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Natural killer cells (NK) are the "professional killer" of tumors and play a crucial role in anti-tumor immunotherapy. NK cell desensitization is a key mechanism of tumor immune escape. Dysregulated NKG2D-NKG2DL signaling is a primary driver of this desensitization process. However, the factors that regulate NK cell desensitization remain largely uncharacterized. Here, we present the first report that circular RNA circARAP2 (hsa_circ_0069396) is involved in the soluble MICA (sMICA)-induced NKG2D endocytosis in the NK cell desensitization model. CircARAP2 was upregulated during NK cell desensitization and the loss of circARAP2 alleviated NKG2D endocytosis and NK cell desensitization. Using Chromatin isolation by RNA purification (ChIRP) and RNA pull-down approaches, we identified that RAB5A, a molecular marker of early endosomes, was its downstream target. Notably, transcription factor CTCF was an intermediate functional partner of circARAP2. Mechanistically, we discovered that circARAP2 interacted with CTCF and inhibited the recruitment of CTCF-Polycomb Repressive Complex 2 (PRC2) to the promoter region of RAB5A, thereby erasing histone H3K27 and H3K9 methylation suppression to enhance RAB5A transcription. These data demonstrate that inhibition of circARAP2 effectively alleviates sMICA-induced NKG2D endocytosis and NK cell desensitization, providing a novel target for therapeutic intervention in tumor immune evasion. [ABSTRACT FROM AUTHOR]

Objective: Variations in immune responses to viral particles and antiretroviral drugs show interference of the cluster of differentiation number 4 T cell monitoring methods, leading to an inaccurate evaluation for human immunodeficiency virus infected patients receiving antiretroviral therapy. Other biological markers; such as cytokine; especially interferon gamma (IFN-γ) and soluble molecules of major histocompatibility complex class I chain related molecule A (sMICA), were designed as a novel severity marker. Material and Methods: Levels of IFN-γ and sMICA were evaluated for 69 patients, who presented with HIV infection; with no other diseases or inflammation. The candidates were classified into four groups, depending on their CD4 T cell count. The IFN-γ and sMICA serum content of the patients was detected in triplicate, using enzyme-linked immunosorbent assay. Results: Mean value of IFN-γ in each severity group was 49.1±9.7, 69.1±21.8, 63.0±12.8, and 69.4±18.4 picograms/ milliliter for none, mild, advanced, and severe cases, respectively. sMICA was detected at 36.8±19.6, 134.7±122.5, 33.6±12.4, and 83.9±40.0 international unit/milliliter, respectively. A significant association between IFN-γ and CD4 cells of normal anti-retroviral treatment response, defined by CD4 cells and viral loads, was observed using Spearman correlation, with p-values 0.033, r -0.434, 0.026 and -0.321, respectively. Conclusion: IFN-γ and sMICA were found to be associated with the CD4 count in the normal responses to antiretroviral treatment. This suggested that IFN-γ could be used as a biological marker for monitoring of immunological severity during anti-retroviral responses.

Background: AML is a leukemic disease that related to the rapidly myeloid proliferation progenitor cells are transformed and leading to stop proliferation and self-renewing. AML have many abilities to evading immune system one of them down expression of NK cells activating receptors NKG2D which is elaborate in in cooperation innate and adaptive immunities, and occupations as a "principal switch" in influential the stimulation of natural killer (NK) cells. NKG2D can binds to a various ligand molecule, which are only expressed at small concentration in usual cells but can be increase by a cellular tension response. And the realizing soluble NKG2D ligands MICA which is express by tumor cells and by binding with NKG2D lead to activated NK cells. Patients and methods: This study consists of 30 new diagnosed patients with AML and 24 out of 30 patients follow up at 14 days after treatment, 20 healthy looking persons match age and sex as control group. NKG2D detection by Flowcytometry and soluble MICA detection by ELISA. Results: The NK cells activation receptor down expression in patients of AML as well as increase releasing of soluble ligand MICA. Conclusion: The NKG2D in patients with AML down expression which may due to increase soluble ligand MICA which lead to mask NKG2D receptors. There was relationship between down expression of NKG2D besides releasing soluble ligand MICA. [ABSTRACT FROM AUTHOR]

