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Article(id=1208106711475392534, tenantId=1146029695717560320, journalId=1189873630562394117, issueId=1208106710208717234, articleNumber=null, orderNo=null, doi=10.11855/j.issn.0577-7402.2022.04.0367, pmid=null, cstr=null, oa=null, hot=null, price=null, onlineType=0, articleFormat=0, articleType=null, articleTypeStr=research-article, receivedDate=1614960000000, receivedDateStr=2021-03-06, revisedDate=null, revisedDateStr=null, acceptedDate=1629734400000, acceptedDateStr=2021-08-24, onlineDate=1765964685552, onlineDateStr=2025-12-17, pubDate=1651075200000, pubDateStr=2022-04-28, doiRegisterDate=null, doiRegisterDateStr=null, onlineIssueDate=1765964685552, onlineIssueDateStr=2025-12-17, onlineJustAcceptDate=null, onlineJustAcceptDateStr=null, onlineFirstDate=null, onlineFirstDateStr=null, sourceXml=null, magXml=null, createTime=1765964685552, creator=13701087609, updateTime=1765964685552, updator=13701087609, issue=Issue{id=1208106710208717234, tenantId=1146029695717560320, journalId=1189873630562394117, year='2022', volume='47', issue='4', pageStart='321', pageEnd='426', issueExtLink='null', onlineDate='null', pubDate='null', beforeIssueId=null, nextIssueId=null, price=null, status=1, issueComplete=1, articleOrder=1, issueType=-1, specialIssue=null, createTime=1765964685250, creator=13701087609, updateTime=1765964685250, updator=13701087609, preIssue=null, nextIssue=null, ext=null, issueFiles=null}, startPage=367, endPage=374, ext={EN=ArticleExt(id=1208106711764799514, articleId=1208106711475392534, tenantId=1146029695717560320, journalId=1189873630562394117, language=EN, title=Correlation between TGFβR2 and MSI in colorectal cancer and its clinicopathological significance, columnId=1190310109000602400, journalTitle=Medical Journal of Chinese People’s Liberation Army, columnName=Clinical Research, runingTitle=null, highlight=null, articleAbstract=

Objective To investigate the correlation between the expressions of TGFβR2 and microsatellite instability (MSI) in colorectal cancer (CRC) tissues, and the relationship between the two protein molecules and clinicopathological parameters. Methods The CRC and adjacent tissues of 184 patients with CRC pathologically diagnosed in the Second Affiliated Hospital of Kunming Medical University from January 1, 2019 to September 30, 2019 were collected, the expression of MSI was detected by capillary electrophoresis (CE), and the expressions of MMR and TGFβR2 proteins were detected by immunohistochemistry (IHC). Kappa consistency test was used to analyze the consistency of IHC and CE MSI results. The relative TGFβR2 mRNA expression was detected by quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR). Rank sum test was used to analyze the correlation between TGFβR2 gene mutation and MSI, and the relationship between TGFβR2 mRNA relative expression level and clinicopathological parameters. Results Among 184 CRC tissue samples, 152 cases (82.6%,152/184) were microsatellite instability low-frequency (MSI-L)/microsatellite stability (MSS) and 32 cases (17.4%, 32/184) were microsatellite instability high-frequency (MSI-H). The main results of MSI detected by CE and IHC were highly consistent, and the Kappa consistency coefficient was 0.922 (P<0.001). Compared with MSI-L/MSS, MSI-H mostly occurred in patients with stagesⅠ-Ⅱ colon cancer without lymph node metastasis (P<0.05). The protein and mRNA expression levels of TGFβR2 in CRC tissues were higher than those in the adjacent tissues (P<0.01). The mutation rate of TGFβR2 gene in MSI-H CRC was higher than that in MSI-L/MSS CRC [93.3%(28/30) vs. 14.9%(23/154), P<0.01]. The relative expression of TGFβR2 mRNA in MSI-H group was higher than that in MSI-L/MSS group (7.93±0.36 vs. 4.47±1.31, P<0.01), was higher in para-cancer tissues than in CRC tissues(9.38±0.82 vs. 4.76±1.63, P<0.01). The relative expressions of TGFβR2 mRNA in colon, tumors without metastasis, lymph node without metastasis and TNM Ⅰ-Ⅱ stages CRC tissues were higher (P<0.05). Conclusion The expressions of MSI and TGFβR2 are consistent and synergistic in tumor site, lymph node metastasis, and TNM stage.

, correspAuthors=Ying-Zhen Su, authorNote=null, correspAuthorsNote=
*E-mail:
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目的 探讨结直肠癌(CRC)组织中TGFβR2的表达与微卫星不稳定性(MSI)的相关性，以及两者与CRC患者临床病理参数的关系。方法 收集2019年1月1日－9月30日昆明医科大学第二附属医院收治的184例CRC患者的CRC组织及癌旁组织，采用多重荧光PCR毛细管电泳法(CE)检测MSI，免疫组化染色(IHC)检测MMR和TGFβR2蛋白的表达情况。采用Kappa一致性检验分析IHC与CE检测MSI结果的一致性。qRT-PCR检测TGFβR2 mRNA的表达情况。采用秩和检验分析TGFβR2基因突变与MSI的相关性以及TGFβR2 mRNA相对表达量与临床病理参数的关系。结果 184例CRC组织样本中，152例(82.6%，152/184)为微卫星低度不稳定(MSI-L)/微卫星稳定(MSS)，32例(17.4%，32/184)为微卫星高度不稳定(MSI-H)。CE与IHC检测MSI的主体结果具有高度一致性，Kappa一致性系数为0.922(P<0.001)。与MSI-L/MSS相比，MSI-H多发生于无淋巴结转移、TNM分期Ⅰ－Ⅱ期的CRC(P<0.05)。TGFβR2 mRNA和蛋白在CRC组织中的表达低于癌旁组织(P<0.01)。TGFβR2基因在MSI-H CRC组织中的突变率高于MSI-L/MSS CRC组织[93.3%(28/30) vs. 14.9%(23/154)，P<0.01]。TGFβR2 mRNA相对表达量在MSI-H肿瘤中高于MSI-L/MSS肿瘤(7.93±0.36 vs. 4.47±1.31，P<0.01)，在癌旁组织中高于CRC组织(9.38±0.82 vs.4.76±1.63，P<0.01)。在无远处转移、无淋巴结转移、TNM分期Ⅰ－Ⅱ期的CRC组织中，TGFβR2 mRNA相对表达量较高(P<0.05)。结论 MSI与TGFβR2的表达在肿瘤发生部位、是否发生淋巴结转移及TNM分期方面存在一致性及协同性。

