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三结构域蛋白29（TRIM29）与HBV复制及聚乙二醇干扰素α-2b抗病毒作用的关联性分析
DOI: 10.12449/JCH241111
Association of TRIM29 with HBV replication and the antiviral effect of pegylated interferon α-2b
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摘要:
目的 三结构域蛋白29（TRIM29）参与多种疾病的发生和发展，与部分DNA和RNA病毒复制密切相关，本研究对TRIM29与HBV复制及聚乙二醇干扰素（PEG-IFN）α-2b抗病毒作用之间的关系展开初步讨论。 方法 选取2021年10月—2022年6月在贵州医科大学附属医院感染内科门诊就诊的CHB患者64例，其中未治疗患者34例（CHB组），经PEG-IFN-α- 2b治疗患者30例，体检中心30例健康志愿者作为对照（健康对照组）。收集志愿者年龄、性别、ALT、AST、TBil、DBil、HBV DNA和外周血单个核细胞（PBMC）。采用HepG2和HepG2.2.15细胞作为细胞模型，将TRIM29特异性过表达质粒或siRNA和对照转染至细胞；PEG-IFN-α-2b（0、10、100、1 000和10 000 U/mL）处理HepG2细胞和Huh7细胞；TRIM29特异性si-RNA或阴性对照联合PEG-IFN-α-2b处理HepG2.2.15细胞。ELISA检测HBsAg和HBeAg的浓度，qRT-PCR检测TRIM29和HBV RNA相对表达水平，Western Blot检测STING、p-TBK1、TBK1、pIRF3、IRF3、MX1和IFIT1蛋白表达情况，免疫共沉淀检测TRIM29与STING蛋白相互作用关系。正态分布的计量资料两组间比较采用成组t检验，多组间比较采用单因素方差分析，进一步两两比较采用LSD-t检验。计数资料两组间比较采用χ2检验或Fisher检验。 结果 CHB组患者外周血TRIM29表达明显高于健康对照组（P<0.001）。在细胞实验中，HBsAg、HBeAg和HBV RNA的表达均随TRIM29表达上调而升高，随TRIM29表达下调而降低（P值均<0.05）。TRIM29与STING互相结合，并通过蛋白酶降解STING，与对照组相比，过表达TRIM29对TBK1和IRF3总蛋白无明显变化，STING、p-TBK1和p-IRF3蛋白表达水平均降低（P值均<0.05）。处理HepG2细胞和Huh7细胞的PEG-IFN-α-2b浓度越高，TRIM29蛋白和mRNA的表达水平越低（P值均<0.01）。CHB患者在PEG-IFN-α-2b治疗期间，TRIM29 mRNA表达水平逐渐降低，且早期应答组和无应答组间差异均有统计学意义（P值均<0.05）。在等量PEG-IFN-α-2b处理下，与对照相比，敲低TRIM29后HepG2.2.15细胞的MX1和IFIT1蛋白表达水平明显增高（P值均<0.05）。在PEG-IFN-α-2b治疗早期，CHB患者PBMC中TRIM29表达逐渐降低。 结论 TRIM29靶向并降解STING，通过抑制STING-TBK1-IRF3信号通路促进HBV复制。TRIM29干扰PEG-IFN-α-2b的抗病毒作用，CHB患者PBMC中TRIM29的表达水平可能作为预测患者对PEG-IFN-α-2b治疗应答的指标。 Abstract:Objective To preliminarily investigate the association of TRIM29 with HBV replication and the antiviral effect of pegylated interferon α-2b （PEG-IFN-α-2b）， since TRIM29 protein is involved in the development and progression of a variety of diseases and is closely associated with the replication of some DNA and RNA viruses. Methods A total of 64 chronic hepatitis B （CHB） patients who attended the outpatient service of Department of Infectious Diseases， The Affiliated Hospital of Guizhou Medical University， from October 2021 to June 2022 were enrolled， among whom there were 34 treatment-naïve patients and 30 patients treated with PEG-IFN-α-2b， and 30 healthy volunteers in Physical Examination Center were enrolled as controls. Related data were collected， including age， sex， alanine aminotransferase， aspartate aminotransferase， total bilirubin， direct bilirubin， HBV DNA， and peripheral blood