The COVID-19 global pandemic and high mortality rates necessitate the development of diagnostic and prognostic tools, as well as expanding testing capacity. Existing methods for detecting and characterizing SARS-CoV-2 infection are typically based on viral genome detection or measuring COVID-19-specific antibody levels. Despite their value, these methods are unable to predict disease outcomes in patients. Given the critical role of innate immune cells, particularly natural killer (NK) cells, in antiviral defense, this study sought to determine the prognostic value of serum secretory MHC class I polypeptide–related sequence A (sMICA) levels as an essential ligand for the NKG2D receptor, the master regulator of NK cell development and responsiveness. Serum MICA levels were measured by ELISA assay. Sera (n = 60) from SARS-CoV-2 positive patients were collected, and disease severity was determined using clinical criteria. The patient group included 30 patients with mild disease and 30 severely ill patients, as well as 30 healthy controls. Our findings revealed that serum MICA levels were significantly higher in patients than in controls, especially in cases with severe complications (P <.0001). Higher serum MICA levels may be associated with respiratory failure in COVID-19 and may serve as a marker of clinical severity in patients infected with SARS-CoV-2, particularly when clinical manifestations are insufficient to make a confident prediction. Higher MICA levels may be associated with respiratory failure in COVID-19 infection. SMICA levels change with age, particularly for patients with severe COVID-19 disease. NKG2D ligands may have prognostic and therapeutic value for COVID-19 patients. [ABSTRACT FROM AUTHOR]

BackgroundThe aim of this study was to analyze the clinical efficacy of different thoracoscopic procedures in patients with non-small cell lung cancer and their correlation with matrix metalloproteinase-7 mRNA (MMPs-7 mRNA) and soluble major histocompatibility complex class I molecule A (sMICA), as well as their effect on T-cell subsets.MethodsA total of 100 patients with non-small cell lung cancer who received different thoracoscopic surgeries were divided into the Control group (three-port thoracoscopic surgery) and the study group (single-port thoracoscopic surgery). The two groups were evaluated to compare the perioperative indicators, MMPs-7 mRNA, sMICA expression levels, T-cell subsets, postoperative pain, complication rates, and prognostic outcomes at 1-year follow-up.ResultsThe operation time, blood loss, drainage tube placement time, incision length, and hospital stay in the study group were less than those in the control group (P < 0.05). There was no significant difference in the number of lymph node dissections between the two groups (P > 0.05). After 3 days, the expression levels of MMPs-7 mRNA and sMICA in the study group were lower than those in the control group (P < 0.05); CD4 +, CD8 +, and CD4 +/CD8 + in the study group were higher than those in the control group (P < 0.05). On days 1, 3, and 5, the visual analog score (VAS) of the study group was lower than that of the control group (P < 0.05); there was no significant difference in the complication rate between the two follow-up groups (P > 0.05), in which all patients completed the follow-up. After 1 year of follow-up, there was no significant difference in the tumor-free survival rate and overall survival rate between the two groups (P > 0.05).ConclusionCompared with three-port thoracoscopic surgery, single-port thoracoscopic surgery can improve perioperative expression, shorten hospital stay, reduce serum tumor micrometastasis levels, improve immune metastasis mechanisms and reduce pain, which is of great significance to patients with non-small cell lung cancer. It is an effective, convenient, and safe surgical option that deserves wide clinical reference.

Background/aims: The genome-wide association study has shown that MHC class I chain-related A (MICA) genetic variants were associated with hepatitis C virus (HCC) related hepatocellular carcinoma. The impact of the genetic variants and its serum levels on post-treatment cohort is elusive. Methods: MICA rs2596542 genotype and serum MICA (sMICA) levels were evaluated in 705 patients receiving antiviral therapy. Results: Fifty-eight (8·2%) patients developed HCC, with a median follow-up period of 48·2 months (range: 6–129 months). The MICA A allele was associated with a significantly increased risk of HCC development in cirrhotic non-SVR patients but not in patients of non-cirrhotic and/or with SVR. For cirrhotic non-SVR patients, high sMICA levels (HR/CI: 5·93/1·86–26.38·61, P = 0·002) and the MICA rs2596542 A allele (HR/CI: 4·37/1·52–12·07, P = 0·002) were independently associated with HCC development. The risk A allele or GG genotype with sMICA > 175 ng/mL provided the best accuracy (79%) and a negative predictive value of 100% in predicting HCC. Conclusions: Cirrhotic patients who carry MICA risk alleles and those without risk alleles but with high sMICA levels possessed the highest risk of HCC development once they failed antiviral therapy.