, correspAuthors=苏莹珍, authorNote=null, correspAuthorsNote=
苏莹珍，E-mail：
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张楚悦，硕士研究生，主要从事腹部肿瘤的诊断与治疗研究

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张楚悦，硕士研究生，主要从事腹部肿瘤的诊断与治疗研究

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张楚悦，硕士研究生，主要从事腹部肿瘤的诊断与治疗研究

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Canc Res Prev Treat, 2006, 33(7):509-511., articleTitle=Mutation analysis of transforming growth factor βⅡ receptor gene in colorectal adenoma carcinogenesis, refAbstract=null), Reference(id=1208444803650536334, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1208106711475392534, doi=null, pmid=null, pmcid=null, year=2006, volume=33, issue=7, pageStart=509, pageEnd=511, url=null, language=null, rfNumber=[19], rfOrder=22, authorNames=王朝晖, 张雪梅, 姜春萌, journalName=肿瘤防治研究, refType=null, unstructuredReference=[王朝晖, 张雪梅, 姜春萌, 等. 转化生长因子βⅡ型受体基因突变在大肠腺瘤癌变过程中的作用[J]. 肿瘤防治研究, 2006, 33(7): 509-511.], articleTitle=转化生长因子βⅡ型受体基因突变在大肠腺瘤癌变过程中的作用, refAbstract=null)], funds=[Fund(id=1208444800269927280, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1208106711475392534, awardId=202001BA070001-045, language=EN, fundingSource=Yunnan Science and Technology Basic Research Project(202001BA070001-045), fundOrder=null, country=null), Fund(id=1208444800324453233, 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650214, China), AuthorCompanyExt(id=1208444795270316843, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1208106711475392534, companyId=1208444795253539625, language=CN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=3昆明学院医学院公共卫生教研室，昆明 650214)])], figs=[ArticleFig(id=1208444799120687970, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1208106711475392534, language=EN, label=Fig.1, caption=CE and IHC detect MSI status in CRC organization, figureFileSmall=rcC4KLMCkFPgGn1zvCghNg==, figureFileBig=W5hIdzE84y2QR9IAK1Zyog==, tableContent=null), ArticleFig(id=1208444799183602531, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1208106711475392534, language=CN, label=图1, caption=CE与IHC检测CRC组织中MSI的状态

CE. 多重荧光PCR毛细管电泳法；IHC. 免疫组化染色；CRC. 结直肠癌；MSI. 微卫星不稳定性；MSI-L/MSS. 微卫星低度不稳定/微卫星稳定；MSI-H. 微卫星高度不稳定；A. 无微卫星位点突变，即MSI-L/MSS；B. 4个微卫星位点突变，即MSI-H；C. MMR蛋白在CRC组织中共表达，即MSI-L/MSS (IHC ×200)；D. MLH1/PMS2在CRC组织中表达共缺失，即MSI-H (IHC ×200)

, figureFileSmall=rcC4KLMCkFPgGn1zvCghNg==, figureFileBig=W5hIdzE84y2QR9IAK1Zyog==, tableContent=null), ArticleFig(id=1208444799271682916, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1208106711475392534, language=EN, label=Fig.2, caption=Expression of TGFβR2 protein in CRC tissues (IHC ×200), figureFileSmall=CTOXBoIe4PNIp3rx+Gwiug==, figureFileBig=7w/Z524gC/BV6QNrfbYlsA==, tableContent=null), ArticleFig(id=1208444799326208869, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1208106711475392534, language=CN, label=图2, caption=TGFβR2蛋白在CRC组织中的表达情况(IHC ×200)

CRC. 结直肠癌；TGFBR2. 转化生长因子β Ⅱ型受体；IHC. 免疫组化染色；A. TGFBR2蛋白在CRC组织中表达情况；B. TGFBR2蛋白在癌旁组织中表达情况

, figureFileSmall=CTOXBoIe4PNIp3rx+Gwiug==, figureFileBig=7w/Z524gC/BV6QNrfbYlsA==, tableContent=null), ArticleFig(id=1208444799401706342, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1208106711475392534, language=EN, label=Fig.3, caption=Expression of TGFβR2 mRNA in CRC tissues, figureFileSmall=XQIJxlic+/DfR0ZY0Vf19g==, figureFileBig=HMgMENkUxP628fcaV1XVDQ==, tableContent=null), ArticleFig(id=1208444799498175335, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1208106711475392534, language=CN, label=图3, caption=TGFβR2 mRNA在CRC组织中的表达情况

MSI-L/MSS. 微卫星低度不稳定/微卫星稳定；MSI-H. 微卫星高度不稳定；TGFBR2. 转化生长因子β Ⅱ型受体；CRC. 结直肠癌；A. TGFβR2 mRNA在MSI-L/MSS组和MSI-H组中的表达情况；B. TGFβR2 mRNA在CRC组织和癌旁组织中的表达情况；(1)P<0.01

, figureFileSmall=XQIJxlic+/DfR0ZY0Vf19g==, figureFileBig=HMgMENkUxP628fcaV1XVDQ==, tableContent=null), ArticleFig(id=1208444799628198760, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1208106711475392534, language=EN, label=Tab.1, caption=

