Cheng, Yating (2016-12). The Role of Long Noncoding RNAs in Cancer and Microbiota-derived Aryl Hydrocarbon Receptor Ligands. Doctoral Dissertation.
Thesis
LncRNAs are a group of non-coding RNAs containing >200 nucleotides and these RNAs have no significant protein coding potential. In the past 10-15 years the role of lncRNAs in cancers have been demonstrated, however, their function in tumors and potential for drug targeting are not well defined. We studied two lncRNAs, HOXA transcript at the distal tip (HOTTIP) and metastasis associated lung adenocarcinoma transcript 1 (MALAT1) in pancreatic cancer using the in vitro cell lines and in vivo xenograft or transgenic mouse models. Our results demonstrated that both lncRNAs are pro-oncogenic in the pancreatic cancer, supported by the observation that knockdown of HOTTIP and MALAT1 decreased cell proliferation, migration/invasion and increased apoptosis. HOTTIP might exhibit some pro-oncogenic functions, via the regulation of HOXA gene clusters in a cis-regulating manner. On the other hand, MALAT1 regulate responses of pancreatic cancer cells in part via polycomb repressive complex 2 (PRC2) dependent and independent pathways. Our transcriptomic results support the important but distinct roles of HOTTIP and MALAT1 in pancreatic cancer and we also show that MALAT1 expression can be targeted by small molecule drugs. In the second part of this dissertation, we studied several microbiota-derived aryl hydrocarbon receptor (AhR) ligands. The AhR is a ligand-activated transcription factor with an evolving role in the normal physiological development and diseases. Gut microbiota metabolites are important for mediating communication between gut microflora and the host. It has recently been shown that the gut microbiota produces several metabolites that are AhR ligands. Microbiota-derived tryptophan metabolites and 1,4-dihydroxy-2-napthoic acid (DHNA) and related compounds are reported to be AhR ligands as evidence by their induction of cytochrome P450, family 1, subfamily A, polypeptide 1 (CYP1A1) and other AhR-responsive genes. We hypothesized the microbiota-derived AhR ligands are selective AhR modulators (sAhRMs) and their induction responses are compound, gene and cell context dependent. We have carried out extensive studies on tryptophan metabolites, DHNA and related compounds in both human and mouse colon cancer cell lines, and have observed that some of these compounds exhibited partial agonist/antagonist activities that are both gene and cell context specific.
