Interleukin 24 is induced by the RET/PTC3 oncoprotein and is an autocrine growth factor for epithelial cells

Abstract

Thyroid cancers, like hematological malignancies, are commonly associated with chromosomal translocations leading to the formation of fusion proteins. Through altered signaling by fusion proteins, cell death and survival pathways are disrupted and the physiological balance of cell-cell communication may be lost. A consequence of this disruption is the release of factors by stressed cells that alert the host. One type of host response is leukocytic infiltration that may develop into chronic inflammation or autoimmune disease. Although inflammation can be associated with neoplastic tissue, the mechanism driving this process is largely unknown. Therefore, to address the mechanism of cancer inflammation we investigated the effects of an oncogene in a murine model system. A comprehensive genetic analysis revealed several soluble factors that were induced by RET/papillary thyroid carcinoma (PTC)3 gene expression including several proinflammatory cytokines, chemokines and immunologically relevant costimulatory molecules. Following a large genetic screen using RP3-expressing thyroid cells, we identified a highly abundant transcript and later identified it as interleukin 24 (Il24), a cytokine with diverse tumor suppressor and inflammatory activities. We show that RET/PTC3 induces Il24 expression in rat thyrocytes and that this expression is dependent on the signaling properties of its tyrosine kinase. Likewise, RET/PTC3 induces large amounts of Il24 following expression in murine thyrocytes, but its expression is dramatically reduced in poorly differentiated carcinomas, a finding that parallels the loss of RET/PTC3 expression. Consistent with its behavior as a tumor suppressor, the loss of Il24 coincided with the loss of RET/PTC3 in poorly differentiated mouse tumors. A functional role of Il24 in the autocrine growth/survival of RET/PTC3-expressing thyroid cells was identified helping to support its role in cellular transformation. These data suggest that the induction of Il24 by oncogenes may support tumor growth at the early stages of cancer.

RET/PTC-induced gene expression in thyroid PCCL3 cells reveals early activation of genes involved in regulation of the immune response

“…Recently, a functional role of interleukin (IL)-24 in autocrine regulation of growth and survival of RET/PTC3-expressing thyroid cells has been identified (Shinohara & Rothstein 2004). However, loss of IL-24 expression in advanced cancers seems to indicate that its induction by oncogenes may support tumor growth only at the early stages of cancer development (Shinohara & Rothstein 2004).…”

“…However, loss of IL-24 expression in advanced cancers seems to indicate that its induction by oncogenes may support tumor growth only at the early stages of cancer development (Shinohara & Rothstein 2004). Moreover, ectopic expression of its human homologue MDA7 in H0-1 human melanoma cells suppressed growth (Jiang et al 1995).…”

The immune network in thyroid cancer

“…However, its expression decreased in poorly differentiated mouse tumors, paralleling the loss of RET/PTC3 expression along with tumor progression, thus supporting a role for IL-24 as tumor suppressor factor. 22 IL-6 is a cytokine involved in the regulation of cell proliferation, survival and metabolism. 23 In an in vitro model of human TC and mast cell (MC) lines, TC-derived conditioned media (CM) induced upregulation of IL-6 in human MCs.…”

RET-mediated modulation of tumor microenvironment and immune response in multiple endocrine neoplasia type 2 (MEN2)

“…Interestingly, CD11b+ Gr1+ myelocyte-, but not CD8+ T lymphocyte-infiltration, was dependent on the integrity of RET/PTC3 Y588, that corresponds to the RET multidocking site Y1062. These data suggest that while CD11b+ Gr1+ recruitment might be due to RET Y1062-dependent proinflammatory signaling, the recruitment of CD8 T cells could be the result of the expression of tumor-specific antigens, possibly endowed in the RET/ PTC3 oncoprotein , Shinohara & Rothstein 2004, Pufnock & Rothstein 2009, Neely et al 2011, Wixted et al 2012.…”