Primer sequence of qRT-PCR

, figureFileSmall=null, figureFileBig=null, tableContent=
基因引物序列(5'-3')
BAT-25正义链：TCGCCTCCAAGAATGTAAGT
反义链：TCTGCATTTTAACTATGGCTC
BAT-26正义链：TGACTACTTTTGACTTCAGCC
反义链：AACCATTCAACATTTTTAACCC
D5S346正义链：ACTCACTCTAGTGATAAATCGGG
反义链：AGCAGATAAGACAGTATTACTAGTT
D17S250正义链：GGAAGAATCAAATAGACAAT
反义链：GCTGGCCATATATATATTTAAACC
D2S123正义链：AAACAGGATGCCTGCCTTTA
反义链：GGACTTTCCACCTATGGGAC
TGFβR2正义链：TGGAAGGACTCATGACCACA
反义链：TTCAGCTCAGGGATGACCTT
GAPDH正义链：CAACATCAACAACACAGAG
反义链：CCGTCTTCCGCTCCTCAG
), ArticleFig(id=1208444799707890537, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1208106711475392534, language=CN, label=表1, caption=

qRT-PCR引物序列

, figureFileSmall=null, figureFileBig=null, tableContent=
基因引物序列(5'-3')
BAT-25正义链：TCGCCTCCAAGAATGTAAGT
反义链：TCTGCATTTTAACTATGGCTC
BAT-26正义链：TGACTACTTTTGACTTCAGCC
反义链：AACCATTCAACATTTTTAACCC
D5S346正义链：ACTCACTCTAGTGATAAATCGGG
反义链：AGCAGATAAGACAGTATTACTAGTT
D17S250正义链：GGAAGAATCAAATAGACAAT
反义链：GCTGGCCATATATATATTTAAACC
D2S123正义链：AAACAGGATGCCTGCCTTTA
反义链：GGACTTTCCACCTATGGGAC
TGFβR2正义链：TGGAAGGACTCATGACCACA
反义链：TTCAGCTCAGGGATGACCTT
GAPDH正义链：CAACATCAACAACACAGAG
反义链：CCGTCTTCCGCTCCTCAG
), ArticleFig(id=1208444799774999402, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1208106711475392534, language=EN, label=Tab.2, caption=

Consistency analysis of MSI results detected by CE and IHC

, figureFileSmall=null, figureFileBig=null, tableContent=
IHCCE合计
MSI-HMSI-L/MSS
dMMR29130
pMMR3151154
合计32152184
), ArticleFig(id=1208444799842108267, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1208106711475392534, language=CN, label=表2, caption=

CE和IHC检测MSI结果的一致性分析

, figureFileSmall=null, figureFileBig=null, tableContent=
IHCCE合计
MSI-HMSI-L/MSS
dMMR29130
pMMR3151154
合计32152184
), ArticleFig(id=1208444799900828524, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1208106711475392534, language=EN, label=Tab.3, caption=

Comparison of clinicopathological parameters of CRC patients between MSI-H group and MSI-L/MSS group [n(%)]

, figureFileSmall=null, figureFileBig=null, tableContent=
项目MSI-H组(n=30)MSI-L/MSS组(n=154)χ2P
性别  0.3460.556
 男15(50.0)86(55.8)
 女15(50.0)68(44.2)
年龄(岁)  0.4300.512
 <6012(40.0)52(33.8)
 ≥6018(60.0)102(66.2)
肿瘤部位6.8640.009
 结肠23(76.7)78(50.6)
 直肠7(23.3)76(49.4)
 肿瘤最大直径(cm)  1.2850.257
 <516(53.3)99(64.3)
 ≥514(46.7)55(35.7)
分化程度  11.9480.001
 高、中分化15(50.0)123(79.9)
 低分化15(50.0)31(20.1)
淋巴结转移  5.0490.025
 阳性7(23.3)70(45.5)
 阴性23(76.7)84(54.5)
TNM分期  4.7750.029
 Ⅰ－Ⅱ23(76.7)85(55.2)
 Ⅲ－Ⅳ7(23.3)69(44.8)
组织病理类型  1.9110.167
 腺癌21(70.0)125(81.2)
 黏液腺癌9(30.0)29(18.8)
肿瘤浸润深度  2.6900.101
 未及全层3(7.7)36(18.6)
 浸及全层27(92.3)118(81.4)
脉管内癌栓  0.2830.595
 有2(6.7)15(9.7)
 无28(93.3)139(90.3)
肿瘤远处转移  1.1150.291
 有2(6.7)21(13.6)
 无28(93.3)133(86.4)  
), ArticleFig(id=1208444799976325997, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1208106711475392534, language=CN, label=表3, caption=

MSI-H组与MSI-L/MSS组CRC患者临床病理参数比较[例(%)]

, figureFileSmall=null, figureFileBig=null, tableContent=
项目MSI-H组(n=30)MSI-L/MSS组(n=154)χ2P
性别  0.3460.556
 男15(50.0)86(55.8)
 女15(50.0)68(44.2)
年龄(岁)  0.4300.512
 <6012(40.0)52(33.8)
 ≥6018(60.0)102(66.2)
肿瘤部位6.8640.009
 结肠23(76.7)78(50.6)
 直肠7(23.3)76(49.4)
 肿瘤最大直径(cm)  1.2850.257
 <516(53.3)99(64.3)
 ≥514(46.7)55(35.7)
分化程度  11.9480.001
 高、中分化15(50.0)123(79.9)
 低分化15(50.0)31(20.1)
淋巴结转移  5.0490.025
 阳性7(23.3)70(45.5)
 阴性23(76.7)84(54.5)
TNM分期  4.7750.029
 Ⅰ－Ⅱ23(76.7)85(55.2)
 Ⅲ－Ⅳ7(23.3)69(44.8)
组织病理类型  1.9110.167
 腺癌21(70.0)125(81.2)
 黏液腺癌9(30.0)29(18.8)
肿瘤浸润深度  2.6900.101
 未及全层3(7.7)36(18.6)
 浸及全层27(92.3)118(81.4)
脉管内癌栓  0.2830.595
 有2(6.7)15(9.7)
 无28(93.3)139(90.3)
肿瘤远处转移  1.1150.291
 有2(6.7)21(13.6)
 无28(93.3)133(86.4)  
), ArticleFig(id=1208444800051823470, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1208106711475392534, language=EN, label=Tab.4, caption=

