Gastric cancer (GC) is a biologically heterogeneous disease accompanying various genetic and epigenetic alterations, and the molecular mechanisms underlying this disease are complex and not completely understood. Increasing evidence shows that abnormal microRNA (miRNA) expression is involved in GC tumorigenesis, but the role of specific miRNAs involved in this disease remains elusive. MiR-141 was previously reported to act as tumor suppressors or oncogenes in diverse cancers. However, their accurate expression, function and mechanism in GC are largely unclear. Here we found that the expression of miR-141 was significantly reduced in GC compared with paired adjacent normal tissues and was significantly correlated with a more aggressive phenotype of GC in patients. Ectopic expression of miR-141 mimics in GC cell lines resulted in reduced proliferation, invasion and migration, and inhibition of miR-141 in GC cell lines promoted cell proliferation, invasion and migration in vitro. We further demonstrated that miR-141 acted as tumor suppressors through targeting transcriptional co-activator with PDZ-binding motif (TAZ) in GC. Moreover, the inverse relationship between miR-141 and its target was verified in patients and xenograft mice. Finally, overexpression of miR-141 suppressed tumor growth and pulmonary metastasis in nude mice. Take together, we identified that miR-141 is a potent tumor suppressor in the stomach, and its growth inhibitory effects are, in part, mediated through its downstream target gene, TAZ. These findings implied that miR-141 might be employed as novel prognostic markers and therapeutic targets of GC.
Melanoma is a cancer of melanocytes, the cells responsible for pigment production in the body. While melanoma has one of the highest cure rates of any cancer when detected early, once melanoma has metastasized the chances of survival dramatically decrease. Fortunately, the approval of numerous targeted and immune-based therapies for metastatic melanoma have had a significant impact on patient survival in the past 8 years. An important catalyst of this therapeutic success has been our significant understanding of the biology and genetics of melanoma. Genomic platforms, including next-generation sequencing, have rapidly increased our knowledge into the diverse sub-types of melanoma. This has allowed us to extract meaningful diagnostic information for use in the clinical management of patients, given us insight into the potential causes of melanoma, and have helped us identify new drug targets. Despite this, drug-resistance, patients not responding to treatment, and unintended side effects are all issues that need to be resolved by the field. In this talk, I will provide an overview of the somatic genetics of melanoma and discuss its diagnostic relevance in context to the current landscape of therapies for late-stage disease. This will be followed by my recent research on understanding the role and potential mechanisms of transcriptional cell states in melanoma and its significance in up-front and acquired drug resistance. Lastly, I will provide an overview of my collaborative efforts with the Broad Institute of Harvard MIT to identify melanoma specific gene dependencies as novel drug targets through use of genome-wide CRISPRknockout screens.
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