Introduction of v-Ha-ras oncogene induces differentiation of cultured human medullary thyroid carcinoma cells.
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.
D002116:Calcitonin / Q000235:genetics / Q000378:metabolism; D015740:Calcitonin Gene-Related Peptide; D002277:Carcinoma / Q000235:genetics* / Q000473:pathology; D002454:Cell Differentiation; D002478:Cells, Cultured; D019204:GTP-Binding Proteins / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D008854:Microscopy, Electron; D009479:Neuropeptides / Q000235:genetics; D009857:Oncogenes; D011493:Protein Kinase C / Q000378:metabolism; D011494:Protein Kinases / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis; D013964:Thyroid Neoplasms / Q000235:genetics* / Q000473:pathology
D009479:Neuropeptides; D012333:RNA, Messenger; D002116:Calcitonin; D011494:Protein Kinases; D011493:Protein Kinase C; D019204:GTP-Binding Proteins; D015740:Calcitonin Gene-Related Peptide