Relationship between TGFβR2 mRNA and clinicopathological parameters of CRC patients ($\bar{x}±s$)

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临床病理参数构成[例(%)]TGFβR2 mRNAZP
性别  –0.1960.845
 男101(54.9)5.10±1.63
 女83(45.1)4.96±1.91
年龄(岁)  –0.6070.544
 <6064(34.8)4.96±1.91
 ≥60120(65.2)5.08±1.68
肿瘤部位  –6.4720.000
 结肠101(54.9)5.76±1.53
 直肠83(45.1)4.15±1.62
肿瘤最大直径(cm)  –0.8490.396
 <5115(62.5)4.94±1.68
 ≥569(37.5)5.20±1.89
分化程度  –1.6530.098
 高、中分化138(75.0)5.11±1.47
 低分化46(25.0)4.81±2.45
淋巴结转移  –9.4150.000
 阳性77(41.8)3.67±1.53
 阴性107(58.2)6.02±1.16
TNM分期  –9.2900.000
 Ⅰ－Ⅱ108(58.7)5.99±1.19
 Ⅲ－Ⅳ76(41.3)3.68±1.54
组织病理类型  –0.0020.999
 腺癌146(79.3)5.03±1.70
 黏液腺癌38(20.7)5.07±1.99
肿瘤浸润深度  –0.8500.395
 未及全层39(21.2)4.81±1.62
 浸及全层145(78.8)5.10±1.80
脉管癌栓  –1.6420.101
 有17(9.2)4.38±2.02
 无167(90.8)5.10±1.72
远处转移  –4.2940.000
 有23(12.5)3.63±1.53
 无161(87.5)5.24±1.70  
), ArticleFig(id=1208444800118932335, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1208106711475392534, language=CN, label=表4, caption=

TGFβR2 mRNA相对表达量与CRC患者临床病理参数的关系($\bar{x}±s$)

, figureFileSmall=null, figureFileBig=null, tableContent=
临床病理参数构成[例(%)]TGFβR2 mRNAZP
性别  –0.1960.845
 男101(54.9)5.10±1.63
 女83(45.1)4.96±1.91
年龄(岁)  –0.6070.544
 <6064(34.8)4.96±1.91
 ≥60120(65.2)5.08±1.68
肿瘤部位  –6.4720.000
 结肠101(54.9)5.76±1.53
 直肠83(45.1)4.15±1.62
肿瘤最大直径(cm)  –0.8490.396
 <5115(62.5)4.94±1.68
 ≥569(37.5)5.20±1.89
分化程度  –1.6530.098
 高、中分化138(75.0)5.11±1.47
 低分化46(25.0)4.81±2.45
淋巴结转移  –9.4150.000
 阳性77(41.8)3.67±1.53
 阴性107(58.2)6.02±1.16
TNM分期  –9.2900.000
 Ⅰ－Ⅱ108(58.7)5.99±1.19
 Ⅲ－Ⅳ76(41.3)3.68±1.54
组织病理类型  –0.0020.999
 腺癌146(79.3)5.03±1.70
 黏液腺癌38(20.7)5.07±1.99
肿瘤浸润深度  –0.8500.395
 未及全层39(21.2)4.81±1.62
 浸及全层145(78.8)5.10±1.80
脉管癌栓  –1.6420.101
 有17(9.2)4.38±2.02
 无167(90.8)5.10±1.72
远处转移  –4.2940.000
 有23(12.5)3.63±1.53
 无161(87.5)5.24±1.70  
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TGFβR2与MSI在结直肠癌中的相关性及临床病理学意义
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张楚悦 1 , 危群 2 , 杨裔坚 1 , 钱程 1 , 付必莽 1 , 谢楠 1 , 魏雷 1 , 李春满 1 , 苏莹珍 3, *
解放军医学杂志 | 临床研究 2022,47(4): 367-374
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解放军医学杂志 | 临床研究 2022, 47(4): 367-374
TGFβR2与MSI在结直肠癌中的相关性及临床病理学意义
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张楚悦1, 危群2, 杨裔坚1, 钱程1, 付必莽1, 谢楠1, 魏雷1, 李春满1, 苏莹珍3, *
作者信息
  • 1昆明医科大学第二附属医院肝胆胰外科，昆明 650032
  • 2昆明医科大学第二附属医院病理科，昆明 650032
  • 3昆明学院医学院公共卫生教研室，昆明 650214

    • 张楚悦，硕士研究生，主要从事腹部肿瘤的诊断与治疗研究

通讯作者:

苏莹珍，E-mail：
Correlation between TGFβR2 and MSI in colorectal cancer and its clinicopathological significance
Chu-Yue Zhang1, Qun Wei2, Yi-Jian Yang1, Cheng Qian1, Bi-Mang Fu1, Nan Xie1, Lei Wei1, Chun-Man Li1, Ying-Zhen Su3, *
Affiliations
  • 1Department of Hepatobiliary and Pancreatic Surgery, the Second Affiliated Hospital of Kunming Medical University, Kunming 650032, China
  • 2Department of Pathology, the Second Affiliated Hospital of Kunming Medical University, Kunming 650032, China
  • 3Department of Laboratory Medicine and Preventive Medicine, School of Medicine, Kunming University, Kunming 650214, China
出版时间: 2022-04-28 doi: 10.11855/j.issn.0577-7402.2022.04.0367
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摘要
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目的 探讨结直肠癌(CRC)组织中TGFβR2的表达与微卫星不稳定性(MSI)的相关性，以及两者与CRC患者临床病理参数的关系。方法 收集2019年1月1日－9月30日昆明医科大学第二附属医院收治的184例CRC患者的CRC组织及癌旁组织，采用多重荧光PCR毛细管电泳法(CE)检测MSI，免疫组化染色(IHC)检测MMR和TGFβR2蛋白的表达情况。采用Kappa一致性检验分析IHC与CE检测MSI结果的一致性。qRT-PCR检测TGFβR2 mRNA的表达情况。采用秩和检验分析TGFβR2基因突变与MSI的相关性以及TGFβR2 mRNA相对表达量与临床病理参数的关系。结果 184例CRC组织样本中，152例(82.6%，152/184)为微卫星低度不稳定(MSI-L)/微卫星稳定(MSS)，32例(17.4%，32/184)为微卫星高度不稳定(MSI-H)。CE与IHC检测MSI的主体结果具有高度一致性，Kappa一致性系数为0.922(P<0.001)。与MSI-L/MSS相比，MSI-H多发生于无淋巴结转移、TNM分期Ⅰ－Ⅱ期的CRC(P<0.05)。TGFβR2 mRNA和蛋白在CRC组织中的表达低于癌旁组织(P<0.01)。TGFβR2基因在MSI-H CRC组织中的突变率高于MSI-L/MSS CRC组织[93.3%(28/30) vs. 14.9%(23/154)，P<0.01]。TGFβR2 mRNA相对表达量在MSI-H肿瘤中高于MSI-L/MSS肿瘤(7.93±0.36 vs. 4.47±1.31，P<0.01)，在癌旁组织中高于CRC组织(9.38±0.82 vs.4.76±1.63，P<0.01)。在无远处转移、无淋巴结转移、TNM分期Ⅰ－Ⅱ期的CRC组织中，TGFβR2 mRNA相对表达量较高(P<0.05)。结论 MSI与TGFβR2的表达在肿瘤发生部位、是否发生淋巴结转移及TNM分期方面存在一致性及协同性。

结直肠癌  /  转化生长因子β Ⅱ型受体  /  微卫星不稳定  /  临床病理参数

Objective To investigate the correlation between the expressions of TGFβR2 and microsatellite instability (MSI) in colorectal cancer (CRC) tissues, and the relationship between the two protein molecules and clinicopathological parameters. Methods The CRC and adjacent tissues of 184 patients with CRC pathologically diagnosed in the Second Affiliated Hospital of Kunming Medical University from January 1, 2019 to September 30, 2019 were collected, the expression of MSI was detected by capillary electrophoresis (CE), and the expressions of MMR and TGFβR2 proteins were detected by immunohistochemistry (IHC). Kappa consistency test was used to analyze the consistency of IHC and CE MSI results. The relative TGFβR2 mRNA expression was detected by quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR). Rank sum test was used to analyze the correlation between TGFβR2 gene mutation and MSI, and the relationship between TGFβR2 mRNA relative expression level and clinicopathological parameters. Results Among 184 CRC tissue samples, 152 cases (82.6%,152/184) were microsatellite instability low-frequency (MSI-L)/microsatellite stability (MSS) and 32 cases (17.4%, 32/184) were microsatellite instability high-frequency (MSI-H). The main results of MSI detected by CE and IHC were highly consistent, and the Kappa consistency coefficient was 0.922 (P<0.001). Compared with MSI-L/MSS, MSI-H mostly occurred in patients with stagesⅠ-Ⅱ colon cancer without lymph node metastasis (P<0.05). The protein and mRNA expression levels of TGFβR2 in CRC tissues were higher than those in the adjacent tissues (P<0.01). The mutation rate of TGFβR2 gene in MSI-H CRC was higher than that in MSI-L/MSS CRC [93.3%(28/30) vs. 14.9%(23/154), P<0.01]. The relative expression of TGFβR2 mRNA in MSI-H group was higher than that in MSI-L/MSS group (7.93±0.36 vs. 4.47±1.31, P<0.01), was higher in para-cancer tissues than in CRC tissues(9.38±0.82 vs. 4.76±1.63, P<0.01). The relative expressions of TGFβR2 mRNA in colon, tumors without metastasis, lymph node without metastasis and TNM Ⅰ-Ⅱ stages CRC tissues were higher (P<0.05). Conclusion The expressions of MSI and TGFβR2 are consistent and synergistic in tumor site, lymph node metastasis, and TNM stage.

