MICA与感染性疾病、肝硬化、肝癌的相关性研究
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摘要
目的：
①研究湖南地区汉族人群感染性疾病和恶性肿瘤患者血清中sMICA的含量及其诊断价值。
②研究MICA基因多态性、sMICA分子与HBsAg阳性肝硬化、肝癌和HBsAg阳性肝癌的相关性。
方法：
①采用ELISA方法检测546例感染性疾病患者、495例恶性肿瘤患者和141例健康人群对照血清中sMICA分子的含量,分析sMICA分子在不同疾病中的含量变化及其与相应疾病的相关性。
②采用PCR-STR微卫星基因分型技术检测101例HBsAg阳性肝硬化患者和141例健康人群对照MICA基因第5外显子的基因多态性,并分析其相关性。
③采用PCR-STR微卫星基因分型技术检测141例肝癌患者和141例健康人群对照MICA基因第5外显子基因多态性,并分析其相关性。
④采用PCR-STR微卫星基因分型技术检测101例HBsAg阳性肝硬化患者和116例HBsAg阳性肝癌患者MICA基因第5外显子基因多态性,并分析其相关性。结果：①细菌、结核杆菌、梅毒螺旋体、HBV、HCV、EBV、HSV、 CMV和COX-V感染患者血清中sMICA分子的含量增高。革兰氏阳性球菌、结核杆菌、肠杆菌、HCV和HBV感染患者血清中,sMICA分子的含量分别为(542.3±382.9) pg/ml、(493.9±256.4) pg/ml、(492.2±295.9) pg/ml、(474.9±123.1) pg/ml和472.4±103.6pg/ml；其他病毒组较低,为(251.2±256.3)pg/ml。血清中的sMICA分子可应用于革兰氏阴性杆菌(AUC=0.742)、结核杆菌(AUC=0.766)、乙型肝炎病毒(AUC=0.712)、梅毒螺旋体(AUC=0.707)和丙型肝炎病毒(AUC=0.701)的辅助诊断。
②不同恶性肿瘤中,肝癌患者血清中的sMICA分子含量最高,为(743.4±110.8)pg/ml；胃癌次之,为(264.4±524.8)pg/ml；女性生殖系统肿瘤和恶性淋巴瘤含量较低,分别为(162.5±116.1)pg/ml和(140.9±137.6)pg/ml。肝癌患者血清中sMICA分子的含量具有辅助诊断价值(AUC=0.843)。
③在101例湖南汉族HBsAg阳性肝硬化患者中检测到5种MICA基因第5外显子等位基因,频率分别为：MICA*A4(10.9%), MICA*A5(37.1%), MICA*A5.1(34.2%), MICA*A6(7.4%), MICA*A9(10.4%)。MICA*A5.1基因与肝硬化发病相关,P=0.042,OR=1.398。
④MICA*A5.1纯合子肝硬化患者血清中的sMICA分子含量较高,达(596.6±163.3) pg/ml, MICA*5.1杂合子患者血清中的sMICA分子含量为(549.1±101.1)pg/ml,非MICA*A5.1患者血清中的sMICA分子含量为(364.4±132.7) pg/ml。
⑤在141例湖南汉族肝癌患者中共发现5种MICA基因第5外显子等位基因,频率分别为：MICA*A4(11.7%), MICA*A5(34.0%), MICA*A5.1(35.1%), MICA*A6(8.2%), MICA*A9(11.0%)。 MICA*A5.1基因与肝癌发病相关,P=0.036,OR=1.466。
㎝ICA*A5.1纯合子肝癌患者血清中的sMICA分子含量较高,达(1284±295)pg/ml,MICA*A5.1杂合子患者血清中的sMICA分子含量为(981.4±252.5)pg/ml,非MICA*A5.1患者血清中的sMICA分子含量为(467.6±48.5)pg/ml.