MICA is a stress-induced protein that, as a rule, is not expressed in healthy tissues, but appears in large amounts on the surface of cells undergoing malignant transformation. In humans, this protein can either initiate antitumor immune response, or facilitate tumor cells for their escape of destruction. After shedding from tumor cell surface, soluble MICA enters blood circulation and contributes to decreased activity of effector cells, due to inactivation of NKG2D receptor. The aim of our study was to determine differences in circulating sMICA concentrations in sera of patients with different types of malignant lymphomas, and to evaluate the impact of sMICA upon NKG2D-positive cytotoxic lymphocytes. In experimental models with C1R-MICA cells, the MICA shedding was shown to occur from the surface of cultured tumor cells into the extracellular space. A reduced NKG2D expression dependent on sMICA concentration in the culture medium was demonstrated by flow cytometry in peripheral mononuclear cells, thus suggesting a role of serum sMICA in suppression of antitumor immune response. The sMICA detection was performed in patients with various types of B- or T-cell non-Hodgkin’s lymphomas by means of enzyme-linked immunosorbent assay. The groups of patients with increased sMICA content were identified and compared with the control group. Minimal amounts of serum sMICA were registered in the control group, with the median of 20 pg/ml. In a combined group of patients with various B-cell lymphomas, an increase in circulating sMICA amounts was shown, at the levels of more than 6.5 times exceeding the control values. The highest values of sMICA were recorded among the patients with chronic lymphocytic leukemia, diffuse large cell lymphoma, and multiple myeloma. Maximal sMICA levels among the investigated groups of patients were observed in the group of patients with T-cell anaplastic lymphoma (median of 574 pg/ml). The study provides preliminary evidence for a suppressive effect of different (immuno)chemotherapy components, in particular, rituximab and radiation therapy, upon serum sMICA contents in the lymphoma patients. Thus, elevated serum sMICA levels in patients with hematological malignancies may be considered as an additional criterion for application of the antitumor therapy. sMICA monitoring at different stages of cytostatic treatment may be useful in order to evaluate its efficiency.

Jiong Chen,1,2,* Hong Xu,1,2,* Xing-Xing Zhu1,21Department of General Surgery, Affiliated Provincial Hospital, Anhui Medical University, 2Anhui Province Key Laboratory of Hepatopancreatobiliary Surgery, Hefei, People’s Republic of China*These authors contributed equally to this workAbstract: Soluble major histocompatibility complex class I-related chain A molecules (sMICA) and natural-killer group 2 member D (NKG2D) not only correlate with tumorigenesis and progression, but also with tumor invasion and metastasis. In this study, we used immunohistochemistry to investigate the correlation and prognostic significance of the differential expression of sMICA and NKG2D in pancreatic carcinoma and paracarcinoma tissues from 70 patients with pancreatic carcinomas. The results showed that sMICA expression was significantly (P

Background and Aim: Major histocompatibility complex class I chain‐related A (MICA) genetic variants and their serum levels (sMICA) were associated with the development of hepatitis C virus‐related hepatocellular carcinoma (HCC) in untreated cohorts. The dynamic changes in serial sMICA levels and their association with HCC in the post‐curative status are elusive. Methods: Single nucleotide polymorphism rs2596542 of MICA and serial sMICA levels were analyzed in chronic hepatitis C patients with a sustained virologic response after antivirals. Forty‐two patients who developed HCC and 84 age‐matched, gender‐matched, and cirrhosis propensity score‐matched non‐HCC controls were compared. Serial sMICA levels were measured within 6 months before treatment initiation (pre‐sMICA), 6 months after the end of treatment (post‐sMICA), and on the last visit before the development (or not) of HCC (last‐sMICA). Results: Cox regression analysis revealed that last‐sMICA was the only predictive factor of HCC development (hazard ratio/95% confidence interval: 2.27 (per 1 log pg/mL increase)/1.672–3.082, P < 0.001). Patients without HCC development showed a significantly reduced trend of sMICA levels during follow‐up (trend P = 0.001), which was observed only in GG genotype (trend P < 0.001) but not A allele carriers (P = 0.88). In contrast, patients with HCC showed an increased trend of sMICA levels (trend P = 0.024). However, only the GG genotype "high expressors" (trend P = 0.06) but not A allele carriers (P = 0.18) showed a correlation of substantially increased trend of sMICA levels and HCC development. Conclusions: Serial sMICA levels were associated with HCC development in SVR patients. The clinical utility of this finding is restricted to MICA rs2596542 GG genotype carriers. [ABSTRACT FROM AUTHOR]

