Zhang Yinjiang, Wei Hongyun, Fan Lu, Fang Mingyan, He Xu, Lu Binan, Pang Zongran
School of Pharmacy, Minzu University of China, Beijing, China.
Key Laboratory of Ethnomedicine, Minzu University of China, Ministry of Education, Beijing, China.
Front Cell Dev Biol. 2021 Aug 2;9:681372. doi: 10.3389/fcell.2021.681372. eCollection 2021.
Immunosuppressive tumor microenvironment in hepatocellular carcinoma (HCC) is critical in tumor development. C-type (Ca -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 . 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.
肝细胞癌（HCC）中的免疫抑制肿瘤微环境在肿瘤发展中至关重要。C型（钙依赖性）凝集素（CLEC）受体在先天性模式识别中起重要作用，对免疫细胞转运具有潜在调节作用，对癌细胞活性具有调节作用。然而，关于CLEC在HCC中的表达和预后价值的信息很少。在此，我们基于TCGA、ONCOMINE、GEPIA、UALCAN、cBioPortal、Metascape、TRRUST和TIMER数据库探讨了CLEC在HCC中的潜在作用。结果表明，HCC组织中CLEC4A和CLEC4L的mRNA水平显著高于正常肝组织。相反，我们发现HCC组织中CLEC4G/H1/H2/M表达显著降低。免疫组化分析显示：正常组织和肝癌组织中不存在CLEC4A/J/K/M；HCC组织中CLEC4C表达高；HCC组织和正常组织中CLEC4D/E/H1/H2/L分别低表达和未检测到。并且使用HepG2和LX-2通过qRT-PCR验证CLEC4s的表达水平。此外，CLEC4H1（ASGR1）和CLEC4H2（ASGR2）的表达与临床分期显著相关。然而，CLEC4A、CLEC4D、CLEC4E、CLEC4J（FCER2）、CLEC4K（CD207）、CLEC4G、CLEC4H1、CLEC4M和CLEC4H2的表达随肿瘤进展而降低。CLEC4H1/H2水平较高的患者总生存期长于表达较低的患者。此外，CLEC4A/D/E/J/K/G/H1/M/H2的启动子甲基化水平显著下调。CLEC4s的表达水平与B细胞、CD8 + T细胞、CD4 + T细胞、巨噬细胞、中性粒细胞和树突状细胞的浸润相关。功能分析揭示了CLECL4s在病毒感染（包括COVID-19）中的潜在作用。此外，还发现了CLEC4s的两个潜在miRNA靶点hsa-miR-4278和hsa-miR-324-5p。本文表明CLEC4对HCC的发展至关重要，并与各种免疫细胞的浸润相关，为HCC新的免疫治疗靶点提供了证据。
