Li X J, Wang D Y, Zhu Y, Guo R J, Wang X D, Lubomir K, Mukai K, Sasaki H, Yoshida H, Oka T, Machinami R, Shinmura K, Tanaka M, Sugimura H
First Department of Pathology, Hamamatsu University School of Medicine.
Jpn J Cancer Res. 1999 Jul;90(7):740-6. doi: 10.1111/j.1349-7006.1999.tb00809.x.
Mxi1 is thought to negatively regulate Myc function and may therefore be a potential tumor suppressor gene. Little effort has yet been made to find alterations involving this gene in human solid tumors. We screened 31 human gastric cancers, 7 esophageal cancers, 85 bone and soft tissue tumors of various types, including 4 neurofibrosarcomas. We also examined 29 human tumor cell lines consisting of 12 esophageal cancers, 7 glioma/glioblastomas and 10 others for Mxi1 mutations in exons 1, 2, 4 (HLH domain), 5 and 6. Polymerase chain reaction-single-strand conformation polymorphism (PCR-SSCP) and subsequent sequencing revealed three distinct polymorphisms in the intron-exon boundary upstream from exon 6. We discovered a missense mutation, GCA to GTA (Ala 54 Val), in exon 2 in a neurofibrosarcoma patient (case 1), two missense mutations, AAA to CAA (Lys 118 Gln) and GAA to GGA (Glu 154 Gly) in exon 5 of another neurofibrosarcoma patient (case 2), and 3 amino acid substitutions, GTG to GCG (Val 179 Ala), GTT to GCT (Val 181 Ala) and TTC to CTC (Phe 186 Leu), in a third neurofibrosarcoma patient (case 3). In case 3, loss of heterozygosity was also demonstrated by informative (TTC)3/(TTC)2 polymorphism. Our data demonstrate that mutations occur in the Mxi1 gene in neurofibrosarcoma. Missense mutations in the functional domain of Mxi1 in these cases may be involved in the pathogenesis of neurofibrosarcoma.
Mxi1被认为对Myc功能起负调控作用，因此可能是一种潜在的肿瘤抑制基因。在人类实体瘤中，尚未开展太多工作来寻找涉及该基因的改变。我们筛查了31例人类胃癌、7例食管癌、85例各种类型的骨和软组织肿瘤，包括4例神经纤维肉瘤。我们还检测了29种人类肿瘤细胞系，其中包括12例食管癌、7例神经胶质瘤/胶质母细胞瘤以及10种其他肿瘤细胞系，以查找外显子1、2、4（HLH结构域）、5和6中的Mxi1突变。聚合酶链反应-单链构象多态性（PCR-SSCP）及后续测序揭示了外显子6上游内含子-外显子边界处的三种不同多态性。我们在一名神经纤维肉瘤患者（病例1）的外显子2中发现了一个错义突变，即GCA突变为GTA（丙氨酸54变为缬氨酸）；在另一名神经纤维肉瘤患者（病例2）的外显子5中发现了两个错义突变，分别是AAA突变为CAA（赖氨酸118变为谷氨酰胺）和GAA突变为GGA（谷氨酸154变为甘氨酸）；在第三名神经纤维肉瘤患者（病例3）中发现了3个氨基酸替换，分别是GTG变为GCG（缬氨酸179变为丙氨酸）、GTT变为GCT（缬氨酸181变为丙氨酸）以及TTC变为CTC（苯丙氨酸186变为亮氨酸）。在病例3中，通过信息性（TTC）3/（TTC）2多态性也证实了杂合性缺失。我们的数据表明，神经纤维肉瘤中存在Mxi1基因突变。这些病例中Mxi1功能域的错义突变可能与神经纤维肉瘤的发病机制有关。