mononuclear cells （PBMCs）. HepG2 and HepG2.2.15 cells were used as cell models and were transfected with TRIM29-specific overexpressed plasmid or siRNA and control plasmid. HepG2 cells and Huh7 cells were treated with PEG-IFN-α-2b （0， 10， 100， 1 000， and 10 000 U/mL）， and HepG2.2.15 cells were treated with TRIM29-specific siRNA or negative control combined with PEG-IFN-α-2b. ELISA was used to measure the concentrations of HBsAg and HBeAg； qRT-PCR was used to measure the relative expression levels of TRIM29 and HBV RNA； Western blot was used to measure the protein expression levels of STING， p-TBK1， TBK1， pIRF3， IRF3， MX1， and IFIT1； co-immunoprecipitation assay was used to observe the interaction between TRIM29 and STING protein. The independent-samples t test was used for comparison of normally distributed continuous data between two groups， and a one-way analysis of variance was used for comparison between multiple groups， with the least significant difference t-test for further comparison between two groups； the chi-square test or the Fisher’s exact test was used for comparison of categorical data between two groups. Results The CHB patients had a significantly higher expression level of TRIM29 in peripheral blood than the healthy controls （P<0.001）. In cell experiments， the expression levels of HBsAg， HBeAg， and HBV RNA increased with the upregulation of TRIM29 expression and decreased with downregulation of TRIM29 expression （P<0.05）. TRIM29 bound to STING and degraded STING via protease， and compared with the control group， there were no significant changes in the total protein levels of TBK1 and IRF3 after overexpression of TRIM29， while there were significant reductions in the expression levels of STING， p-TBK1， and p-IRF3 （P<0.05）. The protein and mRNA expression levels of TRIM29 decreased with the increase in the concentration of PEG-IFN-α-2b for the treatment of HepG2 and Huh7 cells （P<0.01）. During the treatment with PEG-IFN-α-2b， the CHB patients had a gradual reduction in the mRNA expression level of TRIM29， and there was a significant difference between the early response group and the non-response group （P<0.05）. In the context of treatment with an equal volume of PEG-IFN-α-2b， compared with the control group， there were significant increases in the protein expression levels of Mx1 and IFIT1 in HepG2.2.15 cells after TRIM29 knockdown （P<0.05）. There was a gradual reduction in the expression