Visfatin, which is secreted as an adipokine and cytokine, has been implicated in cancer development and progression. In this study, we investigated the NAD-producing ability of visfatin and its relationship with SIRT1 (silent information regulator 2) and p53 to clarify the role of visfatin in breast cancer. MCF-7 breast cancer cells were cultured and treated with visfatin. SIRT1 activity was assessed by measuring fluorescence intensity from fluoro-substrate peptide. To investigate the effect of visfatin on p53 acetylation, SDS-PAGE followed by western blotting was performed using specific antibodies against p53 and its acetylated form. Total NAD was measured both in cell lysate and the extracellular medium by colorimetric method. Visfatin increased both extracellular and intracellular NAD concentrations. It also induced proliferation of breast cancer cells, an effect that was abolished by inhibition of its enzymatic activity. Visfatin significantly increased SIRT1 activity, accompanied by induction of p53 deacetylation. In conclusion, the results show that extracellular visfatin produces NAD that causes upregulation of SIRT1 activity and p53 deacetylation. These findings explain the relationship between visfatin and breast cancer progression.
Thoracic cancers pose a significant global health burden. Immune checkpoint blockade therapies have improved treatment outcomes, but durable responses remain limited. Understanding how the host immune system interacts with a developing tumor is essential for the rational development of improved treatments for thoracic malignancies. Recent technical advances have improved our understanding of the mutational burden of cancer cells and changes in cancer-specific gene expression, providing a detailed understanding of the complex biology underpinning tumor-host interactions. While there has been much focus on the genetic alterations associated with cancer cells and how they may impact treatment outcomes, how host genetics affects cancer development is also critical and will greatly determine treatment response. Genome-wide association studies (GWAS) have identified genetic variants associated with cancer predisposition. This approach has successfully identified host genetic risk factors associated with common thoracic cancers like lung cancer, but is less effective for rare cancers like malignant mesothelioma. To assess how host genetics impacts rare thoracic cancers, we used the Collaborative Cross (CC); a powerful murine genetic resource designed to maximize genetic diversity and rapidly identify genes associated with any biological trait. We are using the CC in conjunction with our asbestos-induced MexTAg mouse model, to identify host genes associated with mesothelioma development. Once genes that moderate tumor development and progression are known, human homologues can be identified and human datasets interrogated to validate their association with disease outcome. Furthermore, our CC−MexTAg animal model enables in-depth study of the tumor microenvironment, allowing the correlation of immune cell infiltration and gene expression signatures with disease development. This strategy provides a detailed picture of the underlying biological pathways associated with mesothelioma susceptibility and progression; knowledge that is crucial for the rational development of new diagnostic and therapeutic strategies. Here we discuss the influence of host genetics on developing an effective immune response to thoracic cancers. We highlight current knowledge gaps, and with a focus on mesothelioma, describe the development and application of the CC-MexTAg to overcome limitations and illustrate how the knowledge gained from this unique study will inform the rational design of future treatments of mesothelioma.
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