Heterochronic genes encode products whose expression changes over time in tissues, temporally regulating developmental changes and organ growth [1]. For example, many heterochronic genes are expressed in fetal, but not adult tissues such that they promote the rapid growth of fetal tissues and are shut off postnatally. Cancers can reactivate these heterochronic genes in adult tissues to enable neoplastic proliferation [2]. The role of these genes in normal and malignant biology is not well understood because developmental timing cannot be studied in vitro, and few of these genes have been systematically investigated in vivo. Lin28 is a heterochronic RNA-binding protein known for its ability to inhibit the biogenesis of let-7 microRNAs (miRNAs), ancient tumor suppressors that suppress the translation of oncogenes to impair cellular growth [3, 4]. Over the last 4 years I have uncovered important roles for heterochronic genes by using murine models that allow temporally specific gain or loss of Lin28 and let-7. I found that modestly increased expression of Lin28a substantially increased mouse growth, height, and time to puberty, demonstrating a conserved role in developmental timing from worms to mice [5]. Next, we showed that Lin28 and let-7 are regulators of mammalian glucose metabolism, implicating heterochronic genes in the pathogenesis of diabetes [6]. More recently, we showed that adult reactivation of Lin28a promotes regeneration capabilities reminiscent of embryonic tissue [7]. Lin28's ability to temporally integrate embryonic metabolism, cell proliferation, and tissue growth raises the possibility that it also promotes adult tumorigenesis through these mechanisms. We will focus on mouse models of liver tumors because LIN28B is overexpressed in up to 40% of pediatric and adult liver cancers, and because liver cancer is a major global problem with limited treatment options [8, 9]. In preliminary studies, we find that LIN28B overexpression is sufficient to induce liver cancer in adult mice. We have also found that MYC overexpression produces liver tumors with high Lin28b and low let-7 expression, and our data suggest that Lin28b is required for the development of these liver cancers.
In AIM 1, we will test whether ongoing Lin28b expression is required for tumor maintenance or growth, then we will assess the metabolic consequences of Lin28b loss.
In AIM 2, we will determine if the suppression of let-7 miRNAs is necessary for the development of liver tumors, and we will assess the metabolic and regenerative mechanisms that might be responsible. We have also shown that Igf2 mRNA-binding proteins 1 and 3 (Imp1 and Imp3), which are known let-7 targets and regulators of mRNA translation, are potently induced in LIN28B overexpressing tumors.
In AIM3, we will test whether Imp1 and Imp3 expression are necessary or sufficient for the growth of liver tumors and whether changes in Imp1/3 mediate effects of Lin28 on metabolism. This proposal has the potential to dissect the role in cancer of a heterochronic pathway that normally regulates growth, metabolism, and regeneration.

Public Health Relevance

Liver cancer is a growing clinical problem with limited treatment options. The Lin28b/let-7 pathway is a fundamentally important regulator of growth and metabolism in embryos. The reactivation of Lin28b promotes liver tumorigenesis by reducing let-7 tumor suppressor expression and increasing the expression of the Imp1 and Imp3 RNA binding proteins. We will examine the mechanisms by which this pathway promotes cancer in adults.

National Institute of Health (NIH)
National Cancer Institute (NCI)
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Molecular Oncogenesis Study Section (MONC)
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Strasburger, Jennifer
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University of Texas Sw Medical Center Dallas
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Zhang, Shuyuan; Zhou, Kejin; Luo, Xin et al. (2018) The Polyploid State Plays a Tumor-Suppressive Role in the Liver. Dev Cell 47:390
Zhang, Shuyuan; Zhou, Kejin; Luo, Xin et al. (2018) The Polyploid State Plays a Tumor-Suppressive Role in the Liver. Dev Cell 44:447-459.e5
Sun, Xuxu; Wang, Sam C; Wei, Yonglong et al. (2018) Arid1a Has Context-Dependent Oncogenic and Tumor Suppressor Functions in Liver Cancer. Cancer Cell 33:151-152
Zhang, Shuyuan; Nguyen, Liem H; Zhou, Kejin et al. (2018) Knockdown of Anillin Actin Binding Protein Blocks Cytokinesis in Hepatocytes and Reduces Liver Tumor Development in Mice Without Affecting Regeneration. Gastroenterology 154:1421-1434
Cinkornpumin, J; Roos, M; Nguyen, L et al. (2017) A small molecule screen to identify regulators of let-7 targets. Sci Rep 7:15973
Celen, Cemre; Chuang, Jen-Chieh; Luo, Xin et al. (2017) Arid1b haploinsufficient mice reveal neuropsychiatric phenotypes and reversible causes of growth impairment. Elife 6:
Sun, Xuxu; Wang, Sam C; Wei, Yonglong et al. (2017) Arid1a Has Context-Dependent Oncogenic and Tumor Suppressor Functions in Liver Cancer. Cancer Cell 32:574-589.e6
Miller, Jason B; Zhang, Shuyuan; Kos, Petra et al. (2017) Non-Viral CRISPR/Cas Gene Editing In Vitro and In Vivo Enabled by Synthetic Nanoparticle Co-Delivery of Cas9 mRNA and sgRNA. Angew Chem Int Ed Engl 56:1059-1063
Zhou, Kejin; Nguyen, Liem H; Miller, Jason B et al. (2016) Modular degradable dendrimers enable small RNAs to extend survival in an aggressive liver cancer model. Proc Natl Acad Sci U S A 113:520-5
Sun, Xuxu; Chuang, Jen-Chieh; Kanchwala, Mohammed et al. (2016) Suppression of the SWI/SNF Component Arid1a Promotes Mammalian Regeneration. Cell Stem Cell 18:456-66

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