Lin, Chin-Yo2023-07-092023-07-09August 2012017-07-31https://hdl.handle.net/10657/14958Pancreatic ductal adenocarcinoma (PDAC) has the worst prognosis of all major malignancies. As there is no effective treatment method, it is emerging as one of the most deadly cancers. Oncogenic activation of KRAS is the most commonly seen mutation with 95% frequency in PDAC. Inhibition or down-regulation of KRAS activity impairs the pancreatic cancer cell metabolism and survival. However, directly targeting mutant KRAS has largely failed. There are numerous attempts to uncover novel targets and therapeutics generating potent response in PDAC treatment. Revealing molecular and genetic underpinnings of PDAC is essential to find effective targeting mechanisms and treatment options. The aim of this dissertation is to characterize new PDAC associated molecules (Chapter 2) and potential therapeutics (Chapter 3). In Chapter 2, we focused our interest in long non-coding RNAs (lncRNAs), which are expressed from nearly one fourth of the total encoded genes in the human genome. Generally, their expression is lower than protein-coding genes; they are strikingly tissue specific and have roles in various concepts of cell biology. We showed abnormal expression and dysregulation of lncRNAs are associated with PDAC and characterized a potentially important novel lncRNA, PANCRNA1, in PDAC formation and progression. We also elucidated the functional role of PANCRNA1 as a cancer driven molecule and determined its expression status depends on KRAS oncogenic mutation. This study shows first time the expression and function of PANCRNA1 in PDAC. Liver X receptor β (LXRβ) has been emerging as a promising therapeutic target in PDAC. It mainly regulates lipid metabolism and cholesterol homeostasis, which are dysregulated in cancer. Targeting LXRβ show anti-tumorigenic effect in PDAC. However, there is no LXRβ-specific ligand designed to use in cancer studies. In Chapter 3, we screened novel LXRβ ligands and reported two ligands that showed significantly greater antigrowth effects on PDAC than currently used synthetic ligands. Our findings provide mechanistic insights on identified ligands in lipid metabolism and also demonstrated the effect of KRAS mutation on treatment outcome. These compounds have the potential to revolutionize the study and treatment of pancreatic cancer and other deadly cancers that currently lack effective treatment options.application/pdfengThe author of this work is the copyright owner. UH Libraries and the Texas Digital Library have their permission to store and provide access to this work. Further transmission, reproduction, or presentation of this work is prohibited except with permission of the author(s).PDACKRASLncRNALXRβ2023-07-09Thesisborn digital