Highlights • MICA-129 val/val genotype may influence sMICA expression. • The deficiency in heterozygotes found may be due LD of MICA and HLA alleles. • There was no difference between MICA- 129 Met/Val genotypes between samples. Abstract The aim of this case- control study was to investigate the association between preterm birth (PTB), MICA- 129 A/G dimorphism and sMICA levels. Fifty pregnant women with singleton pregnancy and previous PTB, or clinic diagnostic of threatened preterm labor in the actual pregnancy, or cervical length less than 25 mm and 50 healthy pregnant women were enrolled. DNA was extracted for genotyping for MICA -129 A/G by real-time PCR and sMICA plasma level was quantified by sandwich ELISA assay. Clinical and socioeconomic characteristics, results of TaqMan® genotyping and ELISA quantification were compared between the groups using qui-square, Fisher´s exact or Mann-Whitney test. A binary logistic regression model was used to predict PTB. The correlation between MICA -129 A/G genotypes and sMICA levels was investigated. There were not statistically significant differences between MICA -129 A/G polymorphism and sMICA plasma level.There was found a correlation between MICA -129 val/val genotype and higher levels of sMICA (ρ: -0.342; p:0.001). The presence of MICA -129 val/val genotype may be influencing sMICA expression. [ABSTRACT FROM AUTHOR]

Abstract: Introduction: Rheumatoid arthritis (RA) is a clinically heterogeneous chronic inflammatory disorder characterized by synovitis leading to joint destruction. Both genetic and environmental factors are involved in the pathogenesis of RA. Significant dysregulation of NKG2D, an activating receptor of natural killer and certain autoreactive T cells as well as its ligand major histocompatibility complex class I chain–related gene A (MICA) has been implicated in perpetuating the pathology of RA. Since the genetic polymorphism in MICA gene (MICA‐129 met/val polymorphism at codon 129) is known to affect its binding affinity to NKG2D, we explored its influence on RA susceptibility and disease severity. Methods: The MICA‐129 met/val polymorphism was examined in 270 patients with RA and 232 healthy controls by TaqMan 5′‐nuclease assay. Serum soluble MICA (sMICA) was measured in a subset of 89 patients and 80 controls by enzyme‐linked immunosorbent assay. Results: We observed that the frequency of MICA‐129 val allele (73% vs. 65%, Pc = 0.006, odds ratio = 1.48, 95% CI = 1.12–1.95) was higher in patients than in controls. sMICA levels were significantly higher in patients with RA than in controls (P < 0.0001). sMICA levels were higher in patients with val/val genotype than in those with met/val or met/met genotype (P = 0.03). The MICA‐129 val/val genotype was associated with high titers of sMICA in patients with deforming RA phenotype (P = 0.02), suggesting a role in determination of severity of RA. Conclusion: MICA‐129 val/val genotype, associated with higher levels of circulating sMICA, may influence disease susceptibility and associate with increased severity of RA in south Indian Tamils. [ABSTRACT FROM AUTHOR]

Metastatic melanoma is a rapidly spreading cancer whose prognosis remains poor although important therapy advances in recent years. Ipilimumab, an anti-CTLA-4 immunotherapy used in advanced melanoma, is an effective immunotherapy alone or combined with other agents but with few predictive biomarkers of response. Here, we sought to analyze the potential of S100B, MIA, soluble MICA, anti-MICA antibodies and LDH as serum biomarkers of response and survival in a cohort of 77 advanced melanoma patients subjected to ipilimumab. Lower levels of S100B, and LDH at baseline and at weeks 3 and 6 correlated to a better response and survival. After multivariate analysis LDH maintained its independence at baseline and week 6, whereas S100B might be a useful tool for anti-CTLA-4 treatment monitoring after the first two doses of ipilimumab (W6). In addition, higher sMICA serum levels at baseline were associated with less frequency of irAEs. [ABSTRACT FROM AUTHOR]

