Long noncoding RNAs: Understanding their nexus with oncogenic and tumor suppressor pathways

Despite advances in oncology, our ability to cure cancer stands at unsatisfactory rate and still requires developing new therapies.

Recent evidence suggests that long noncoding RNAs (lncRNAs) have highly specific roles in cancer, but their mechanisms of action are poorly characterized.

Here, under aim1, using lung cancer as a model, we will study how early embryo expressed lncRNAs drive oncogenesis by favoring stemness maintenance and self-renewal. We will test their therapeutic potential in pre-clinical models using antisense oligonucleotides.

In aim2 and 3, using neuroblastoma (NB) as a model, we will investigate how lncRNAs NBAT1 and lncATXN1, which are regulated by a risk-associated SNP in locus 6p22.3, contribute to NB pathogenesis.

On the one hand, we will study how lncATXN1 suppresses the oncogenic action of its interacting proteins Myh9/Myh10 to maintain mitochondrial functions. We will explore if targeting Myh9/Myh10 with blebbistatin can be used as a new treatment for NB. NBAT1, on the other hand, shown to promote tumor suppression by activating p53 pathway.

Leveraging on these findings, we have earlier proposed nutlin and selinexor combination for the treatment of NBs. In aim3, we will investigate the molecular basis of this targeted therapy in conjunction with NBAT1.

In sum, we will decipher the roles of specific lncRNAs in oncogenic and tumor suppressor pathways and explore if these lncRNAs or their downstream pathways can be exploited in novel cancer therapies.