Immune Molecules on Inhibiting Nasopharyngeal Carcinoma

Nasopharyngeal carcinoma (NPC) is a malignant tumor that arises from the nasopharyngeal epithelium, a region frequently exposed to various harmful carcinogens. Chronic inflammation of the nasopharyngeal epithelium is a significant risk factor for the development of NPC. The nasopharyngeal mucosa secretes mucus containing a series of proteins and peptides that form the body’s primitive immune protection barrier. These innate immune molecules, including lactotransferrin (LTF) and bactericidal/permeability-increasing (BPI) protein family members, play crucial roles in sensing, binding, degrading, and removing harmful substances, thereby inhibiting the progression of NPC.

The BPI protein family includes two members, BPIFA1 (also known as SPLUNC1) and BPIFB1 (LPLUNC1), which are specifically expressed in the human nasopharyngeal mucosa and the upper respiratory tract epithelium. These proteins have bactericidal functions and can neutralize endotoxins by binding to the cell wall components of Gram-negative bacteria. BPIFA1, in particular, has been shown to inhibit bacterial growth and directly bind to lipopolysaccharide (LPS) through its BPI domain, thereby eliminating bacteria. This antibacterial activity is essential for maintaining the integrity of the nasopharyngeal epithelium and preventing infections that could lead to chronic inflammation and subsequent carcinogenesis.

Epstein-Barr virus (EBV) is a well-established causative agent of NPC. EBV primarily infects lymphocytes through the interaction of its viral envelope glycoprotein gp350 with the CD21 receptor on the surface of lymphocytes. Interestingly, CD21 is not expressed on epithelial cells, but EBV can be transferred from infected lymphocytes to nasopharyngeal epithelial cells. BPIFA1 has been shown to promote the apoptosis and lysis of EBV-infected cells and cause structural damage to the virus. Additionally, BPIFA1 inhibits the expression of the EBV-encoded tumor gene LMP1 and promotes the expression of gp350, which facilitates the recognition of EBV by the immune system and initiates the complement pathway and antibody-dependent cell-mediated cytotoxicity (ADCC) to eliminate the virus.

LTF, another innate immune molecule, is highly expressed in the normal nasopharyngeal epithelium. LTF reduces the efficiency of EBV infection in lymphocytes and inhibits the transfer of EBV from lymphocytes to epithelial cells. LTF binds to CD21 on lymphocytes, blocking the binding site of EBV and preventing its entry into lymphocytes and subsequent transfer to nasopharyngeal epithelial cells. Both LTF and BPIFA1 are significantly downregulated in NPC, and their low expression is associated with a worse prognosis, suggesting that these molecules act as tumor suppressors in NPC.

The progression of nasopharyngeal tissue from mild dysplasia to severe dysplasia and eventually to NPC is accompanied by a gradual reduction in the expression levels of BPIFA1 and BPIFB1. The concentrations of these proteins in the nasopharyngeal secretions of NPC patients are significantly lower than those in normal controls, indicating their potential as molecular markers for the early screening of NPC.

Chronic inflammation plays a critical role in the malignant transformation of the nasopharyngeal epithelium. Inflammatory factors released in the inflammatory microenvironment can activate signaling pathways such as NF-kB and STAT3, promoting the proliferation of NPC cells. EBV can also activate the NF-kB pathway through the interaction of its surface glycoprotein gp350 with TLR2 on macrophages. Additionally, EBV particles, EBV DNA, and various encoded products can be recognized by TLR9 on macrophages, leading to the activation of the NF-kB pathway and the release of pro-inflammatory factors such as IL-8 and MCP-1. CD14, a co-receptor of TLR9, enhances the ability of TLR9 to recognize ligands and promotes inflammatory responses.

