Aberrant regulation of transforming growth factor-α during the establishment of growth arrest and quiescence of growth factor independent cells

Autocrine transforming growth factor alpha (TGF alpha) is an important positive growth effector in malignant cells and plays a significant role in generating the growth factor-independent phenotype associated with malignant progression. However, the molecular mechanisms by which TGF alpha confers a growth advantage in progression is poorly understood. The highly tumorigenic cell line HCT116 up-regulates TGF alpha mRNA expression during growth arrest, whereas the poorly tumorigenic growth factor-dependent FET cell line down-regulates TGF alpha mRNA expression as it becomes quiescent. We have identified a 25-bp sequence at -201 to -225 within the TGF alpha promoter which mediates the differential regulation of TGF alpha expression during quiescence establishment in these two cell lines. This same sequence confers TGF alpha promoter responsiveness to exogenous growth factor or autocrine TGF alpha. The abberant upregulation of TGF alpha mRNA in quiescent HCT116 cells may allow them to return to the dividing state under more stringent conditions (nutrient replenishment alone) then quiescent FET cells (requires nutrients and growth factors). Antisense TGF alpha approaches showed that the dysregulated TGF alpha expression in quiescent HCT116 cells is a function of the strong TGF alpha autocrine loop (not inhibited by blocking antibodies) in these cells.