Breast cancer is the most common cancer in women worldwide. In this study, we correlated the serum level of major histocompatibility complex class I-related chain A (sMICA) with expression and presentation of NKG2D receptors on NK cells among patients with breast cancer. Peripheral blood (PB) samples were collected from 49 healthy and 49 breast cancer patients before surgery and chemotherapy. The expression and presentation of NKG2D were assessed using qRT-PCR and flow cytometry, respectively. Furthermore, sMICA levels were determined using ELISA. In flow cytometry, whole blood samples were stained with anti-CD56/NKG2D/CD3 and the obtained results were analyzed using WinMDI software. In addition, SPSS software was used for statistical analysis of data. Significantly higher levels sMICA were detected in the sera of the majority of cancer patients in contrast to healthy volunteers ( P < 0.001). The expression and presentation of NKG2D receptor were significantly lower than those in healthy persons, and with an inverse correlation to sMICA and positively correlated with tumor stage. Our study showed that sMICA may have an important role in diminishing the expression and presentation of NKG2D receptor in breast cancer patients and proposes the notion that sMICA can be a target candidate for treatment of breast cancer. [ABSTRACT FROM AUTHOR]

The aim of this study was to examine the expression levels of NF-κB, MMP-9, and MICA and their relationship between each other in pituitary adenomas as a histological basis for the study of the expression and shedding mechanism of MICA and mechanism of immune escape of pituitary adenomas. Our study indicated that MICA, MMP-9 and NF-κB mRNA and protein levels were more highly expressed in pituitary adenomas than healthy tissues. The expression levels of NF-κB, MMP-9, and MICA were positively related in patients with pituitary adenomas. In conclusion, the activation of NF-κB can up-regulate the expression of MICA and induce the expression of MMP-9, which hydrolyzes MICA into sMICA to promote tumor immune escape. The interactions of NF-κB, MMP-9, and MICA play an important role in the development of pituitary adenomas, and MMP-9 could be used as a new target for inhibiting tumor cell immune escape. [ABSTRACT FROM AUTHOR]

Abstract: This study analyses aspects of the immune system in prolactinoma and non-secreting pituitary adenoma. Serum soluble major histocompatibility complex class I-related chain A protein (sMICA) concentrations were measured by enzyme-linked immunosorbent assay. NKG2D-expressing natural killer and T cells were analyzed by flow cytometry. A correlation analysis was also performed to associate sMICA levels with NKG2D expression. The expression of MICA was examined in specific tissues by use of the reverse transcription-polymerase chain reaction. A significant amount of sMICA was detected in the serum of nearly all patients. We found decreased percentage and mean fluorescence intensity of NKG2D-expressing natural killer and T cells from patients with prolactinoma and non-secreting pituitary adenoma compared to those from healthy donors. Pearson analysis showed a negative correlation between sMICA and NKG2D-expressing cells. The immune-escape of pituitary adenoma is related to the down-regulation of NKG2D and the up-regulation of its ligand MICA. [Copyright &y& Elsevier]

Ataxia-telangiectasia (A-T) is a multisystem disorder caused by biallelic pathogenic variants in the gene encoding A-T mutated (ATM) kinase, a master regulator of the DNA damage response (DDR) pathway. Most A-T patients show cellular and/or humoral immunodeficiency that has been associated with cancer risk and reduced survival, but NK cells have not been thoroughly studied. Here we investigated NK cells of A-T patients with a special focus on the NKG2D receptor that triggers cytotoxicity upon engagement by its ligands (NKG2DLs) commonly induced via the DDR pathway on infected, transformed, and variously stressed cells. Using flow cytometry, we examined the phenotype and function of NK cells in 6 A-T patients as compared with healthy individuals. NKG2D expression was evaluated also by western blotting and RT-qPCR; plasma soluble NKG2DLs (sMICA, sMICB, sULBP1, ULBP2) were measured by ELISA. Results showed that A-T NK cells were skewed towards the CD56neg anergic phenotype and displayed decreased expression of NKG2D and perforin. NKG2D was reduced at the protein but not at the mRNA level and resulted in impaired NKG2D-mediated cytotoxicity in 4/6 A-T patients. Moreover, in A-T plasma we found 24-fold and 2-fold increase of sMICA and sULBP1, respectively, both inversely correlated with NKG2D expression. Overall, NK cells are disturbed in A-T patients showing reduced NKG2D expression, possibly caused by persistent engagement of its ligands, that may contribute to susceptibility to cancer and infections and represent novel targets for therapeutic interventions. • The CD56neg NK-cell subset was expanded in A-T patients. • NK cells of A-T patients showed reduced NKG2D and perforin expression. • NKG2D down-regulation in A-T NK cells occurred post-transcriptionally. • Increased sMICA and sULBP1 levels in A-T plasma were inversely correlated with NKG2D+ NK cells. • NKG2D-mediated NK cell activation was impaired in 4/6 A-T patients. [ABSTRACT FROM AUTHOR]