colorectal cancer  /  transforming growth factor β receptor Ⅱ  /  microsatellite instability  /  clinicopathological parameters
张楚悦, 危群, 杨裔坚, 钱程, 付必莽, 谢楠, 魏雷, 李春满, 苏莹珍. TGFβR2与MSI在结直肠癌中的相关性及临床病理学意义. 解放军医学杂志, 2022 , 47 (4) : 367 -374 . DOI: 10.11855/j.issn.0577-7402.2022.04.0367
Chu-Yue Zhang, Qun Wei, Yi-Jian Yang, Cheng Qian, Bi-Mang Fu, Nan Xie, Lei Wei, Chun-Man Li, Ying-Zhen Su. Correlation between TGFβR2 and MSI in colorectal cancer and its clinicopathological significance[J]. Medical Journal of Chinese People’s Liberation Army, 2022 , 47 (4) : 367 -374 . DOI: 10.11855/j.issn.0577-7402.2022.04.0367
正文
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结直肠癌(colorectal cancer，CRC)是发生于大肠黏膜上皮和腺体的恶性肿瘤，大多数呈散发性[1-2]，仅少数有遗传背景，其中遗传性非息肉病性大肠癌[又称林奇综合征(Lynch syndrome，LS)]占CRC的3%~5%，90%以上的LS和10%~15%的散发性CRC与微卫星不稳定性(microsatellite instability，MSI)有关[3]。转化生长因子β Ⅱ型受体(transforming growth factor β receptor Ⅱ，TGFβR2)基因位于人染色体3p22，含有6个内含子和7个外显子，编码蛋白分子量为70~80 kD，由567个氨基酸组成属于丝氨酸/苏氨酸蛋白激酶受体家族[4]。TGFβR2在CRC中表达缺失或下降可促进肿瘤的发生和发展，且90%以上的TGFβR2突变发生在MSI CRC中[4]。本研究探讨CRC中TGFβR2表达与MSI的关系，分析两者与CRC临床病理参数的相关性，以期为获得可用于CRC早期诊断、治疗及病情评价的生物标志物奠定基础，为探寻CRC靶向治疗及免疫检查点治疗的新靶点提供思路。
1 资料与方法
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1.1 研究对象
收集2019年1月1日－9月30日于昆明医科大学第二附属医院接受结直肠癌根治性手术的184例CRC患者的CRC组织(原发病灶组织)及癌旁组织(结肠癌切缘距离肿瘤≥10 cm、中高位直肠癌远端切缘距离肿瘤≥5 cm、低位直肠癌远端切缘距离肿瘤≥2 cm)，其中，结肠包括升结肠、横结肠、降结肠和乙状结肠。纳入标准：术前未接受放疗、化疗等任何治疗；临床资料和组织病理学资料完整。排除标准：合并其他恶性肿瘤；复发性结直肠癌；手术未达到R0切除；术中淋巴结清扫不足12个。CRC患者各项病理资料(包括性别、年龄、肿瘤发生部位、肿瘤最大直径、分化程度、淋巴结转移个数、TNM分期、组织病理类型、肿瘤浸润深度、是否有脉管内癌栓、肿瘤有无远处转移)由昆明医科大学第二附属医院病理科提供。病理分期标准按照美国癌症联合委员会(AJCC)/国际抗癌联盟(UICC)结直肠癌TNM分期系统(2017年第八版)确定。本研究经昆明医科大学医学伦理委员会审核。
1.2 主要试剂及仪器
MLH1(MAB-0838)、MSH2(MAB-0836)、MSH6(MAB-0831)、PMS2(MAB-0656)抗体及羊抗小鼠/兔IgG聚合物二抗购自福州迈新生物技术开发有限公司；兔抗TGFβR2抗体(ab270440)购自英国Abcam公司；DNA提取试剂盒(TSP201-200)购自北京擎科生物科技有限公司；反转录试剂盒EntiLinkTM 1st Strand cDNA Synthesis Kit购自上海翊圣生物科技有限公司；EnTurboTM SYBR Green PCR SuperMix试剂盒购自武汉ELK Biotechnology公司。组织切片处理机购自德国Leica公司；倒置显微镜IX53购自日本Olympus公司；PCR仪购自杭州朗基科学仪器有限公司；StepOneTM qRT-PCR仪购自美国Life Technologies公司。
1.3 免疫组化染色(IHC)检测错配修复(mismatch repair，MMR)蛋白和TGFβR2蛋白的表达情况
取CRC组织和癌旁组织，加入10%多聚甲醛溶液固定12~24 h，经脱水、透明、石蜡包埋制成石蜡块，切片后脱蜡和复水，EDTA法进行抗原修复，30%过氧化氢室温孵育15 min阻断内源性过氧化物酶；滴加MLH1(1:250)、MSH2(1:250)、MSH6(1:250)、PMS2(1:250)一抗，于37 ℃恒温箱中孵育1h；滴加即用型羊抗小鼠/兔IgG聚合物二抗，于37 ℃恒温箱中孵育0.5 h，DAB显色0.5~1 min后复染，中性树胶封片。显微镜下观察MMR蛋白和TGFβR2蛋白的表达情况。MMR蛋白包括MLH1、MSH2、MSH6和PMS2，其中4种MMR蛋白均表达提示为微卫星低度不稳定(microsatellite instability low-frequency，MSI-L)/微卫星稳定(microsatellite stability，MSS)，1种或多种MMR蛋白表达缺失提示为微卫星高度不稳定(microsatellite instability high-frequency，MSI-H)，阳性判定标准参照文献[5]。依据IHC检测结果，将184例CRC患者分为MSI-H组与MSI-L/MSS组，比较两组的临床病理参数。
1.4 多重荧光PCR毛细管电泳法(CE)检测MSI
采用动物DNA提取试剂盒(TSP201-200)提取CRC组织和癌旁组织DNA，5'端合成5/6-羟基荧光素(FAM)引物，R引物合成PAGE引物，DNA样品稀释后作为PCR模板，以2×TSINGKE Master Mix (blue)进行扩增，将扩增后的PCR产物进行琼脂糖凝胶电泳(电压300 V，时间12 min)，获取鉴定胶图，加水稀释至毛细管电泳所需浓度后行毛细管检测，收集数据进行统计分析。
1.5 实时荧光定量PCR(qRT-PCR)检测TGFβR2 mRNA相对表达量