⑦在HBsAg阳性肝硬化和HBsAg阳性肝癌患者中MICA基因多态性呈一致性分布。sMICA分子在HBsAg阳性肝硬化和HBsAg阳性肝癌含MICA*A5.1纯合子患者血液中的含量分别为(596.6±163.3)pg/ml和(983.3±266.6)pg/ml,MICA*A5.1杂合子患者血液中的含量分别为(549.1土101.1)pg/ml和(813.6士212.3)pg/ml。而非A5.1基因患者的含量分别为(529.1士186.2)pg/ml和(364.4±132.7)pg/ml。
结论：
①肝癌、HBV、HCV、结核杆菌和梅毒螺旋体感染后,可能通过某种机制导致血清中的sMICA分子显著性增加；血清中的sMICA分子含量对肝癌、革兰氏阴性杆菌、结核杆菌、乙型肝炎病毒、梅毒螺旋体和丙型肝炎病毒感染具有一定的辅助诊断价值。
②MICA*A5.1基因与乙肝后肝硬化发病正相关,提示该基因可能是乙肝后出现肝硬化的重要易感基因。与非MICA*A5.1组肝硬化患者相比较,含MICA*A5.1基因的肝硬化患者血清中sMICA分子的含量明显增高,提示MICA*A5.1基因与血清sMICA分子的升高有定联系。
③MICA*A5.1基因与肝癌存在正相关,提示该基因可能是肝癌的重要易感基因。同非MICA*A5.1组肝癌患者相比较,含MICA*A5.1基因的肝癌患者血清中sMICA分子浓度明显增高,提示MICA*A5.1基因与血清sMICA分子的升高有一定联系。
④MICA基因第5外显子基因多态性在肝癌组和肝硬化组的分布一致,而在两组患者中均发现sMICA分子含量在MICA*A5.1纯合子组和MICA*A5.1杂合子组之间存在显著性差异,提示MICA*A5.1基因和血清sMICA分子含量与肝硬化向肝癌的发展相关。
Objective:
①To study the distribution and the diagnosis value of sMICA in infectious diseases and malignant tumor in Han population in Hunan Province.
②To study MICA gene polymorphism and the expression levels of sMICA in HBsAg positive cirrhosis, HBsAg positive and other types of liver cancer.
Methods:
①ELISA was used to detect the serum levels of sMICA in495patients with malignant tumor,546patients with infectious diseases and141normal controls. The correlation between the serum levels sMICA and different deseases was then analyzed.
②PCR-STR microsatellite genotyping was used to characterize the polymorphism of MICA in exon5in101patients with HBsAg positive Cirrhosis and141normal controls, and the relevance index between them was calculated.
③PCR-STR microsatellite genotyping was used to detect the polymorphism of MICA in Exon5in141cases of liver cancer and141cases of normal controls, and the relevance index between them was calculated.
④PCR-STR microsatellite genotyping was used to detect the polymorphism of MICA in Exon5in101cases of HBsAg positive Cirrhosis and116cases of HBsAg positive liver cancer, and the relevance index between them was calculated.
Results:
①The serum levels of sMICA of patients by bacteria, tuberculosis, syphilis helicoid, HBV, HCV, EBV, HSV, CMV and COX-V infection could increase. From high to low levels of s-MICA were found in patients with gram-positive aureus(542.3±382.9pg/ml), tubercle bacillus (493.9±256.4pg/ml), enterobacter (492.2±295.9pg/ml), HCV (474.9±123.1pg/ml) and HBV (472.4±103.6pg/ml), respectively. The lowest serum levels of s-MICA (251.2±256.3pg/ml) was found in the patients with EBV, HSV, CMV, or COX-V infections. The serum levels of sMICA could be employed to diagnose diseases infected by gram-negative bacilli (AUC=0.742), tubercle bacili (AUC=0.766), hepatitis bvirus (AUC=0.712), syphilis helicoid (AUC=0.707) and hepatitis cvirus (AUC=0.701).
