Rapamycin-independent IGF2 expression in Tsc2-null mouse embryo fibroblasts and human lymphangioleiomyomatosis cells

• DOI: 10.1371/journal.pone.0197105
• Publication Date: 2018-05-14T17:34:08Z
• Authors: Blanca E. Himes; Kseniya Obraztsova; Lurong Lian; Maya Shumyatcher; Ryan Rue; Elena N. Atochina...; Stella K. Hur; Marisa S. Bartolomei; Jilly F. Evans; Vera P. Krymskaya
• Keywords: TSC2; Lymphangioleiomyomatosis; Pleiotrophin

Lymphangioleiomyomatosis (LAM) is a rare, almost exclusively female lung disease linked to inactivating mutations in tuberous sclerosis complex 2 (TSC2), tumor suppressor gene that controls cell metabolic state and growth via regulation of the mechanistic target rapamycin (mTORC1) signaling. mTORC1 frequently activated human cancers and, although inhibitor has cytostatic effect, it is, general, unable elicit robust curative effect or regression. Using RNA-Seq, we identified (1) Insulin-like Growth Factor (IGF2) as one genes with highest fold-change difference between TSC2-null TSC2-expressing angiomyolipoma cells from patient LAM, (2) mouse IGF2 homolog Igf2, top-ranking according fold change Tsc2-/- Tsc2+/+ embryo fibroblasts (MEFs). We extended transcript-level findings protein level, observing increased Igf2 expression secretion by MEFs. Increased was not due epigenetic imprinting, but partially mediated through Stat3 pathway completely insensitive treatment. An siRNA-mediated decrease resulted decreased phosphorylation, suggesting presence an autocrine Igf2/Stat3 amplification cycle In pulmonary LAM lesions metastatic clusters, high levels were associated activation. addition, treatment three primary IGF2-expressing lines did result level changes. Thus, targeting signaling may be therapeutic value patients, particularly those who are unresponsive rapamycin.