HLA-G与肿瘤研究进展

人类白细胞抗原-G（human leukocyte antigen G,HLA—G1属于非经典的HLAI类分子,是机体内重要的免疫耐受分子。HLA．G可以与表达在免疫细胞上的受体结合直接发挥免疫抑制功能,同时通过诱导产生调节性T细胞（regulatory Tcells,Treg）或“Trogocytosis”机制参与机体的免疫耐受,以协助肿瘤细胞实现免疫逃逸。近年来研究发现,HLA．G在多种恶性肿瘤中均存在异常表达并抑制宿主的抗肿瘤免疫反应。对HLA-G在肿瘤中的表达及可能的作用机制研究进展作一综述。     

Altered expression of cellular membrane molecules of HLA-DR, HLA-G and CD99 in cervical intraepithelial neoplasias and invasive squamous cell carcinoma

OBJECTIVE: The aim of this study was to investigate the role of HLA-DR, HLA-G and CD99 during cervical carcinogenesis and to examine the prognostic significance of these protein expressions in invasive squamous cell carcinoma (SCC). METHODS: Using specific antibodies for HLA-DR, HLA-G and CD99, we examined protein expressions in 19 normal cervix, 15 mild dysplasia (CIN I), 22 moderate dysplasia (CIN II), 23 severe dysplasia (CIN III), and 34 invasive squamous cell carcinoma by immunohistochemistry. And we detected the expression of Ki67 in the same specimens. RESULTS: None of normal cervix and CINs except three cases of CIN III expressed HLA-DR. HLA-DR expression increased progressively with the grade of the tumor, and significant differences could be observed between grade 1 and grade 2 (P<0.01) and between grade 1 and grade 3 (P<0.05). In all normal epithelial control samples, HLA-G expression was seen in ectocervical squamous and endocervical columnar epithelium and the staining was strong and uniform. Only a small proportion of CINs and SCCs showed reduced expression of HLA-G. Compared with the results in the control samples, CINs and SCCs showed significantly reduced expression of HLA-G (P<0.001). SCCs showed significantly increased expression of CD99 when compared with normal cervix and CINs (P<0.05). Ki67 was expressed in all specimens. Significant differences were observed between CINs and normal cervix (P<0.001) and SCCs and controls (P<0.001), but no significant differences could be observed between SCCs and CINs. None of the expressions of these proteins was associated with any of clinicopathological parameters. CONCLUSIONS: These results indicate that increased expression of HLA-DR and CD99 may be related to the evolution of cervical cancer. All protein expressions were not associated with clinicopathological parameters.     

Induction of HLA-G expression in a melanoma cell line OCM-1A following the treatment with 5-aza-2''''-deoxycytidine

~~Induction of HLA-G expression in a melanoma cell line OCM-1A following the treatment with 5-aza-2'-deoxycytidine@Chien Chung CHANG$Department of Immunology,Roswell Park Cancer Institute,Buffalo.NY 14263,USA @Soldano FERRONE$Department of Immunology,R…     

血清皮质抑素、分拣蛋白、人类白细胞抗原-G与妊娠期糖尿病患者糖代谢紊乱、胰岛素抵抗的关系及对妊娠结局的影响

摘要 目的：探讨血清皮质抑素（CST）、分拣蛋白（sortilin）、人类白细胞抗原-G（HLA-G）与妊娠期糖尿病（GDM）患者糖代谢紊乱、胰岛素抵抗的关系及对妊娠结局的影响。方法：选取2019年6月至2021年5月本院收治的333例GDM患者为研究组,另选取同期42例妊娠糖耐量正常的健康孕妇为对照组,比较两组研究对象糖代谢指标、胰岛素抵抗指标及血清CST、sortilin、HLA-G水平,采用Pearson相关性分析法分析糖代谢、胰岛素抵抗指标与血清CST、sortilin、HLA-G水平的相关性。根据随访期间的妊娠结局将GDM患者分为不良结局组与良好结局组,比较两组血清CST、sortilin、HLA-G水平及临床资料的差异,采用Logistic回归分析法明确导致GDM患者不良妊娠结局的危险因素。结果：研究组糖尿病家族史、合并高脂血症占比及空腹血糖（FPG）、服糖后1 h血糖（1hPG）、服糖后2 h血糖（2hPG）、糖化血红蛋白（HbAlc）、空腹胰岛素（FINS）、胰岛素抵抗指数（HOMA-IR）及sortilin水平均高于对照组（P＜0.05）,研究组血清CST、HLA-G水平低于对照组（P＜0.05）。GDM患者血清CST、HLA-G与FPG、2hPG、HbAlc、FINS、HOMA-IR均呈负相关（P<0.05）,血清sortilin与FPG、2hPG、HbAlc、FINS、HOMA-IR均呈正相关（P<0.05）。研究组不良妊娠结局发生率为15.32%。不良结局组年龄≥35岁、孕前1个月体质量指数（BMI）≥24 kg/m²、有不良孕产史、糖尿病家族史、合并高脂血症、血糖控制不佳占比及血清sortilin水平均高于良好结局组,血清CST及HLA-G水平低于良好结局组（P＜0.05）。Logistic回归分析结果显示,年龄≥35岁、孕前1个月BMI≥24 kg/m²、血糖控制不佳、血清CST低水平、血清sortilin高水平、血清HLA-G低水平为GDM患者妊娠结局不良的危险因素（P＜0.05）。结论：GDM患者血清CST、sortilin、HLA-G与糖代谢紊乱、胰岛素抵抗及不良妊娠结局关系密切,提示临床在加强血糖监测和控制的同时,检测血清CST、sortilin、HLA-G可能有助于评估GDM患者病情和预测不良妊娠结局的发生风险。     