②Among the patients with different types of malignant cancers, patients with liver cancer had the highest levels of sMICA (743.4±110.8pg/ml), and patients with gastric cancer had the second highest levels of sMICA (264.4±524.8pg/ml).In comparision, the serum levels of sMICA were relatively lower in patients with female reproductive system tumors and malignant lymphoma (140.9±137.6pg/ml and162.5±116.1pg/ml). The serum levels of sMICA in liver cancer patients exhibited diagnostic value (AUC=0.843).
③5allelic genes and their frequencies were identified in MICA Exon5and showed as below:MICA*A4(10.9%), MICA*A5(37.1%), MICA*A5.1(34.1%), MICA*A6(7.4%), MICA*A9(10.4%). Only MICA*A5.1is positively associated with liver cirrhosis onset.
④The serum levels of soluble MICA in the MICA*A5.1homozygous patients were the highest, up to596.6±163.3pg/ml. While the serum levels of soluble MICA in MICA*5.1heterozygous patients and patients without MICA*A5.1polymorphism were (549.1±101.1) pg/ml and (364.4±132.7)pg/ml, respectively.
(5)5allelic genes were also identified in MICA Exon5in141patients with liver cancer in Hunan province. The alleles and their frequencies were MICA*A4(11.7%), MICA*A5(34.0%), MICA*A5.1(35.1%), MICA*A6(8.2%) and MICA*A9(11.0%), respectively. MICA*A5.1is positively associated with liver cancer incidence.
⑥The soluble MICA levels appeared to be the highest in the serum of MICA*A5.1homozygous patients with liver cancer, up to (1284±295) pg/ml, compared to (981.4±252.5) pg/ml in MICA*A5.1heterozygote patients and (467.6±48.5)pg/ml in patients without MICA*A5.1.
⑦MICA gene polymorphism was uniformly distributed in patients with HbsAg positive Cirrhosis and patients with HbsAg positive HCC. The sMICA level in the blood of MICA*A5.1homozygous patients with HbsAg positive Cirrhosis was (596.6±163.3)pg/ml, and was (983.3±266.6) pg/ml in those patients with HbsAg positive HCC, where was (549.1±101.1)pg/ml in the blood of A5.1heterozygote patients with HbsAg positive Cirrhosis and (813.6±212.3)pg/ml in the blood of A5.1heterozygote patients with HbsAg positive HCC. It appeared the lowest in the patients without A5.1genes, respectively529.1±186.2pg/ml in those with HbsAg positive Cirrhosis and (364.4±132.7)pg/ml in those with HbsAg positive HCC.
Conclusion:
①Infection of liver cancer, HBV, HCV, tuberculosis bacili and syphilis helicoid may cause significant increase of sMICA molecular in the serum of patients through some kind of mechanism; sMICA has some auxiliary diagnostic value in treating liver cancer, gram-negative bacilli, tuberculosis bacili, Hepatitis B virus, syphilis helicoid and Hepatitis C vims infection.
②MICA*A5.1gene may be an important susceptibility gene leading to liver cirrhosis after infected with hepatitis B according to the positive correlation between MICA Exon5alleles A5.1and hepatitis b induced liver cirrhosis. Compared with the liver cirrhosis patients without MICA*A5.1, those with MICA*A5.1genes have a significantly higher serum levels of sMICA, indicating MICA*A5.1alleles take certain advantages in the production of serum sMICA molecules.
③MICA Exon5alleles A5.1is positively correlated with liver cancer. Compared with liver cancer patients without MICA*A5.1, HCC patients with MICA*A5.1gene have significantly higher concentration of serum soluble MICA, indicating that the serum level of sMICA molecules is associated with the progress of liver cancer.
④MICA Exon5gene polymorphism is uniformly distributed in liver cancer patients group and liver cirrhosis patients group. In both groups, levels of sMICA molecules in MICA*A5.1homozygous patients appeared to be greatly different from that in MICA*A5.1heterozygous patients. From the above results, it can be considered that serum sMICA molecular content is related to the progress of liver cirrhosis directing to liver cancer, and this is the function reflect of MICA Exon5alleles A5.1in protein levels.
