Interleukin-like EMT inducer regulates partial phenotype switching in MITF-low melanoma cell lines

• Published in: PloS one 2017-05, Vol.12 (5), p.e0177830-e0177830
• Main Authors: Noguchi, Ken, Dalton, Annamarie C, Howley, Breege V, McCall, Buckley J, Yoshida, Akihiro, Diehl, J Alan, Howe, Philip H
• Format: Article
• Language: English
• Subjects: Autophagy; Biochemistry; Biological activity; Biology and Life Sciences; Biotechnology; Brain-derived neurotrophic factor; Cell Line, Tumor; Cell Movement; Cell Proliferation; Chemoresistance; Cytokines; Cytokines - genetics; Cytokines - metabolism; Epithelial-Mesenchymal Transition; Gene expression; Gene Expression Regulation, Neoplastic; Gene Regulatory Networks; Gene set enrichment analysis; Genes; Genetic aspects; Genetic engineering; Genomics; Growth factors; Humans; In vitro methods and tests; Interleukins; Kinases; Medicine; Medicine and Health Sciences; Melanoma; Melanoma - genetics; Melanoma - metabolism; Mesenchyme; Metastases; Metastasis; Microphthalmia-associated transcription factor; Microphthalmia-Associated Transcription Factor - genetics; Microphthalmia-Associated Transcription Factor - metabolism; Molecular biology; Neoplasm Metastasis; Neoplasm Proteins - genetics; Neoplasm Proteins - metabolism; Phenotype; Research and Analysis Methods; Skin cancer; Stem cells; Switching; Transcription factors; Tumors; Up-Regulation
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0177830

ILEI (FAM3C) is a secreted factor that contributes to the epithelial-to-mesenchymal transition (EMT), a cell biological process that confers metastatic properties to a tumor cell. Initially, we found that ILEI mRNA is highly expressed in melanoma metastases but not in primary tumors, suggesting that ILEI contributes to the malignant properties of melanoma. While melanoma is not an epithelial cell-derived tumor and does not undergo a traditional EMT, melanoma undergoes a similar process known as phenotype switching in which high (micropthalmia-related transcription factor) MITF expressing (MITF-high) proliferative cells switch to a low expressing (MITF-low) invasive state. We observed that MITF-high proliferative cells express low levels of ILEI (ILEI-low) and MITF-low invasive cells express high levels of ILEI (ILEI-high). We found that inducing phenotype switching towards the MITF-low invasive state increases ILEI mRNA expression, whereas phenotype switching towards the MITF-high proliferative state decreases ILEI mRNA expression. Next, we used in vitro assays to show that knockdown of ILEI attenuates invasive potential but not MITF expression or chemoresistance. Finally, we used gene expression analysis to show that ILEI regulates several genes involved in the MITF-low invasive phenotype including JARID1B, HIF-2α, and BDNF. Gene set enrichment analysis suggested that ILEI-regulated genes are enriched for JUN signaling, a known regulator of the MITF-low invasive phenotype. In conclusion, we demonstrate that phenotype switching regulates ILEI expression, and that ILEI regulates partial phenotype switching in MITF-low melanoma cell lines.