The innate immune molecules LTF, BPIFA1, and BPIFB1 play important roles in inhibiting the malignant transformation of the nasopharyngeal epithelium. LTF reduces the ability of TLR9 to recognize EBV DNA and inhibits the activation of the NF-kB pathway, thereby reducing the EBV-induced inflammatory response. LTF also regulates the G1/S phase of the cell cycle and inhibits NPC cell growth and proliferation through the downregulation of c-Jun and the AKT pathway. BPIFA1 and BPIFB1 significantly inhibit the growth of NPC cells, induce apoptosis, and partially reverse their malignant phenotype. BPIFA1 upregulates the expression of PTEN, a target gene of miR-141, and inhibits the proliferation of NPC cells through the PTEN signaling pathway. BPIFB1 inhibits the activity of the MAPK signaling pathway, downregulates the expression of cyclinD1 and CDK4, and blocks the proliferation of NPC cells. BPIFB1 also promotes apoptosis by regulating the expression levels of Bcl-2 and Bax and inhibits the activation of the NF-kB pathway induced by inflammatory factors such as IL-6.

The inflammatory microenvironment can lead to the occurrence of malignant tumors and promote the invasion and metastasis of tumors. However, innate immune molecules can inhibit the invasion and metastasis of NPC in various ways. Overexpression of LTF in NPC cells significantly decreases their ability to invade and metastasize. LTF binds to the NPC cytoskeletal protein K18 and inhibits invasion and metastasis through the regulation of the 14-3-3 protein and its downstream signaling pathway. LTF also inhibits PDK1, leading to the inhibition of AKT phosphorylation and membrane translocation, which inhibits tumor cell proliferation, invasion, and metastasis through the PDK1/AKT pathway. LTF is the target gene of miR-214, and inhibition of miR-214 expression can significantly increase the expression of LTF and reduce the invasion and metastatic ability of NPC cells.

Radiotherapy is the preferred clinical treatment for NPC, but some patients experience radiotherapy resistance, local recurrence, and distant metastasis. BPIFB1 expression is associated with higher progression-free survival (PFS) and overall survival (OS) in NPC patients treated with radiotherapy. BPIFB1 inhibits the invasion and metastasis of NPC cells by downregulating the expression of VTN and ITGAV and inhibiting the formation of the VTN/ITGAV complex and the activation of the FAK-Src-ERK pathway. BPIFB1 also binds to the mesenchymal marker VIM, inhibiting its expression and preventing epithelial-mesenchymal transition (EMT). Additionally, BPIFB1 enhances the sensitivity of NPC cells to ionizing radiation by inhibiting the activation of the ATM/Chk2 and ATR/Chk1 DNA damage repair pathways, reducing the survival ability of NPC cells after ionizing radiation, and promoting cell apoptosis.

The carcinogenic mechanism of EBV is complex and involves the regulation of immune and inflammation-related pathways by EBV-encoded microRNAs (miRNAs). LTF, BPIFA1, and BPIFB1 are innate immune proteins secreted by the human nasopharyngeal epithelium that resist pathogenic microbial infections, inhibit chronic inflammation, and arrest the development of tumors. These proteins regulate the proliferation, apoptosis, invasion, metastasis, and radiotherapy resistance of NPC cells through multiple signaling pathways, including the NF-kB, MAPK, and AKT pathways. Further research is needed to explore the cross-talk between these innate immune molecules and their downstream signaling pathways and the potential involvement of non-coding RNAs, including miRNA, long non-coding RNA, and circular RNA (circRNA).

In conclusion, innate immune molecules such as LTF, BPIFA1, and BPIFB1 play critical roles in inhibiting the development and progression of NPC. These molecules exert their effects through multiple mechanisms, including the inhibition of EBV infection, the regulation of inflammatory responses, and the modulation of key signaling pathways involved in cell proliferation, apoptosis, invasion, and metastasis. Understanding the roles and mechanisms of these innate immune molecules has important implications for the development of novel therapeutic strategies for NPC.

doi.org/10.1097/CM9.0000000000000132

Was this helpful?

YesNo

0 / 0