Introduction of v-Ha-ras oncogene induces differentiation of cultured human medullary thyroid carcinoma cells.
Introduction of v-Ha-ras oncogene induces differentiation of cultured human medullary thyroid carcinoma cells.
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引入v-Ha-ras癌基因可诱导培养的人甲状腺髓样癌细胞的分化。
DOI：
10.1073/pnas.84.16.5923
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发表时间：
1987
影响因子：
11.1
通讯作者：
Baylin,SB
中科院分区：
文献类型：
--
作者：
Nakagawa,T;Mabry,M;deBustros,A;Ihle,JN;Nelkin,BD;Baylin,SB
甲状腺髓样癌(MTC)是一种甲状腺C细胞的内分泌肿瘤，表达高水平的神经内分泌肽激素降钙素。在宿主的肿瘤进展过程中，MTC细胞有明显的分化丧失，包括肿瘤细胞降钙素含量的持续下降，伴随着降钙素基因表达的减少和/或远离亲代甲状腺C细胞特征的mRNA替代加工模式的变化。我们现在报道，将病毒Harvey ras(v-Ha-ras)癌基因导入培养的人MTC细胞可以逆转这种基因表达的变化，并可以诱导肿瘤细胞的内分泌分化。V-Ha-ras的表达与细胞增殖和DNA合成减少有关。细胞质分泌颗粒的数量明显增加，这是分化的甲状腺C细胞的典型特征。V-Ha-ras的表达诱导降钙素基因表达增加，原基因转录本的加工转移到有利于降钙素基因相关肽(CGRP)mRNA的产生。这些对培养的人MTC细胞的研究为研究Ha-ras及其相关基因在神经内分泌分化中的作用提供了一个模型系统。这一发现表明了一种重要的方法来识别实体肿瘤中表达变化的基因，这些基因的表达变化可能在肿瘤进展过程中癌细胞成熟能力受损的特征中发挥作用。
Medullary thyroid carcinoma (MTC) is an endocrine tumor of the thyroid C cells that expresses high levels of the neuroendocrine peptide hormone calcitonin. During tumor progression in the host, there is an apparent loss of differentiation in MTC cells that involves a consistent decrease in calcitonin content of the tumor cells associated with decreased expression of the calcitonin gene and/or changes in a mRNA alternative-processing pattern away from that characteristic of the parent thyroid C cell. We now report that introduction of the viral Harvey ras (v-Ha-ras) oncogene into cultured human MTC cells can reverse such changes in gene expression and can induce endocrine differentiation of the tumor cells. The expression of v-Ha-ras is associated with decreased cellular proliferation and DNA synthesis. There is a marked increase in the number of cytoplasmic secretory granules that are a classic feature of differentiated thyroid C cells. v-Ha-ras expression induces increased expression of the calcitonin gene and the processing of the primary gene transcript is shifted to favor calcitonin mRNA rather than calcitonin-gene-related peptide (CGRP) mRNA production. These studies with cultured human MTC cells provide a model system to study the role of Ha-ras and related genes in neuroendocrine differentiation. The findings suggest an important approach for identifying genes in solid tumors whose altered expression may play a role in the impaired maturational capacity characteristic of cancer cells during tumor progression.