The polymorphic major histocompatibility complex class I chain-related molecule A (MICA) and its soluble form (sMICA) interact with activating receptor natural-killer group 2 member D (NKG2D) on natural-killer (NK) and T cells, thereby modifying immune responses to transplantation and infectious agents (e.g., cytomegalovirus). Two single-nucleotide polymorphisms (SNPs), rs2596538GA in the MICA promoter and rs1051792AG in the coding region (MICA-129Val/Met), influence MICA expression or binding to NKG2D, with MICA-129Met molecules showing higher receptor affinity. To investigate the impact of these SNPs on the occurrence of cytomegalovirus infection or acute rejection (AR) in individuals who underwent simultaneous pancreas–kidney transplantation (SPKT), 50 recipient-donor pairs were genotyped, and sMICA levels were measured during the first year post-transplantation. Recipients with a Val-mismatch (recipient Met/Met and donor Val/Met or Val/Val) showed shorter cytomegalovirus infection-free and shorter kidney AR-free survival. Additionally, Val mismatch was an independent predictor of cytomegalovirus infection and kidney AR in the first year post-transplantation. Interestingly, sMICA levels were lower in rs2596538AA and MICA129Met/Met-homozygous recipients. These results provide further evidence that genetic variants of MICA influence sMICA levels, and that Val mismatch at position 129 increases cytomegalovirus infection and kidney AR risk during the first year post-SPKT. [ABSTRACT FROM AUTHOR]

Background/aims: Genetic variants of MHC class I polypeptide-related chain A (MICA) at rs2596542 have been associated with hepatocellular carcinoma. The linkage between serum MICA (sMICA) and liver fibrosis in chronic hepatitis C is elusive., Results: Linear regression analysis revealed that sMICA were independently correlated to α-fetoprotein (β: 0.149; 95% confidence interval [CI]: 0.001, 0.003; P = 0.007)and MICA rs2596542 GG genotype (β: 0.209; 95% CI: 0.153, 0.483; P < 0.001). While patients were stratified by MICA genetic variants, advanced fibrosis was the only factor independently correlated to sMICA among A allele carriers (β: 0.234; 95% CI: 0.107, 0.543; P = 0.004) but not among non-A allele carriers. Logistic regression analysis revealed that factors associated with advanced liver fibrosis was sMICA (OR/CI: 2.996/1.428-6.287, P = 0.004) and platelet counts (OR/CI: 0.988/0.982-0.994, P < 0.001) in MICA rs2596542 A allele carriers. sMICA > 50 pg/mL provided a positive predictive value of 72 % in predicting advanced liver fibrosis (F3-4) and of 90% in significant fibrosis (> F2) in MICA rs2596542 A allele carriers., Materials and Methods: Serum level and single nucleotide polymorphism at rs2596542 of MICA were tested for the association with liver fibrosis in 319 biopsy proven chronic hepatitis C patients., Conclusions: Levels of sMICA were highly correlated to liver disease severity in chronic hepatitis C patients who carried the MICA rs738409 A allele. Patients possessing the genetic predisposition had a higher likelihood of progressed liver fibrosis if they expressed higher sMICA levels.

