RESUMO
The CTNNB1 gene, encoding ß-catenin, is frequently mutated in hepatocellular carcinoma (HCC, â¼30%) and in hepatoblastoma (HB, >80%), in which DLK1/DIO3 locus induction is correlated with CTNNB1 mutations. Here, we aim to decipher how sustained ß-catenin activation regulates DLK1/DIO3 locus expression and the role this locus plays in HB and HCC development in mouse models deleted for Apc (ApcΔhep) or Ctnnb1-exon 3 (ß-cateninΔExon3) and in human CTNNB1-mutated hepatic cancer cells. We identified an enhancer site bound by TCF-4/ß-catenin complexes in an open conformation upon sustained ß-catenin activation (DLK1-Wnt responsive element [WRE]) and increasing DLK1/DIO3 locus transcription in ß-catenin-mutated human HB and mouse models. DLK1-WRE editing by CRISPR-Cas9 approach impaired DLK1/DIO3 locus expression and slowed tumor growth in subcutaneous CTNNB1-mutated tumor cell grafts, ApcΔhep HB and ß-cateninΔExon3 HCC. Tumor growth inhibition resulted either from increased FADD expression and subsequent caspase-3 cleavage in the first case or from decreased expression of cell cycle actors regulated by FoxM1 in the others. Therefore, the DLK1/DIO3 locus is an essential determinant of FoxM1-dependent cell proliferation during ß-catenin-driven liver tumorigenesis. Targeting the DLK1-WRE enhancer to silence the DLK1/DIO3 locus might thus represent an interesting therapeutic strategy to restrict tumor growth in primary liver cancers with CTNNB1 mutations.
Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Animais , Humanos , Camundongos , beta Catenina/genética , beta Catenina/metabolismo , Proteínas de Ligação ao Cálcio/genética , Proteínas de Ligação ao Cálcio/metabolismo , Carcinogênese/genética , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Cateninas/genética , Cateninas/metabolismo , Proliferação de Células/genética , Neoplasias Hepáticas/genética , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Regulação para CimaRESUMO
In recent years, important efforts have been made to understand how the expression of a specific gene repertoire correlates with chromatin accessibility, histone mark deposition, as well as with chromatin looping establishing connectivity with regulatory regions. The emergence of new techniques for genome-wide analyses and their progressive optimization to work on low amounts of material allows the scientific community to obtain an integrated view of transcriptional landscapes in physiology and disease. Here, we describe our own experience aiming at correlating the TCF-4/ß-catenin cistrome during liver tumorigenesis with chromatin remodeling, histone mark modifications, and long-distance DNA looping.
Assuntos
Cromatina , Neoplasias Hepáticas , Animais , Camundongos , Cromatina/genética , Estudo de Associação Genômica Ampla , Cromossomos , DNA , Neoplasias Hepáticas/genéticaRESUMO
Hepatocellular carcinoma (HCC) is the most common primary liver tumor, which stands fourth in rank of cancer-related deaths worldwide. The incidence of HCC is constantly increasing in correlation with the epidemic in diabetes and obesity, arguing for an urgent need for new treatments for this lethal cancer refractory to conventional treatments. HCC is the paradigm of inflammation-associated cancer, since more than 80% of HCC emerge consecutively to cirrhosis associated with a vast remodeling of liver microenvironment. In the recent decade, immunomodulatory drugs have been developed and have given impressive results in melanoma and later in several other cancers. In the present review, we will discuss the recent advancements concerning the use of immunotherapies in HCC, in particular those targeting immune checkpoints, used alone or in combination with other anti-cancers agents. We will address why these drugs demonstrate unsatisfactory results in a high proportion of liver cancers and the mechanisms of resistance developed by HCC to evade immune response with a focus on the epigenetic-related mechanisms.