Neuropilins as potential biomarkers in hepatocellular carcinoma: a systematic review of basic and clinical implications

Abstract

Hepatocellular carcinoma (HCC) is one of the most common and deadly cancers worldwide and is characterized by complex molecular carcinogenesis. Neuropilins (NRPs) NRP1 and NRP2 are the receptors of multiple proteins involved in key signaling pathways associated with tumor progression. We aimed to systematically review all the available findings on their role in HCC. We searched the Scopus, Web of Science (WOS), PubMed, Cochrane and Embase databases for articles evaluating NRPs in preclinical or clinical HCC models. This study was registered in PROSPERO (CRD42022349774) and include 49 studies. Multiple cellular and molecular processes have been associated with one or both NRPs, indicating that they are potential diagnostic and prognostic biomarkers in HCC patients. Mainly NRP1 has been shown to promote tumor cell survival and progression by modulating several signaling pathways. NRPs mainly regulate angiogenesis, invasion and migration and have shown to induce invasion and metastasis. They also regulate the immune response and tumor microenvironment, showing a crucial interplay with the hypoxia response and microRNAs in HCC. Altogether, NRP1 and NRP2 are potential biomarkers and therapeutic targets, providing novel insight into the clinical landscape of HCC patients.

Keywords: Biomarker; Hepatocellular carcinoma; Neuropilins; Systematic review.

Figure 1.

PRISMA flowchart of the study selection process. HCC, hepatocellular carcinoma; NRP, neuropilin; PRISMA, Preferred Reporting Items for Systematic Reviews and Meta-analyses; WOS, Web of Science.

Figure 2.

Main cellular and molecular mechanisms modulated by NRP1 and NRP2. NRPs are expressed in tumor cells and other tumor-associated populations that constitute the tumor microenvironment and participate in the immune response. Both NRP1 and NRP2 are expressed in a broad number of cell types and are involved in different cellular and molecular mechanisms responsible for HCC development and progression, modulating several cellular processes. EMT, epithelial-to-mesenchymal transition; IFN-β, interferon beta; IFN-γ, interferon gamma; IL-10, interleukin-10; NRP, neuropilin; TGF-β, transforming growth factor β; TNF-α, tumoral necrosis factor-α.

Figure 3.

Main findings from the studies included in this systematic review describing modulatory effects associated to NRP1 and NRP2 in HCC. Specific modulatory effects exerted by both NRPs are graphically shown, together with correlations observed in different cellular processes and molecular mechanisms. α-SMA, α smooth muscle actin; CSC, cancer stem cell; DFS, disease-free survival; IFN-β, interferon beta; IFN-γ, interferon gamma; OS, overall survival; PFS, progression-free survival; RFS, recurrence-free survival; TFAP4, transcription factor activating enhancer binding protein 4; TGF-β, transforming growth factor beta; TNF-α, tumoral necrosis factor-α; VEGF, vascular endothelial growth factor.