提取CRC组织和癌旁组织总RNA，按照反转录试剂盒EntiLinkTM 1st Strand cDNA Synthesis Kit说明书步骤合成cDNA，使用EnTurboTM SYBR Green PCR SuperMix试剂盒进行扩增，每个样品设置3个复孔。反应条件：95 ℃预变性30 s；95 ℃变性10 s，60 ℃退火20 s，72 ℃延伸20 s，共40个循环。以GAPDH为内参，采用2–ΔΔCt法计算TGFβR2 mRNA相对表达量。引物序列如表1所示。
1.6 IHC与CE检测MSI结果的一致性分析
采用Kappa一致性检验分析IHC与CE检测MSI结果的一致性。
1.7 统计学处理
应用SPSS 26.0软件进行统计分析。计量资料以$\bar{x}±s$表示，经大样本正态性检验，TGFβR2 mRNA相对表达量不服从正态分布，其与临床病理参数的关系分析采用配对样本非参数秩和检验；TGFβR2 mRNA在MSI-H组和MSI-L/MSS组中的表达分析采用Wilcoxon符号两独立样本秩和检验；TGFβR2 mRNA在CRC组织和癌旁组织中的表达分析采用配对样本非参数秩和检验；计数资料以例(%)表示。P<0.05为差异有统计学意义。
2 结果
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2.1 CRC组织及癌旁组织样本的MSI状态
CE检测结果显示，184例CRC组织样本中，152例(82.6%，152/184)为MSI-L/MSS，表现为只有一个位点不稳定(MSI-L)，或无不稳定位点(MSS)；32例(17.4%，32/184)为MSI-H，表现为两个或多个位点不稳定(图1、表2)。
IHC检测结果显示，4种MMR蛋白阳性反应产物定位于细胞核，为棕黄色或棕褐色颗粒。184例CRC组织样本中，154例(83.7%，154/184)为MSI-L/MSS，表现为4种MMR蛋白均表达；30例(16.3%，30/184)为MSI-H，表现为1种或多种MMR蛋白表达缺失(图1、表2)。
2.2 CE与IHC检测MSI结果的一致性
Kappa检验结果显示，Kappa一致性系数为0.922(P<0.001)，拒绝接受零假设，CE与IHC检测MSI的主体结果存在高度一致性(表2)。
2.3 MSI-H组与MSI-L/MSS组CRC患者临床病理参数比较
依据IHC检测结果，将184例CRC患者分为MSI-H组(n=30)与MSI-L/MSS组(n=154)，MSI-H多发生于结肠、无淋巴结转移及TNM分期Ⅰ－Ⅱ期的CRC，MSI-L/MSS多发生于高、中分化的CRC(P<0.05，表3)。
2.4 TGFβR2蛋白在CRC组织中的表达情况
IHC检测结果显示，TGFβR2蛋白阳性反应产物定位于细胞膜和细胞质，颜色为棕褐或棕黄色，在细胞膜上呈线状，在细胞质内呈弥漫状。TGFβR2蛋白在CRC组织中低表达或不表达，阳性表达率为27.7%(51/184)；在癌旁组织中高表达，阳性表达率为85.9%(158/184)，差异有统计学意义(P<0.01)(图2)。
2.5 TGFβR2基因突变与MSI的关系
30例MSI-H CRC组织中，28例(93.3%，28/30)TGFβR2蛋白表达缺失；154例MSI-L/MSS CRC组织中，23例(14.9%，23/154)TGFβR2蛋白表达缺失。TGFβR2基因在MSI-H CRC组织中的突变率高于MSI-L/MSS CRC组织(χ2=77.028，P<0.01)。
2.6 TGFβR2mRNA在CRC组织中的表达情况
qRT-PCR检测结果显示，MSI-H组TGFβR2 mRNA相对表达量高于MSI-L/MSS组，差异有统计学意义(7.93±0.36 vs. 4.47±1.31，Z=–4.782，P<0.01，图3A)；癌旁组织中TGFβR2 mRNA相对表达量高于CRC组织，差异有统计学意义(9.38±0.82 vs.4.76±1.63，Z=–11.763，P<0.01，图3B)。
2.7 TGFβR2mRNA相对表达量与临床病理参数的关系
TGFβR2 mRNA相对表达量在无远处转移、无淋巴结转移、TNM分期Ⅰ－Ⅱ期的CRC组织中较高，差异有统计学意义(P<0.05，表4)。
3 讨论
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微卫星DNA广泛分布于原核及真核生物基因组中，最主要的特征是突变率非常低，可作为衡量基因组稳定性的良好标志物。MMR系统出现异常会引起错配修复功能缺陷(deficient mismatch repair，dMMR)，使微卫星的复制错误无法及时纠正并不断积累造成MSI[6-8]。由于MSI肿瘤中大量基因突变，产生了多种新的特异性抗原，这些新抗原在体内经过加工、提呈和识别激活了免疫系统，因此MSI肿瘤预后较好[9]。研究发现，MSI CRC患者大多表现为TNM分期较早、较少发生淋巴结转移和远处转移，对化疗药物5-氟尿嘧啶(5-FU)耐受[10]，而对细胞程序性死亡受体1(programmed cell death 1 ligand 1，PD-L1)抑制剂(如帕博利珠单抗和纳武利尤单抗)敏感，是CRC预后评估和疗效评价的有效指标[10-11]。
TGFβ信号通路在肿瘤的发生发展中起着重要作用，TGFβ结合TGFβR2是该信号通路的起点[12]。TGFβR2广泛分布于正常细胞和肿瘤细胞表面。有研究发现，TGFβR2在肿瘤中表达缺失或下降能促进肿瘤的发生和进展，提示TGFβR2是一种抑癌基因，TGFβR2在CRC组织中较正常组织表达下调，且TGFβR2低表达的CRC患者整体生存率低于TGFβR2高表达的患者[4]，因此，TGFβR2可作为独立的预后因子。Grady等[13]对38种CRC细胞株进行研究发现，其中11种表现为MSI(其中9种CRC细胞株中TGFβR2表达缺失)，27种表现为MSS(其中3种CRC细胞株中TGFβR2表达缺失)，因此TGFβR2突变与伴有MSI的CRC密切相关。
本研究采用IHC检测184例CRC组织样本发现，dMMR表型有30例，pMMR表型有154例；采用CE检测CRC组织样本发现，30例dMMR表型CRC组织中有29例为MSI-H，1例为MSI-L/MSS；154例pMMR表型CRC组织中有3例为MSI-H，151例为MSI-L/MSS。假设CE检测结果为真，则IHC检测的敏感度和特异度分别为90.6%和99.3%，两者准确度的一致性为97.8%；假设IHC检测结果为真，则CE检测的敏感度和特异度分别为96.7%和98.1%，两者准确度的一致性为97.8%。由于IHC的敏感度高于CE，因此本研究数据以IHC检测结果为准，即184例CRC样本中，dMMR表型有30例，pMMR表型有154例。通过Kappa检验得出，Kappa一致性系数为0.922(P<0.05)，拒绝接受零假设，CE与IHC检测的主体结果存在高度一致性(表2)。两种方法检测的结果差异有统计学意义且一致性为97.8%，与Shia等[14]的研究结果相近。对比分析两种方法检测MSI的结果，发现IHC的敏感度高于CE，而特异度相反，与Karahan等[15]的研究结果一致。