of TRIM29 in CHB patients during the early stage of PEG-IFN-α-2b treatment. Conclusion TRIM29 targets and degrades STING and promotes HBV replication by inhibiting the STING-TBK1-IRF3 signaling pathway. TRIM29 interferes with the antiviral effect of PEG-IFN-α-2b， and the expression level of TRIM29 in PBMCs of CHB patients may be used as an indicator for predicting the response of patients to PEG-IFN-α-2b therapy. -
Key words:
- Hepatitis B Virus /
- Tripartite Motif-Containing Protein 29 /
- PEG-IFNα /
- Signaling Pathway
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1. 病例资料
病例1：患者女性，58岁，以“体检发现胰腺尾部占位3天”于2019年3月4日入本院，患者2年来体质量下降5 kg，增强CT检查示：胰腺尾部动脉期以及门静脉期显著强化结节，动脉期CT值为198 HU，考虑神经内分泌肿瘤（图1）。超声胃镜示：胰腺尾部低回声病灶（0.6 cm×0.8 cm），为富血供结节。患者癌胚抗原、糖类抗原（CA）19-9、CA125等肿瘤标志物指标正常，既往无糖耐量异常病史，口服葡萄糖耐量试验结果正常。术前诊断为胰腺神经内分泌肿瘤（pancreatic neuroendocrine tumor，pNET），患者在全麻下行腹腔镜下胰腺体尾切除术，术后标本可见胰腺内副脾（intrapancreatic accessory spleen，IPAS）组织，切面红褐色、质韧（图2）；术后病理示：胰腺体尾部副脾组织，胰腺组织切缘未见癌（图3）。
注： a，平扫期；b，动脉期；c，静脉期。胰腺尾部可见大小为0.8 cm×0.7 cm的结节样异常强化影，平扫期显示不清，动脉期明显强化，静脉期呈稍高强化，且动脉期和静脉期强化程度均高于胰腺组织（红色箭头）。图 1 病例1患者术前CT扫描结果Figure 1. Preoperative CT scan of patient 1
图 3 病例1患者术后病理结果（HE染色，×100）Figure 3. Postoperative pathology of patient 1（HE staining，×100）病例1误诊原因分析：（1）CT影像学表现是主要原因之一。胰腺尾部动脉早期和门静脉期均呈显著强化结节，边缘规则，未见腹膜后和周围肿大淋巴结，这些影像学特点与pNET的特点相符。其中，非功能性pNET患者的症状隐蔽，激素水平正常，缺乏特异性肿瘤标志物，因其血供丰富且内部可有变性坏死，当病灶较大时，增强CT可见不均匀强化，但当pNET病灶较小也可表现为均匀强化，此时较难与IPAS区分；（2）该患者虽行超声胃镜检查，但患者家属拒绝行穿刺，遂未操作；（3）未能将病灶强化程度与脾脏强化程度相比，对IPAS的诊断缺乏经验。
病例2：患者男性，60岁，因“间断性腹痛10余天”于2022年9月15日入本院。既往病史：30年前因外伤行脾切除。CT平扫+增强检查示：胰腺钩突部占位，考虑恶性肿瘤可能（图4）；胰尾部见类圆形低密度影，较大直径为3 cm，边缘见钙化，增强扫描轻度不均匀强化，实性假乳头状瘤待排除（图5）。术前诊断：胰头钩突肿瘤；胰尾部占位，考虑胰腺实性假乳头状瘤；脾切除术后。肿瘤标志物：CA19-9 1 537.07 U/mL，CA125 125.68 U/mL。术中行胰十二指肠联合胰尾部分切除术；术后病理示：钩突部胰腺导管腺癌（中低分化）；胰体尾副脾组织（图6），胰腺组织切缘未见癌。
注： a，平扫期；b，动脉期；c，静脉期。胰腺钩突部不规稍低密度影，大小为2.7 cm×3.1 cm，增强扫描呈弱强化，边缘不规则，紧贴肠系膜上静脉，与十二指肠水平段分界不清（红色箭头）。图 4 病例2患者术前胰腺钩突部占位CT扫描Figure 4. Preoperative pancreatic uncinate process space occupying CT scan of patient 2
注： a，平扫期；b，动脉期；c，静脉期。平扫期可见胰尾部直径3 cm的类圆形稍低密度影，动脉期和静脉期扫描轻度不均匀强化，边缘可见钙化（红色箭头）。图 5 病例2患者术前胰腺尾部占位CT扫描Figure 5. Preoperative pancreatic tail space occupying CT scan of patient 2
图 6 病例2患者术后病理结果（HE染色，×100）Figure 6. Postoperative pathology of patient 2（HE staining，×100）病例2误诊原因分析：（1）该患者有脾切除病史，术前影像学检查提示脾脏缺如，主观上忽视了副脾存在的可能，客观上影像学检查时缺少副脾组织与正常脾脏组织的影像学特点比较。（2）该患者CT特征为胰尾部见类圆形稍低密度影，增强扫描示轻度不均匀强化，边缘可见钙化，可能为胰腺实性假乳头状瘤，或者其他低度恶性肿瘤。而脾脏组织较少发生钙化，该患者胰尾部分占位的钙化表现进一步干扰了临床判断。而胰腺实性假乳头状瘤实性部分和囊壁常呈轻、中度强化，病灶内可见钙化灶，往往位于病灶实性部分、分隔处或其周边包膜。该患者的影像学表现与胰腺实性假乳头状瘤极为相似，对明确鉴别诊断造成严重影响［1］。