①研究湖南地区汉族人群感染性疾病和恶性肿瘤患者血清中sMICA的含量及其诊断价值。
②研究MICA基因多态性、sMICA分子与HBsAg阳性肝硬化、肝癌和HBsAg阳性肝癌的相关性。
方法：
①采用ELISA方法检测546例感染性疾病患者、495例恶性肿瘤患者和141例健康人群对照血清中sMICA分子的含量,分析sMICA分子在不同疾病中的含量变化及其与相应疾病的相关性。
②采用PCR-STR微卫星基因分型技术检测101例HBsAg阳性肝硬化患者和141例健康人群对照MICA基因第5外显子的基因多态性,并分析其相关性。
③采用PCR-STR微卫星基因分型技术检测141例肝癌患者和141例健康人群对照MICA基因第5外显子基因多态性,并分析其相关性。
④采用PCR-STR微卫星基因分型技术检测101例HBsAg阳性肝硬化患者和116例HBsAg阳性肝癌患者MICA基因第5外显子基因多态性,并分析其相关性。结果：①细菌、结核杆菌、梅毒螺旋体、HBV、HCV、EBV、HSV、 CMV和COX-V感染患者血清中sMICA分子的含量增高。革兰氏阳性球菌、结核杆菌、肠杆菌、HCV和HBV感染患者血清中,sMICA分子的含量分别为(542.3±382.9) pg/ml、(493.9±256.4) pg/ml、(492.2±295.9) pg/ml、(474.9±123.1) pg/ml和472.4±103.6pg/ml；其他病毒组较低,为(251.2±256.3)pg/ml。血清中的sMICA分子可应用于革兰氏阴性杆菌(AUC=0.742)、结核杆菌(AUC=0.766)、乙型肝炎病毒(AUC=0.712)、梅毒螺旋体(AUC=0.707)和丙型肝炎病毒(AUC=0.701)的辅助诊断。
②不同恶性肿瘤中,肝癌患者血清中的sMICA分子含量最高,为(743.4±110.8)pg/ml；胃癌次之,为(264.4±524.8)pg/ml；女性生殖系统肿瘤和恶性淋巴瘤含量较低,分别为(162.5±116.1)pg/ml和(140.9±137.6)pg/ml。肝癌患者血清中sMICA分子的含量具有辅助诊断价值(AUC=0.843)。
③在101例湖南汉族HBsAg阳性肝硬化患者中检测到5种MICA基因第5外显子等位基因,频率分别为：MICA*A4(10.9%), MICA*A5(37.1%), MICA*A5.1(34.2%), MICA*A6(7.4%), MICA*A9(10.4%)。MICA*A5.1基因与肝硬化发病相关,P=0.042,OR=1.398。
④MICA*A5.1纯合子肝硬化患者血清中的sMICA分子含量较高,达(596.6±163.3) pg/ml, MICA*5.1杂合子患者血清中的sMICA分子含量为(549.1±101.1)pg/ml,非MICA*A5.1患者血清中的sMICA分子含量为(364.4±132.7) pg/ml。
⑤在141例湖南汉族肝癌患者中共发现5种MICA基因第5外显子等位基因,频率分别为：MICA*A4(11.7%), MICA*A5(34.0%), MICA*A5.1(35.1%), MICA*A6(8.2%), MICA*A9(11.0%)。 MICA*A5.1基因与肝癌发病相关,P=0.036,OR=1.466。
㎝ICA*A5.1纯合子肝癌患者血清中的sMICA分子含量较高,达(1284±295)pg/ml,MICA*A5.1杂合子患者血清中的sMICA分子含量为(981.4±252.5)pg/ml,非MICA*A5.1患者血清中的sMICA分子含量为(467.6±48.5)pg/ml.
