Microsatellite instability (MSI) has been recognized as an important factor in colorectal cancer (CRC). It arises due to deficient mismatch repair (MMR), mostly attributed to MLH1 and MSH2 loss of function leading to a global MMR defect affecting mononucleotide and longer microsatellite loci. Recently, microsatellite instability at tetranucleotide loci, independent of the global MMR defect context, has been suggested to represent a distinct entity with possibly different consequences for tumorigenesis. It arises as a result of an isolated MSH3 loss of function due to its translocation from the nucleus to the cytoplasm under the influence of interleukin-6 (IL-6). In this study the influence of MSH3 and IL-6 signaling pathway polymorphisms (MSH3exon 1,MSH3+3133A/G,IL-6-174G/C,IL-6R+48892A/C, andgp130+148G/C) on the occurrence of different types of microsatellite instability in sporadic CRC was examined by PCR–RFLP and real-time PCR SNP analyses. A significant difference in distribution ofgp130+148G/Cgenotypes (p= 0.037) and alleles (p= 0.031) was observed in CRC patients with theCallele being less common in tumors with di- and tetranucleotide instability (isolated MSH3 loss of function) compared to tumors without microsatellite instability. A functional polymorphism in gp130 might modulate the IL-6 signaling pathway, directing it toward the occurrence of microsatellite instability corresponding to the IL-6-mediated MSH3 loss of function.
微卫星不稳定性（MSI）已被确认为结直肠癌（CRC）的重要影响因素。其产生源于错配修复（MMR）功能缺陷，主要归因于MLH1和MSH2功能丧失导致的整体MMR缺陷，进而影响单核苷酸及更长微卫星位点。近期研究表明，四核苷酸位点的微卫星不稳定性独立于整体MMR缺陷背景，可能代表一种具有不同致癌机制的特殊类型。这种不稳定性由MSH3功能孤立性丧失引起，其机制是在白细胞介素-6（IL-6）作用下，MSH3从细胞核易位至细胞质所致。本研究通过PCR-RFLP和实时PCR SNP分析技术，探讨了MSH3及IL-6信号通路基因多态性（MSH3外显子1、MSH3+3133A/G、IL-6-174G/C、IL-6R+48892A/C和gp130+148G/C）对散发性结直肠癌中不同类型微卫星不稳定性发生的影响。结果显示，与无非卫星不稳定性的肿瘤相比，具有二核苷酸和四核苷酸不稳定性（孤立性MSH3功能丧失）的CRC患者中，gp130+148G/C基因型（p=0.037）和等位基因（p=0.031）分布存在显著差异，其中C等位基因在具有此类不稳定性的肿瘤中出现频率较低。gp130的功能性多态性可能通过调节IL-6信号通路，促使肿瘤发生与IL-6介导的MSH3功能丧失相对应的微卫星不稳定性。
肿瘤(癌症)患者之家