Impact of LIF (leukemia inhibitory factor) expression in malignant melanoma.

Leukemia inhibitory factor (LIF) signaling regulates cellular processes to maintain the self-renewal and pluripotency of embryonic stem (ES) cells. Independent of these capabilities, LIF was also identified to be responsible for cancer development and progression. However, its detailed cellular function in cancer remains unclear thus far. We found LIF to be expressed in melanoma cell lines of primary and metastatic origin and in melanoma tissue. We further elucidated stimuli that are responsible for the high expression levels of LIF. Interestingly, hypoxia, specifically through HIF-1α, is involved in regulating LIF. Furthermore, our data showed that the signaling of LIF was not mediated by the classically described pathway via STAT3, but rather through BMP4 and BMP7. We hypothesize that the co-expression of LIF and BMP is necessary for a de-differentiated cancer phenotype. Ancillary to BMP4 and BMP7, classical stem cell proteins, e.g., SOX2, NANOG, OCT3/4 and GBX2, are regulated by LIF. We therefore speculate that LIF can induce a typical "cancer stem cell"-like behavior, as the appropriate genes are regulated by LIF. Particularly, the expression of these genes has been proposed as a driving force for tumorigenesis and the initiation of metastasis. Notably, LIF has an important role not only for ES cells but also for cancer development. Melanoblast-related cells (MBrcs), which resemble the neural crest precursor cells of melanocytes, expressed LIF in minor amounts compared to normal human melanocytes. These data, along with the data that LIF is upregulated in melanoma cell lines compared to melanocytes, strongly indicate that LIF is important for the stabilization of the melanoma phenotype. To elucidate the role of LIF in cellular melanoma behavior, we analyzed proliferation, attachment, migration and colony formation after silencing LIF by siRNA, and found all four characteristics restricted. In summary, we can show that LIF is an important factor in melanoma progression.