Journal
CANCER LETTERS
Volume 297, Issue 1, Pages 31-41Publisher
ELSEVIER IRELAND LTD
DOI: 10.1016/j.canlet.2010.04.021
Keywords
Medullary thyroid cancer; Leukemia inhibitory factor; Ras/Raf; Ret; Growth inhibition
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Funding
- FAMRI [062438]
- DOD [W81XWH-07-01-0089]
- American Cancer Society IRG [2204256]
- Wisconsin Breast Cancer Showhouse
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Medullary thyroid carcinoma (MTC) is a multiple endocrine neoplasia type 2 syndrome caused by mutations in extracellular receptor or intracellular kinase domains of the RET proto-oncogene. Activation of the Ras/Raf/MEK/ERK pathway can lead to growth arrest by secreting leukemia inhibitory factor (LIF) in MTC cells harboring a RET receptor domain mutation. Here, we report that Ras/Raf/MEK/ERK can also mediate, via LIF, growth inhibition in MTC cells harboring a RET kinase domain mutation. Ras/Raf/MEK/ERK activation was sufficient to induce growth inhibition and LIF expression in the human MTC line MZ-CRC-1. Presence of LIF-mediated signaling was determined by blocking the activity of culture medium conditioned by Raf-activated cells using anti-LIF neutralizing antibody. In addition, recombinant LIF effectively suppressed cell proliferation via cell cycle arrest in G0/G1 phase. Expression of dominant negative STAT3 abrogated LIF effects, indicating that LIF mediates its signaling through the JAK/STAT3 pathway. These results suggest that growth inhibition and activation of the autocrine/paracrine signaling through LIF/JAK/STAT may be a common response to Ras/Raf activation in different MTC types, and justify further evaluation of LIF as a potential anticancer agent for MTC. (C) 2010 Elsevier Ireland Ltd. All rights reserved.
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