2. 讨论
副脾与胚胎阶段脾脏的胚芽形成密切相关，正常情况下，在胚胎发育第5周，来自间充质细胞的胃背系膜分化为脾脏，但如果脾脏胚芽未完全融合，或者分离出单个细胞，则发育形成副脾［2］。80%的副脾发生在脾门附近，17%发生在胰腺尾部，还可见于胃壁、大网膜、脾结肠韧带、睾丸、肾上腺等部位。副脾的发生率约为10%，其中完全包裹在胰腺内的副脾发生率仅为2%［3］，即IPAS。IPAS最常被误诊为pNET，pNET分为功能性pNET和非功能性pNET，功能性pNET易通过患者激素水平及其他临床症状与IPAS鉴别诊断，而IPAS最易被误诊为非功能性pNET。pNET在所有胰腺肿瘤中占比不超过2%，非功能性pNET仅占全部pNET的15%～41%，其中大多数为恶性，肿瘤根治性切除是实现患者长期生存最重要的手段，因此对肿瘤最大径>2 cm的非功能性pNET必须手术切除，此外，除了肿瘤最大径<1 cm或手术风险较大者，其余≤2 cm的非功能性pNET也均应行手术切除。但IPAS无需外科干预，故对二者的明确鉴别诊断具有重要的临床意义［4］。
IPAS无明显特异性临床表现，其诊断主要依靠影像学检查。在CT平扫中，IPAS表现的密度与脾脏相似，增强扫描强化程度高于胰腺组织，与脾脏一致，动脉期表现为“花斑样”不均匀强化，门静脉期为均匀强化，但当IPAS直径较小时，动脉期也表现为均匀强化［5］。MRI对IPAS的诊断也有重要价值，IPAS的T1WI信号低于胰腺，T1WI可显示肿块的位置、边缘、形态，T2WI信号表现为与脾脏等信号，MRI强化特点与CT强化类似。由于IPAS的白髓与红髓比例较高，有时在T2加权像上IPAS的信号强度略高于脾脏［6］。此外，弥散加权成像对IPAS的诊断也有积极意义，尤其在鉴别IPAS与胰腺实体肿瘤方面［7］。比IPAS更罕见的是IPAS伴上皮样囊肿（epidermoid cyst in intrapancreatic accessory spleen，ECIPAS）［8］。ECIPAS直径通常为2～4 cm；病理学镜下通常表现为囊肿内衬复层鳞状上皮，囊外可见脾脏组织；CT和MRI检查的主要着眼点为识别囊肿周围的脾脏组织，ECIPAS的CT表现为实性部分强化，强化程度与脾脏类似，囊性部分CT平扫呈低密度，增强后不强化［9］。明确的术前影像学诊断和术中冰冻病理切片对于避免过度治疗至关重要。
此外，由于副脾和脾脏具有相同的生理功能，因此具有脾脏功能显示作用的放射性核素扫描在鉴别IPAS和pNET也有重要价值。脾脏组织利用网状内皮细胞可拦截并破坏衰老的红细胞，99mTc标记的热变性红细胞（99mTc-heat denaturation RBC，99mTc-HDRBC）可以在脾脏和IPAS处浓聚，并在核素检查中显影。然而，当脾脏包裹胰尾或覆盖IPAS时，IPAS处的显影被正常脾脏组织掩盖，易造成误诊［10］。非功能性pNET因其含有生长抑素受体，故可通过68Ga生长抑素类似物（68Ga somatostatin analogue imaging，68Ga-SSA）核素扫描进行鉴别，其在诊断pNET方面比MRI更敏感，但假阳性率较高，只有当68Ga-SSA图像中摄取显著高于脾脏才具有诊断价值，可能与脾脏组织中淋巴细胞同样含有生长抑素受体有关［11］。常规超声内镜（endoscopic ultrasonography，EUS）对IPAS的诊断价值有限，但可利用Levovist或Sonazid作为静脉造影剂的对比增强EUS来提高诊断IPAS的能力。Makino等［12］研究发现，以Sonazoid作为造影剂的增强EUS对IPAS中存在的丰富血管和网状内皮细胞系统较为敏感。此外，IPAS与pNET在EUS定性定量弹性成像下表现也有差异，IPAS由于病灶质地松软呈现绿色为主的图像，pNET则由于病灶质地较硬呈现质地均匀的蓝色图像［13］。进一步将弹性成像结果量化为弹性应变率比值可以提高诊断效率［14］。
除了影像学检查以外，EUS引导下细针穿刺（EUS-FNA）检查是鉴别IPAS的高特异性手段。Tatsas等［15］研究发现，脾窦薄层血管的内皮细胞中的CD8经免疫细胞化学染色可检出，只要取得脾窦的内皮细胞即可诊断为副脾。但由于肿块较小、位置较深等不利因素，往往无法准确取得病理标本，且细针穿刺可能导致胰漏、出血等不良事件。当影像学检查无法确诊且胰腺内肿块较大时，EUS-FNA仍值得考虑。近年来，基于探针的激光共聚焦显微内镜检查（confocal laser endomicroscopy，CLE）在诊断胰腺占位肿块的应用成为研究热点，CLE可以通过获取放大1 000倍后的黏膜图像来识别细胞和亚细胞的微结构，并进行活体组织学诊断（光学虚拟活检）。CLE既可以避免EUS-FNA的副损伤，又可与EUS-FNA联合应用提高胰腺肿块的诊断准确度［16］。
避免副脾的误诊，首先需要临床医师对IPAS具备充分的认识，对位于胰腺尾部、直径1～3 cm、边界清、质地均匀的富血管病灶，应考虑IPAS的可能性。其次，在鉴别诊断过程中需要综合利用CT、MRI、PET-CT等影像学检查，尤其是99mTc-HDRBC等敏感性较高的检查。必要时可采用EUS-FNA检查，但要提高操作技巧，避免发生不良事件。确诊IPAS的患者无需手术治疗，随访观察即可。总之，临床上应进一步提升对IPAS的认识与鉴别，避免IPAS患者被误诊并接受非必要手术，增加医疗负担。
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注： a，CHB组与健康对照组TRIM29 mRNA表达差异；b，HepG2和HepG2.2.15细胞TRIM29蛋白表达差异。
