Metabolic reprogramming, cell fate decision and non-coding RNA in tumor-initiating stem-like cells

抄録

Stem cell markers such as Nanog have been implicated in various cancer, but whether they are functionally contributing to cancer pathogenesis has remained unclear. Tumor-initiating stem-like cells (TICs) were isolated from mouse hepatocellular carcinoma (HCC) and human HCC patients. Using knowledge gained from the oncogenic signaling of TICs, we addressed new mechanistic hypotheses based on the novel discovery that the pluripotent transcription factor, NANOG, can reprogram the metabolism of HCC-derived TICs. These studies will motivate novel strategies for targeting and removing TICs and suggest new avenues to treat malignancies associated with human HCV and alcoholism and/or obesity. We determined novel targets of NANOG in TICs from patient and mouse models of HCC using genome-wide NANOG-binding site analysis (ChIP-seq) and how Nanog is regulated at the transcriptional to promote oncogenesis and self-renewal in TICs. NANOG-mediated metabolic reprogramming through suppression of mitochondria function in both experimental and clinical HCC downstream of TLR4/NANOG generates TICs and drives liver tumorigenesis. The p53 tumor suppressor acts as a barrier against stem cell proliferation, and inactivation of p53, or its stabilizing partner NUMB (cell fate decision molecule), leads to expansion of TICs. Although treatment efficacy of HCV has been dramatically improved in recent years, the incidence of HCV-associated HCC keeps rising due to the prevalence of obesity, alcoholism and illicit drug usage in HCV patients. RNA-binding protein MSI2 is elevated in several cancers and is linked to poor prognosis. We also performed RIP-seq using anti-MSI2 antibody in TICs and subsequent validation by qPCR analysis. Among the MSI2-bound RNAs, MYC mRNA and long noncoding RNA (LncRNA) were identified by RIP-qPCR analysis. MSI2 promotes liver tumorigenesis by maintenance of MYC expression by inhibition of LncRNA processing. This newly discovered mechanistic framework for TIC proliferation represents a key innovation and holds significant potential as a therapeutic target.