Molecular Analyses of h-Warts/Latsl Alterations in Human neoplasms

人类肿瘤中 h-Warts/Latsl 改变的分子分析

• 批准号: 12670184
• 负责人: HASHIMOTO Hiroshi
• 金额: $ 1.92万
• 依托单位: University of Occupational and Environmental Health
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2000
• 资助国家: 日本
• 起止时间: 2000 至 2002
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-12670184/
• 关键词: Soft tissue tumor; Tumor suppressor gene; Lats1; Gene analysis; Molecular cytogenetics; Gene promoter; Methylated CpG; 卵巣腫瘍; RT-PCR; サザンブロット法; PCR-SSCP

h-Warts/LATS1 is a human homologue of the Drosophila warts tumor suppressor gene, that functions as a component of the mitotic apparatus, and LATS1-deficient (Lats1^+) mice have been reported to develop ovarian stromal tumors and soft tissue sarcomas. We investigated the status of the h-Warts/LATS1 in 50 human soft tissue sarcomas to address its potential function as a tumor suppressor in human sarcoma development. In our reverse transcription-polymerase chain reaction (PCR) assay, 7 (14%) (3 of 4 myxoid liposarcomas, 3 of 7 leiomyosarcomas, 1 of 9 malignant fibrous histiocytomas) of 50 sarcomas examined had no or a reduced expression of the h-Warts/LATS1, indicating down-regulated gene expression. We further analyzed alterations of the h-Warts/LATS1 in these 7 sarcomas. Using microsatellite markers for chromosome 6q23-25.1 to which the h-Warts/LATS1 is localized, an allelic loss of this locus was detected in one leiomyosarcoma, in which a misssense point mutation of the h-Warts/LATS1 was detected by PCR-single-strand conformation polymorphism. Clusters of CpG dinucleotides in a 5' putative promoter region were hypermethylated in the other 6 sarcomas. Our data suggest that the molecular alterations of the h-Warts/LATS1 could be of pathological importance in human sarcomagenesis, and provide potential clues for further clinical treatments of human soft tissue sarcomas.

h-Warts/LATS 1是果蝇疣肿瘤抑制基因的人类同源物，作为有丝分裂装置的一个组成部分发挥作用，LATS 1缺陷（Lats 1 ^+）小鼠已被报道发生卵巢间质瘤和软组织肉瘤。我们研究了h-Warts/LATS 1在50例人类软组织肉瘤中的状态，以解决其在人类肉瘤发展中作为肿瘤抑制因子的潜在功能。在我们的逆转录-聚合酶链反应（PCR）检测中，50例肉瘤中有7例（14%）（4例粘液样脂肪肉瘤中的3例，7例平滑肌肉瘤中的3例，9例恶性纤维组织细胞瘤中的1例）没有h-Warts/LATS 1表达或表达减少，表明基因表达下调。我们进一步分析了h-Warts/LATS 1在这7例肉瘤中的改变。利用染色体6 q23 -25.1的微卫星标记，h-Warts/LATS 1定位，该基因座的等位基因丢失检测在一个平滑肌肉瘤，其中的错义点突变的h-Warts/LATS 1的PCR-单链构象多态性检测。在其他6例肉瘤中，5'端启动子区的CpG二核苷酸簇呈高甲基化。我们的数据表明h-Warts/LATS 1的分子改变可能在人类软组织肉瘤的发生中具有重要的病理意义，并为人类软组织肉瘤的进一步临床治疗提供了潜在的线索。

项目成果

Sumika Okamoto: "Juxta-articular myxoma and intramuscular myxoma are two distinct entities. Activating Gsα mutation at Arg 201 codon does not occur in juxta-articular myxoma"Virchows Archiv. 440・1. 12-15 (2002)

Sumika Okamoto：“关节旁粘液瘤和肌内粘液瘤是两个不同的实体。在关节旁粘液瘤中不会发生 Arg 201 密码子处的激活 Gsα 突变”Virchows Archive 440・1 (2002)。

Li X-Q, Hisaoka M, Morio T, Hashimoto H.: "Intranasal pericytic tumors (glomus tumor and sinonasal hemangiopericytoma-like tumor): report of two cases with review of the literature"Pathol Int. 53 (in press).

李X-Q，Hisaoka M，Morio T，Hashimoto H.：“鼻内周细胞肿瘤（血管球瘤和鼻窦血管外皮细胞瘤样肿瘤）：两例报告并文献复习”Pathol Int.

Hisaoka M, Okamoto S, Koyama S, Ishida T, Imamura T, Kanda H, Kameya T, Meis-Kindblom JM, Kindblom L-G, Hashimoto H.: "Microtubule-associated protein-2 and class III β-tubulin are expressed in extraskeletal myxoid chodrosarcoma"Med Pathol. 16 (in press).

Hisaoka M、Okamoto S、Koyama S、Ishida T、Imamura T、Kanda H、Kameya T、Meis-Kindblom JM、Kindblom L-G、Hashimoto H.：“微管相关蛋白 2 和 III 类 β-微管蛋白在骨骼外表达粘液样软骨肉瘤”Med Pathol.16（印刷中）。

Masanori Hisaoka: "Specific but variable expression of h-caldesmon in leiomyosarcomas. An immunohistochemical reassessment of a novel myogenic marker"Applied Immunohistochemistry & Molecular Morphology. 9・4. 302-308 (2001)

Masanori Hisaoka：“h-caldesmon 在平滑肌肉瘤中的特异性但可变的表达。新型肌源性标记物的免疫组织化学重新评估”应用免疫组织化学和分子形态学 9·4（2001）。

Masanori Hisaoka: "Gene expression of TrkC (NTRK3) in human soft tissue tumours"Journal of Pathology. 197・8. 661-667 (2002)

Masanori Hisaoka：“人软组织肿瘤中TrkC（NTRK3）的基因表达”病理学杂志197・8（2002）。