RNAi Screens in Mice Identify Physiological Regulators of Oncogenic Growth

Nature. 2013 Sep 12;501(7466):185-90. doi: 10.1038/nature12464. Epub 2013 Aug 14.

Abstract

Tissue growth is the multifaceted outcome of a cell's intrinsic capabilities and its interactions with the surrounding environment. Decoding these complexities is essential for understanding human development and tumorigenesis. Here we tackle this problem by carrying out the first genome-wide RNA-interference-mediated screens in mice. Focusing on skin development and oncogenic (Hras(G12V)-induced) hyperplasia, our screens uncover previously unknown as well as anticipated regulators of embryonic epidermal growth. Among the top oncogenic screen hits are Mllt6 and the Wnt effector β-catenin, which maintain Hras(G12V)-dependent hyperproliferation. We also expose β-catenin as an unanticipated antagonist of normal epidermal growth, functioning through Wnt-independent intercellular adhesion. Finally, we validate functional significance in mouse and human cancers, thereby establishing the feasibility of in vivo mammalian genome-wide investigations to dissect tissue development and tumorigenesis. By documenting some oncogenic growth regulators, we pave the way for future investigations of other hits and raise promise for unearthing new targets for cancer therapies.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carcinogenesis / genetics*
  • Carcinogenesis / metabolism
  • Carcinogenesis / pathology*
  • Cell Adhesion
  • Cell Proliferation
  • DNA-Binding Proteins / deficiency
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism
  • Embryo, Mammalian / embryology
  • Embryo, Mammalian / metabolism
  • Embryo, Mammalian / pathology
  • Epidermis / embryology
  • Epidermis / metabolism
  • Epidermis / pathology*
  • Female
  • Genome / genetics
  • Humans
  • Hyperplasia / genetics
  • Hyperplasia / metabolism
  • Hyperplasia / pathology
  • Male
  • Mice
  • Neoplasm Proteins / deficiency
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / metabolism
  • Neoplasms / genetics*
  • Neoplasms / metabolism
  • Neoplasms / pathology*
  • Oncogene Protein p21(ras) / metabolism
  • Oncogenes / genetics*
  • RNA Interference*
  • Reproducibility of Results
  • Signal Transduction
  • Skin Neoplasms / genetics
  • Skin Neoplasms / metabolism
  • Skin Neoplasms / pathology
  • Time Factors
  • Wnt Proteins / metabolism
  • Wnt Signaling Pathway
  • beta Catenin / deficiency
  • beta Catenin / genetics
  • beta Catenin / metabolism

Substances

  • CTNNB1 protein, mouse
  • DNA-Binding Proteins
  • Mllt6 protein, mouse
  • Neoplasm Proteins
  • Wnt Proteins
  • beta Catenin
  • Oncogene Protein p21(ras)

Associated data

  • GEO/GSE48480