CLEC4s as Potential Therapeutic Targets in Hepatocellular Carcinoma Microenvironment.

Yinjiang Zhang,Mingyan Fang,Hongyun Wei,Binan Lu,Zongran Pang,Lu Fan,Xu He

doi:10.3389/fcell.2021.681372

Abstract

Immunosuppressive tumor microenvironment in hepatocellular carcinoma (HCC) is critical in tumor development. C-type (Ca2+ -dependent) lectin (CLEC) receptors, essential in innate pattern recognition, have potential regulatory effects on immune cell trafficking and modulatory effects on cancer cell activity. However, information on the expression and prognostic value of CLECs in HCC is scanty. Herein, we explored the potential role of CLECs in HCC based on TCGA, ONCOMINE, GEPIA, UALCAN, cBioPortal, Metascape, TRRUST, and TIMER databases. Results demonstrated a significantly higher mRNA level of CLEC4A and CLEC4L in HCC tissues than normal liver tissues. Contrarily, we found significantly low CLEC4G/H1/H2/M expression in HCC tissues. The IHC analysis revealed the following: Absence of CLEC4A/J/K/M in normal and liver cancer tissues; high CLEC4C expression in HCC tissues; low expression and zero detection of CLEC4D/E/H1/H2/L in HCC tissues and normal tissues, respectively. And the HepG2 and LX-2 were used to verify the expression level of CLEC4s via qRT-PCR in vitro. Furthermore, the expression of CLEC4H1 (ASGR1) and CLEC4H2 (ASGR2) exhibited a significant relation to clinical stages. However, the expression of CLEC4A, CLEC4D, CLEC4E, CLEC4J (FCER2), CLEC4K (CD207), CLEC4G, CLEC4H1, CLEC4M, and CLEC4H2 decreased with tumor progression. Patients expressing higher CLEC4H1/H2 levels had longer overall survival than patients exhibiting lower expression. Moreover, CLEC4A/D/E/J/K/G/H1/M/H2 had significant down-regulated levels of promoter methylation. The expression level of CLEC4s was correlated with the infiltration of B cells, CD8 + T cells, CD4 + T cells, macrophage cells, neutrophil cells, and dendritic cells. Functional analysis revealed the potential role of CLECL4s in virus infection, including COVID-19. Also, hsa-miR-4278 and hsa-miR-324-5p, two potential miRNA targets of CLEC4s, were uncovered. This article demonstrates that CLEC4 is crucial for the development of HCC and is associated with infiltration of various immune cells, providing evidence for new immunotherapy targets in HCC.

Highlights

Hepatocellular carcinoma (HCC) is among the most causes of cancer-related deaths worldwide
We found significantly higher mRNA levels of CLEC4A and CLEC4L in hepatocellular carcinoma (HCC) tissues compared to normal liver tissues (Figure 2 and Table 1), whereas the expression of CLEC4G/H1/H2/M was significantly lower in liver carcinoma (Table 1) (Chen et al, 2002; Wurmbach et al, 2007; Mas et al, 2009; Roessler et al, 2010)
The expression level of CLEC4s, including CLEC4C (P < 0.05), CLEC4D (P < 0.05), CLEC4E (P < 0.05), CLEC4J (P < 0.05), CLEC4K (P < 0.05), CLEC4G (P < 0.05), CLEC4H (P < 0.05), CLEC4M (P < 0.05), were significantly lower in HCC samples compared to normal hepatic samples, whereas the expression

Summary

Introduction

Hepatocellular carcinoma (HCC) is among the most causes of cancer-related deaths worldwide. Treatments for HCC include chemotherapy, target therapy, and immune checkpoint inhibitors (Falzone et al, 2018; Christofi et al, 2019). Single-cell cytometry and transcriptome sequencing of TME in 13 HCC patients demonstrated that 17,432,600 immune cells, including tumor-associated CD4/CD8 double-positive T cells, and high IFN-γ/TNF-α levels were located at TME of HCC (Zheng et al, 2020). These immune cells could secret cytokines, such as interleukin-10, that potentially induced angiogenesis (Shiraki et al, 2011). We analyzed the potential function in reshaping immune system, their interacted proteins and evaluation effects based on the public database

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