Effect of Ha-ras^val12 on nm23 expression, tumor formation and metastasis of the transformants, and immunomodulation in tumor-bearing mice

Overexpression of the Ha-ras^val12 oncogene has frequently been detected in primary and metastatic carcinomas. NM23 is a metastasis inhibition factor and plays a suppressive role in metastasis in many types of cancer. In this study, a stable NIH/3T3 cell line harboring an inducible Ha-ras ^val12 oncogene (designated as 7-4) and small interfering RNAs (siRNAs) were used to clarify the inverse correlation between nm23 and Ha-ras expression both in vitro and in vivo. A derivative 7-4/Z-3 cell line harboring a β-galactosidase reporter gene was used to trace cell metastasis in a murine tumor model. The data presented here reveal that Ha-ras^val12 is able to cause cell morphological changes, induce tumor formation, and promote metastasis of tumor cells to the lungs. In mice with metastases, the immune surveillance against tumor formation was suppressed by Ha-ras^val12 overexpression through an increase in T-reg cells and a decrease of cytotoxic T lymphocytes and natural killer cell populations. Our results suggest that the Ha-ras oncogene regulates morphogenesis, tumorigenesis, and metastasis through suppressing nm23 expression and modulation of immune cell function.