Dysfunction of natural killer (NK) cells has been implicated in the failure of antitumor immune responses in hepatocellular carcinoma (HCC) patients. However, the changes of NK profile in peripheral blood after surgery and tumor tissues of HCC patients, as well as the underlying reason and the significance are vague. Here, we observed that the frequencies of circulating NKG2D+CD56dimNK cells decreased significantly in HBV-related HCC and were negatively correlated with the levels of serum TGF-β and soluble MICA (sMICA).In vitroexperiments confirmed that the TGF-β and sMICA in tumor tissue homogenates, as well as sMICA in HCC cells culture supernatants could reduce the frequency of NKG2D+CD56dimNK cells. In addition, in HCC patients the lower frequency of circulating NKG2D+CD56dimNK cells was associated with larger tumor size and/or higher serum GGT. Noticeably, the frequency of NKG2D+CD56dimNK cells at one month after surgery usually failed to restore in early recurrent patients, and that frequency was negatively associated with early recurrence and shorter overall survival. These results suggest that declined frequency of NKG2D+CD56dimNK cells in HCC was associated with higher TGF-β and sMICA production, and low frequency of circulating NKG2D+CD56dimNK cells at one month after surgery may predict poor prognosis of HBV-related HCC patients accepting hepatectomy. [ABSTRACT FROM PUBLISHER]

Breast cancer is the most common cancer in women worldwide. In this study, we correlated the serum level of major histocompatibility complex class I-related chain A (sMICA) with expression and presentation of NKG2D receptors on NK cells among patients with breast cancer. Peripheral blood (PB) samples were collected from 49 healthy and 49 breast cancer patients before surgery and chemotherapy. The expression and presentation of NKG2D were assessed using qRT-PCR and flow cytometry, respectively. Furthermore, sMICA levels were determined using ELISA. In flow cytometry, whole blood samples were stained with anti-CD56/NKG2D/CD3 and the obtained results were analyzed using WinMDI software. In addition, SPSS software was used for statistical analysis of data. Significantly higher levels sMICA were detected in the sera of the majority of cancer patients in contrast to healthy volunteers (P < 0.001). The expression and presentation of NKG2D receptor were significantly lower than those in healthy persons, and with an inverse correlation to sMICA and positively correlated with tumor stage. Our study showed that sMICA may have an important role in diminishing the expression and presentation of NKG2D receptor in breast cancer patients and proposes the notion that sMICA can be a target candidate for treatment of breast cancer.

Background and Objective: Human major histocompatibility complex class I-related gene A (MICA) is reportedly associated with poor transplant outcomes and a high risk of acute and chronic rejection in solid organ transplantation. However, studies on these risks have found conflicting results. In the present study, we investigate the MICA expression and serum MICA (sMICA) as well as the MICA antibodies (anti-MICA) in serum of recipients during acute rejection (AR) in a rat-to-mouse cardiac transplantation model., Methods: Construct rat-to-mouse concordant cardiac transplantation models, histological examination of the heart in recipients during AR at 2-6 hours time point was done. We then studied the MICA gene expression of the heart in recipients during AR at 2-6 hours time point by western blot and RT-PCR assay. We latter studied the anti-MICA and sMICA levels in serum of recipients during AR at 2-6 hours time point by Flow cytometry and ELISA measurement., Results: We found that Lewis rat hearts transplanted into BALB/c mice developed typical AR in 6 days. The level of severity of xenograft rejection from 2 d to 6 d was increased in a time-dependant way. MICA protein and MICA mRNA was also increased in time-dependant way and reached the highest value at 6 h. The prevalence of anti-MICA was significantly higher among those with severe acute rejection. However, sMICA was significantly increased during AR at 2 hours, then gradually decreased, and reached the lowest value at 6 h., Conclusions: MICA expression in recipients' heart and anti-MICA antibodies in recipients' sera may associated with high risk of AR in rat-to-mouse transplantation. sMICA showed a negative association with acute rejection and may be a good predictor of heart transplant outcomes.

A soluble isoform of MHC class I chain-related molecule A (soluble MICA), generated by proteolytic shedding from the membrane-bound MICA of various tumor cells, has been shown to downregulate both the expression of natural killer group 2-member D receptor and the cytotoxic function of effectors cells and was postulated as a mechanism for tumor immune evasion. Its effect on the expression of cytokines by the effector cells remained unexplored. Here we demonstrate that the sMICA molecules upregulate interferon gamma expression by interleukin-12/interleukin-18-activated CD3(-)CD56(+) natural killer cells, witnessing the pro-inflammatory effect of soluble MICA. Overall, these data are in line with our previous observations that the raised serum levels of soluble MICA, following allogeneic hematopoietic stem cell transplantation, confer susceptibility to and the presence of pre-transplantation anti-MICA antibodies in the patient's serum confer protection against chronic graft versus host disease., (Copyright © 2013. Published by Elsevier Inc.)