因此，使用简便、快捷且经济的IHC检测CRC组织MMR蛋白可作为一种初筛手段，易于在临床工作中开展。Ashktorab等[16]收集1997－2015年15 105例CRC患者进行Meta分析，结果显示，Ⅲ期和Ⅳ期CRC患者多表现为MSI-H，本研究结果与之不一致。分析其原因为，本研究对象为术后CRC患者且大多数TNM分期较早，而大部分Ⅳ期患者接受了放化疗及靶向药物治疗，接受手术患者较少，并且Ashktorab等[16]的研究起始时间为1997年，时间偏早且筛查手段和诊断技术受到限制，大多数患者在治疗时处于晚期。本研究中MSI-H CRC患者多为Ⅰ－Ⅱ期，与MSI-L/MSS组相比，MSI-H组患者较少出现淋巴结转移，可能与MSI-H引起较强的免疫反应有关，后者可以协助机体抵抗肿瘤细胞对机体的攻击，从而抑制肿瘤向淋巴结转移，最终导致MSI-H肿瘤较MSI-L/MSS肿瘤预后好。本研究中MSI-H CRC多无肿瘤远处转移，与Ward等[17]的研究结果一致，但由于本研究纳入样本量有限，所以无明显统计学差异。
TGFβ信号通路在肿瘤的发生发展中起着重要作用，TGFβ结合TGFβR2是该信号通路的起点[18]。研究发现，TGFβR2为抑癌基因[4]。王朝晖等[19]发现，伴有MSI的18例CRC中，16例发生TGFβR2突变，突变率为88.9%，与本研究结果一致。本研究运用qRT-PCR分别对MSI-H组和MSI-L/MSS组CRC患者TGFβR2 mRNA的表达情况进行检测，结果显示，与癌旁组织相比，CRC组织中TGFβR2 mRNA相对表达量降低，分析原因可能与TGFβR2阻碍肿瘤细胞的生长、扩散有关，但其具体作用机制尚未明确。与MSI-H组相比，MSI-L/MSS组中TGFβR2 mRNA相对表达量偏低，这可能与研究样本的差异以及CRC的复杂性有关。MSI和TGFβR2的表达与临床病理特征中肿瘤发生部位、淋巴结是否转移、TNM分期和肿瘤有无远处转移有关。MSI-H多发生于结肠，TGFβR2在结肠部位的表达量偏高；MSI-H CRC倾向于淋巴结转移阴性，TGFβR2在淋巴结无转移的CRC组织中表达量偏高；MSI-H CRC的TNM分期大多为Ⅰ－Ⅱ期，TGFβR2在Ⅰ－Ⅱ期CRC组织中表达偏高，且两者均与性别、年龄、病理类型及肿瘤浸润深度无关。
本研究存在以下局限性：(1)由于入组患者有限，研究结果可能存在偏倚；(2)采用CE和IHC检测CRC的MSI状态时未进行相关基因测序分析，且两种检测结果的对比分析缺乏金标准，因此得到的数据可能存在偏差；(3)对可疑的LS患者，未收集其家族史信息，缺乏完整的家系资料，影响了本研究分析的深度和广度。
综上所述，MSI-H CRC预后较好可能与TGFβR2低表达或缺失有关，TGFβR2低表达或缺失与MSI关系密切。基于MSI和TGFβR2的分子机制并结合其特点，对个体化治疗具有指导意义，或可成为评估CRC生存预后的驱动基因；通过评价CRC中TGFβR2的表达与临床病理特征的关系，或可寻找到预测CRC患者生存预后的新的生物标志物。
基金
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  • 云南省科技计划项目(202001BA070001-045)
  • 云南省科技计划项目(202001AY070001-213)
  • 云南省教育科学研究基金(2019J0567)
  • 昆明学院引进人才科研项目(YJL18019)
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2022年第47卷第4期
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doi: 10.11855/j.issn.0577-7402.2022.04.0367
  • 接收时间：2021-03-06
  • 首发时间：2025-12-17
  • 出版时间：2022-04-28
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出版历史
  • 收稿日期：2021-03-06
  • 录用日期：2021-08-24
基金
Yunnan Science and Technology Basic Research Project(202001BA070001-045)
云南省科技计划项目(202001BA070001-045)
Yunnan Science and Technology Basic Research Project(202001AY070001-213)
云南省科技计划项目(202001AY070001-213)
Yunnan Educational Science Research Fund(2019J0567)
云南省教育科学研究基金(2019J0567)
Technical Talents Introduction Program of Kunming University(YJL18019)
昆明学院引进人才科研项目(YJL18019)
作者信息
    1昆明医科大学第二附属医院肝胆胰外科，昆明 650032
    2昆明医科大学第二附属医院病理科，昆明 650032
    3昆明学院医学院公共卫生教研室，昆明 650214

通讯作者:

苏莹珍，E-mail：
参考文献
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https://castjournals.cast.org.cn/joweb/jfjyxzz/CN/10.11855/j.issn.0577-7402.2022.04.0367
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2种不同金属材料的力学参数
科
Family		 属数
Number of
genus		 种数
Number of
species		 占总种数比例
Percentage of
total species (%)		 属
Genus		 种数
Number of
species		 占总种数比例
Percentage of total
species (%)
鹅膏菌科Amanitaceae 2 11 5.26 鹅膏菌属 Amanita 10 4.78
小菇科 Mycenaceae 2 12 5.74 丝盖伞属 Inocybe 5 2.39
多孔菌科 Polyporaceae 8 14 6.70 蜡蘑属 Laccaria 5 2.39
红菇科 Russulaceae 3 23 11.00 小皮伞属 Marasmius 6 2.87
小菇属 Mycena 11 5.26
光柄菇属 Pluteus 5 2.39
红菇属 Russula 17 8.13
栓菌属 Trametes 5 2.39
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