The impact of RB deficiency on hepatocyte biology and tumorigenesis

The integrity of the RB tumor suppressor pathway is critical for inhibition of inappropriate proliferation and suppression of tumor development in a wide variety of human tissues. RB has been shown to play a number of distinct roles in contributing to tumor suppression; studies have implicated the RB pathway in DNA damage response, genome instability, establishment of senescence, and promotion of differentiation, among other processes. Despite intensive research, however, the specific functions of RB as they relate to individual disease contexts and distinct facets of cellular stress response remain unclear. Herein, research is directed at first unmasking the immediate underlying impact of RB deletion in vivo, and then subsequently probing the specific disease-relevant functions of RB deficiency during DNA damage response and subsequent liver tumorigenesis. Tissue specific deletion of RB revealed a profound induction of E2F-mediated DNA replication that was characterized by hyper-physiological formation of pre-replication complexes. These phenotypes were not accompanied by productive mitoses. Uniquely, RB-deficient hepatocytes accumulated aberrant ploidy and significant levels of DNA damage. Furthermore, in vitro and in vivo analyses demonstrate the LXCXE-binding function of RB, while dispensable for E2F-promoter association, is required for mediating appropriate transcriptional control during DNA damage response in the liver. Such aberrant responses were mediated preferentially through E2F3. Long-term studies demonstrated that disruption of LXCXE-binding accelerated DNA damage mediated tumorigenesis in vivo and gene expression profiling revealed that the transcriptional program mediated by this function of RB was associated with progression to HCC in humans. Surprisingly, gene expression profiling also revealed an unexpected role for RB in modulation of immune response gene transcription. Together, these studies demonstrate and establish highly tissue-specific and context-dependent roles for RB in transcriptional control and tumor suppression