⑦在HBsAg阳性肝硬化和HBsAg阳性肝癌患者中MICA基因多态性呈一致性分布。sMICA分子在HBsAg阳性肝硬化和HBsAg阳性肝癌含MICA*A5.1纯合子患者血液中的含量分别为(596.6±163.3)pg/ml和(983.3±266.6)pg/ml,MICA*A5.1杂合子患者血液中的含量分别为(549.1土101.1)pg/ml和(813.6士212.3)pg/ml。而非A5.1基因患者的含量分别为(529.1士186.2)pg/ml和(364.4±132.7)pg/ml。
结论：
①肝癌、HBV、HCV、结核杆菌和梅毒螺旋体感染后,可能通过某种机制导致血清中的sMICA分子显著性增加；血清中的sMICA分子含量对肝癌、革兰氏阴性杆菌、结核杆菌、乙型肝炎病毒、梅毒螺旋体和丙型肝炎病毒感染具有一定的辅助诊断价值。
②MICA*A5.1基因与乙肝后肝硬化发病正相关,提示该基因可能是乙肝后出现肝硬化的重要易感基因。与非MICA*A5.1组肝硬化患者相比较,含MICA*A5.1基因的肝硬化患者血清中sMICA分子的含量明显增高,提示MICA*A5.1基因与血清sMICA分子的升高有定联系。
③MICA*A5.1基因与肝癌存在正相关,提示该基因可能是肝癌的重要易感基因。同非MICA*A5.1组肝癌患者相比较,含MICA*A5.1基因的肝癌患者血清中sMICA分子浓度明显增高,提示MICA*A5.1基因与血清sMICA分子的升高有一定联系。
④MICA基因第5外显子基因多态性在肝癌组和肝硬化组的分布一致,而在两组患者中均发现sMICA分子含量在MICA*A5.1纯合子组和MICA*A5.1杂合子组之间存在显著性差异,提示MICA*A5.1基因和血清sMICA分子含量与肝硬化向肝癌的发展相关。
Objective:
①To study the distribution and the diagnosis value of sMICA in infectious diseases and malignant tumor in Han population in Hunan Province.
②To study MICA gene polymorphism and the expression levels of sMICA in HBsAg positive cirrhosis, HBsAg positive and other types of liver cancer.
Methods:
①ELISA was used to detect the serum levels of sMICA in495patients with malignant tumor,546patients with infectious diseases and141normal controls. The correlation between the serum levels sMICA and different deseases was then analyzed.
②PCR-STR microsatellite genotyping was used to characterize the polymorphism of MICA in exon5in101patients with HBsAg positive Cirrhosis and141normal controls, and the relevance index between them was calculated.
③PCR-STR microsatellite genotyping was used to detect the polymorphism of MICA in Exon5in141cases of liver cancer and141cases of normal controls, and the relevance index between them was calculated.
④PCR-STR microsatellite genotyping was used to detect the polymorphism of MICA in Exon5in101cases of HBsAg positive Cirrhosis and116cases of HBsAg positive liver cancer, and the relevance index between them was calculated.
Results:
①The serum levels of sMICA of patients by bacteria, tuberculosis, syphilis helicoid, HBV, HCV, EBV, HSV, CMV and COX-V infection could increase. From high to low levels of s-MICA were found in patients with gram-positive aureus(542.3±382.9pg/ml), tubercle bacillus (493.9±256.4pg/ml), enterobacter (492.2±295.9pg/ml), HCV (474.9±123.1pg/ml) and HBV (472.4±103.6pg/ml), respectively. The lowest serum levels of s-MICA (251.2±256.3pg/ml) was found in the patients with EBV, HSV, CMV, or COX-V infections. The serum levels of sMICA could be employed to diagnose diseases infected by gram-negative bacilli (AUC=0.742), tubercle bacili (AUC=0.766), hepatitis bvirus (AUC=0.712), syphilis helicoid (AUC=0.707) and hepatitis cvirus (AUC=0.701).
