Human germ cell tumor cell lines express novel leukemia inhibitory factor transcripts encoding differentially localized proteins.

Abstract

The polyfunctional cytokine leukemia inhibitory factor (LIF) has been implicated in the maintenance of many stem and progenitor cell populations and as an autocrine growth factor for many tumor cell populations, including germ cell tumors. Studies of LIF transcript expression in germ cell tumor cell lines identified two novel human LIF transcripts, hLIF-M and hLIF-T, containing noncoding alternate first exons that are conserved among all reported LIF genes. Embryonal carcinoma (EC) cell lines expressed these transcripts at consistent levels and hLIF-M was generally the predominant LIF transcript in these cells. This expression pattern was characteristic of EC cells since variable independently regulated expression of these transcripts was evident in other cell lines. Overexpression analysis demonstrated that each alternate hLIF transcript generated different levels of extracellular LIF activity as a consequence of the translation of distinct but partially overlapping sets of proteins. Secreted LIF proteins translated from alternate initiation codons were expressed from the hLIF-D and hLIF-M transcripts. Intracellular, potentially cell-autonomous, proteins were encoded by the hLIF-M and hLIF-T transcripts. Since EC cell lines also expressed LIF receptor transcripts, the novel LIF transcription profiles and proteins identified here suggest a role for autocrine and/or cell-autonomous LIF signaling during germ cell tumorigenesis.