图 1 TRIM29表达水平与HBV感染的关系
Figure 1. The relationship between TRIM29 and HBV infection
注： a、c，Western Blot和qRT-PCR检测TRIM29转染效率；b、d，ELISA检测细胞培养基中HBsAg和HBeAg的浓度，qRT-PCR检测HBV RNA的相对表达水平。
图 2 过表达TRIM29对HBV复制的影响
Figure 2. Effect of TRIM29 overexpression on HBV replication and gene expression
注： a、c，Western Blot和qRT-PCR检测TRIM29特异性si-RNA转染效率；b、d，ELISA检测细胞培养基中HBsAg和HBeAg的浓度，qRT-PCR检测HBV RNA表达水平。
图 3 敲低TRIM29对HBV复制的影响
Figure 3. Effect of TRIM29 knockdown on HBV replication and gene expression
注： a，免疫共沉淀检测TRIM29和STING相互作用；b、c，qRT-PCR检测IFN-α mRNA表达水平；d、e，Western Blot检测STING、TBK1、IRF3、p-TBK1、p-IRF3蛋白水平。
图 4 TRIM29对STING-TBK1-IRF3信号通路的调控作用
Figure 4. Regulatory effect of TRIM29 on STING-TBK1-IRF3 signaling pathway
注： a、b HepG2细胞；c、d，Huh7细胞。a、c，Western Blot检测TRIM29蛋白表达水平；b、d，qRT-PCR检测TRIM29 mRNA水平。
图 5 PEG-IFN-α-2b对TRIM29表达的影响
Figure 5. Effect of PEG-IFN-α-2b on TRIM29 expression
图 6 TRIM29表达对PEG-IFN-α-2b的抗病毒作用的影响
Figure 6. Effect of TRIM29 expression on the antiviral effect of PEG-IFN-α-2b
表 1 引物序列
Table 1. List of primers
引物 序列（5'-3'） HBV RNA-F TCTTGCCTTACTTTTGGAAG HBV RNA-R AGTTCTTCTTCTAGGGGACC Hu-TRIM29-F TGCGAGCTGCATCTCAAGC Hu-TRIM29-R GGTGCTATGATTCTTGTGCTCC Hu-IFN-α-F TGACCTCAAAGCCTGTGTGATG Hu-IFN-α-R AAGTATTTCCTCACAGCCAGCAG Hu-GAPDH-F CGGATTTGGTCGTATTGGG Hu-GAPDH-R TCTCGCTCCTGGAAGATGG 
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表 2 健康对照组和CHB组患者的一般资料比较
Table 2. Comparison of clinical characteristics between healthy and CHB patients
指标 健康对照组（n=30） CHB组（n=34） 统计值 P值 年龄（岁） 38.2±10.4 33.8±5.0 t=0.451 0.328 男/女（例） 15/15 16/18 χ2=0.055 0.814 汉族/其他（例） 23/7 24/10 χ2=0.302 0.583 ALT（U/L） 19.4±4.8 17.4±4.9 t=1.702 0.094 AST（U/L） 17.3±3.3 18.4±3.3 t=-1.293 0.201 TBil（μmol/L） 6.2±3.7 8.6±2.7 t=-1.791 0.195 DBil（μmol/L） 3.4±0.8 4.6±1.6 t=-2.219 0.138
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表 3 一般临床资料
Table 3. Clinical characteristics of patients
指标 早期应答组（n=11） 早期无应答组（n=19） t值 P值 女性（例） 7 12 >0.05 年龄（岁） 26.8±4.49 29.3±7.20 -2.041 0.643 HBV DNA （log10 IU/mL） 0周 2.35±0.26 2.11±0.18 2.380 0.010 12周 1.33±0.10 1.84±0.23 2.598 <0.001 24周 1.09±0.16 1.56±0.27 -4.260 <0.001 ALT（U/L） 0周 23.64±3.70 24.09±4.00 -0.546 0.99 12周 59.78±6.30 36.25±5.73 8.127 <0.001 24周 33.66±6.74 45.68±4.96 -3.893 <0.001 TRIM29 mRNA 0周 1.57±0.43 1.32±0.75 2.07 0.047 12周 1.22±0.26 0.72±0.34 3.83 <0.001 24周 0.94±0.27 0.43±0.11 7.20 <0.001
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