②Among the patients with different types of malignant cancers, patients with liver cancer had the highest levels of sMICA (743.4±110.8pg/ml), and patients with gastric cancer had the second highest levels of sMICA (264.4±524.8pg/ml).In comparision, the serum levels of sMICA were relatively lower in patients with female reproductive system tumors and malignant lymphoma (140.9±137.6pg/ml and162.5±116.1pg/ml). The serum levels of sMICA in liver cancer patients exhibited diagnostic value (AUC=0.843).
③5allelic genes and their frequencies were identified in MICA Exon5and showed as below:MICA*A4(10.9%), MICA*A5(37.1%), MICA*A5.1(34.1%), MICA*A6(7.4%), MICA*A9(10.4%). Only MICA*A5.1is positively associated with liver cirrhosis onset.
④The serum levels of soluble MICA in the MICA*A5.1homozygous patients were the highest, up to596.6±163.3pg/ml. While the serum levels of soluble MICA in MICA*5.1heterozygous patients and patients without MICA*A5.1polymorphism were (549.1±101.1) pg/ml and (364.4±132.7)pg/ml, respectively.
(5)5allelic genes were also identified in MICA Exon5in141patients with liver cancer in Hunan province. The alleles and their frequencies were MICA*A4(11.7%), MICA*A5(34.0%), MICA*A5.1(35.1%), MICA*A6(8.2%) and MICA*A9(11.0%), respectively. MICA*A5.1is positively associated with liver cancer incidence.
⑥The soluble MICA levels appeared to be the highest in the serum of MICA*A5.1homozygous patients with liver cancer, up to (1284±295) pg/ml, compared to (981.4±252.5) pg/ml in MICA*A5.1heterozygote patients and (467.6±48.5)pg/ml in patients without MICA*A5.1.
⑦MICA gene polymorphism was uniformly distributed in patients with HbsAg positive Cirrhosis and patients with HbsAg positive HCC. The sMICA level in the blood of MICA*A5.1homozygous patients with HbsAg positive Cirrhosis was (596.6±163.3)pg/ml, and was (983.3±266.6) pg/ml in those patients with HbsAg positive HCC, where was (549.1±101.1)pg/ml in the blood of A5.1heterozygote patients with HbsAg positive Cirrhosis and (813.6±212.3)pg/ml in the blood of A5.1heterozygote patients with HbsAg positive HCC. It appeared the lowest in the patients without A5.1genes, respectively529.1±186.2pg/ml in those with HbsAg positive Cirrhosis and (364.4±132.7)pg/ml in those with HbsAg positive HCC.
Conclusion:
①Infection of liver cancer, HBV, HCV, tuberculosis bacili and syphilis helicoid may cause significant increase of sMICA molecular in the serum of patients through some kind of mechanism; sMICA has some auxiliary diagnostic value in treating liver cancer, gram-negative bacilli, tuberculosis bacili, Hepatitis B virus, syphilis helicoid and Hepatitis C vims infection.
②MICA*A5.1gene may be an important susceptibility gene leading to liver cirrhosis after infected with hepatitis B according to the positive correlation between MICA Exon5alleles A5.1and hepatitis b induced liver cirrhosis. Compared with the liver cirrhosis patients without MICA*A5.1, those with MICA*A5.1genes have a significantly higher serum levels of sMICA, indicating MICA*A5.1alleles take certain advantages in the production of serum sMICA molecules.
③MICA Exon5alleles A5.1is positively correlated with liver cancer. Compared with liver cancer patients without MICA*A5.1, HCC patients with MICA*A5.1gene have significantly higher concentration of serum soluble MICA, indicating that the serum level of sMICA molecules is associated with the progress of liver cancer.
④MICA Exon5gene polymorphism is uniformly distributed in liver cancer patients group and liver cirrhosis patients group. In both groups, levels of sMICA molecules in MICA*A5.1homozygous patients appeared to be greatly different from that in MICA*A5.1heterozygous patients. From the above results, it can be considered that serum sMICA molecular content is related to the progress of liver cirrhosis directing to liver cancer, and this is the function reflect of MICA Exon5alleles A5.1in protein levels.
引文
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