Expression of human leukocyte antigen G is associated with prognosis in nasopharyngeal carcinoma

Human leukocyte antigen G (HLA-G) has multiple immune regulatory functions including the induction of immune tolerance in malignancies. The roles of HLA-G have not been investigated in nasopharyngeal carcinoma (NPC). This study is aimed to evaluate the role of HLA-G as prognostic factor for NPC patients as well as its role in the immune regulation. Western assays showed high HLA-G expression in NPC cell lines, but low in the immortalized nasopharyngeal epithelial cell line NP69. HLA-G protein was further detected in 79.2% of 552 NPC specimens with immunohistochemistry (IHC), but not in normal nasopharyngeal epithelium tissue. Moreover, high expression of HLA-G predicted poor survival of NPC patients and positively correlated with tumor N classification and recurrence or metastasis. Multivariate analysis indicated that HLA-G was an independent and unfavorable prognostic factor. Furthermore, the presence of CD68+ macrophages and IL-10 were also examined, which are two prognostic markers of NPC and important factors for regulating immune surveillance. The correlations of HLA-G with these two immune factors were revealed in NPC tissues. Taken together, our results suggest that HLA-G is an independent biomarker for NPC prognosis, and HLA-G might contribute to NPC progression, which might jointly regulate immune surveillance in NPC together with macrophages and IL-10.     

Residues Met~(76) and Gln~(79) in HLA-G α1 domain involved in KIR2DL4 recognition

INTRODUCTIONThe non-classical HLA class I antigen HLA-G is mainlyexpressed on extravillous cytotrophoblasts that invade de-ciduae in uterine pregnancy. Furthermore, HLA-G canmodulate the function of most immune component cellssuch as NK cells, T cells and…     

Heterogeneity of HLA-G Genes Identified by Polymerase Chain Reaction/Single Strand Conformational Polymorphism (PCR/SSCP)

A genomic HLA-G clone named 7.0E was isolated from a Japanese placenta. The deduced amino acid sequence of the 7.0E was identical to two HLA-G genomic clones and two cDNA clones previously described. The DNA sequences of α1 and α2 domains of the HLA-G gene from 5 cell lines also encoded the same amino acids. However, a 14 bp insertion, ATTTGTTCATGCCT, was present in the 3′ untranslated region of 7.0E compared with the originally described HLA-G clone (HLA 6.0). Polymerase chain reaction (PCR)/single strand conformational polymorphism (SSCP) analysis of exon 8 allowed the HLA-G gene to be classified into two alternative types, G6.0 and 7.0 E, those correlated to the absence or the presence of the 14 bp stretch. Each group had minor sequence variant(s), and the alleles of the 7.0E-type were more heterogeneous than those of the G6.0- type. The 14 bp deletion is present only in the G6.0-type of HLA-G alleles among HLA class I genes. Thus it was suggested that G6.0 alleles were generated after diversification of the HLA-G.     

GPER mediated estradiol reduces miR-148a to promote HLA-G expression in breast cancer

Breast cancer is the most common malignant diseases in women. miR-148a plays an important role in regulation of cancer cell proliferation and cancer invasion and down-regulation of miR-148a has been reported in both estrogen receptor (ER) positive and triple-negative (TN) breast cancer. However, the regulation mechanism of miR-148a is unclear. The role of estrogen signaling, a signaling pathway is important in development and progression of breast cancer. Therefore, we speculated that E2 may regulate miR-148a through G-protein-coupled estrogen receptor-1 (GPER). To test our hypothesis, we checked the effects of E2 on miR-148a expression in ER positive breast cancer cell MCF-7 and TN cancer cell MDA-MB-231. Then we used GPER inhibitor G15 to investigate whether GPER is involved in regulation of E2 on miR-148a. Furthermore, we analyzed whether E2 affects the expression of HLA-G, which is a miR-148a target gene through GPER. The results showed that E2 induces the level of miR-148a in MCF-7 and MDA-MB-231 cells, GPER mediates the E2-induced increase in miR-148a expression in MCF-7 and MDA-MB-231 cells and E2-GPER regulates the expression of HLA-G by miR-148a. In conclusion, our findings offer important new insights into the ability of estrogenic GPER signaling to trigger HLA-G expression through inhibiting miR-148a that supports immune evasion in breast cancer.