IFI16 is an essential mediator of growth inhibition, but not differentiation, induced by the leukemia inhibitory factor/JAK/STAT pathway in medullary thyroid carcinoma cells

Activation of Ras or Raf in the human medullary thyroid carcinoma (MTC) cell line, TT, induces growth arrest and differentiation via two parallel, yet independent, pathways. One of these pathways is intracellular and the other is a cell-extrinsic, autocrine/paracrine pathway mediated by the leukemia inhibitory factor (LIF)/JAK/STAT pathway. Here, we show that IFI16 is a necessary and sufficient downstream effector for LIF effects in MTC cells, specifically required for the LIF/JAK/STAT pathway-induced growth inhibition in these cells. IFI16 was induced by Raf or LIF. Dominant-negative STAT3 could block the induction, indicating that Raf can induce IFI16 only via the cell-extrinsic pathway. Knock-down of IFI16 using siRNA abrogated LIF-induced changes in cellular levels of E2F1, cyclin D1, and p21(WAF/CIP1), and cell cycle arrest. In addition, adenovirus-mediated overexpression of IFI16 was sufficient to induce growth arrest. In contrast to its essential role for LIF-mediated growth arrest, IFI16 was not required for differentiation induced by LIF. Knock-down of IFI16 could not block changes in differentiation markers of the MTC cells, including calcitonin, RET, and cell morphology. Our study identifies IFI16 as an essential growth-specific effector of the cell-extrinsic growth inhibitory pathway of Ras/Raf signaling in MTC cells.