Indiana University-Purdue University Indianapolis (IUPUI) / The overexpression of protein arginine methyltransferase 5 (PRMT5) is strongly correlated to poor clinical outcomes for colorectal cancer (CRC) patients. Previously, we demonstrated that PRMT5 overexpression could substantially augment activation of NF-κB via methylation of arginine 30 (R30) on its p65 subunit, while knockdown of PRMT5 showed the opposite effect on the transcriptional competence of p65. However, the precise mechanisms governing this PRMT5/NF-κB axis are still largely unknown. We report a novel finding that PRMT5 is phosphorylated on serine 15 (S15) in response to interleukin-1β (IL-1β) stimulation. Overexpression of the serine-to-alanine mutant of PRMT5 (S15A-PRMT5), in either HEK293 cells or HT29, DLD1 and HCT116 CRC cells attenuated NF-κB activation compared to wild type (WT)-PRMT5, confirming that S15 phosphorylation is critical for the activation of NF-κB by PRMT5. Furthermore, we found that overexpression of S15A-PRMT5 mutant attenuated the expression of a subset of NF-κB target genes through decreased p65 occupancy at their respective promoters. Importantly, the S15A-PRMT5 mutant also reduced IL-1β-induced methyltransferase activity of PRMT5 as well as its ability to form a complex with p65. Finally, we observed that the S15A-PRMT5 mutant diminished the growth, migratory and colony-forming abilities of CRC cells compared to the WT-PRMT5. Collectively, our findings provide strong evidence that novel phosphorylation of PRMT5 at S15 is critical to its regulation of NF-κB and plays an essential role in promoting the cancer-associated functions exerted by the PRMT5/NF-κB axis. Therefore, development of inhibitors to block phosphorylation of PRMT5 at S15 could become a potential novel therapeutic approach to treat CRC. / 2020-10-15

Indiana University-Purdue University Indianapolis (IUPUI) / Because colorectal cancer (CRC) is the fourth most common cancer and the second leading cause of cancer death in the US, identifying biomarkers that might inform disease prevention and early diagnosis is of great public health importance. Mitochondria are key cytoplasmic organelles containing an independent genome, i.e., mitochondrial DNA (mtDNA). It has been increasingly recognized that mtDNA copy number (mtDNAcn) is a biomarker for mitochondrial function and cellular oxidative stress. To date, the few studies that have assessed associations between mtDNAcn and CRC outcomes have yielded inconsistent findings. Further, no epidemiologic study has examined the relationship between insulinemic potential of lifestyle and mtDNAcn. Therefore, in this dissertation, three studies were conducted using data from the Nurses’ Health Study and the Health Professionals Follow-Up Study. First, the association between pre-diagnostic leukocyte mtDNAcn and CRC risk was studied in a nested casecontrol study (324 cases/658 controls). Lower mtDNAcn was significantly associated with increased risk of CRC and proximal colon cancer. That inverse association remained significant among individuals with ≥ 8 years’ follow-up since blood collection, suggesting that mtDNAcn might serve as a long-term predictor of CRC risk. Second, possible associations of pre-diagnostic mtDNAcn with overall and CRC-specific survival were examined among 587 CRC patients. MtDNAcn was not significantly associated with survival overall or in subgroups by cancer location, grade, or stage. Among current smokers, there was an inverse association between one standard deviation (SD) decrease in mtDNAcn and increased overall death risk. Among patients diagnosed at or before 70.5 years of age and those with anti-inflammatory diets, reduced mtDNAcn was associated with lower CRC-specific death risk. Lastly, the cross-sectional association between empirical lifestyle index for hyperinsulinemia (ELIH) and mtDNAcn was investigated among 2,835 subjects without major chronic diseases (cancers, diabetes, and cardiovascular diseases). A significant inverse association was found: least-squares means ± SD of mtDNAcn z-score decreased dramatically across ELIH quintiles. Overall, the findings from this dissertation will contribute to the evaluation of mtDNAcn as a potential biomarker for CRC risk and prognosis, and inform future interventions designed to reduce the insulinemic potential of lifestyle factors to preserve mitochondrial function. / 2022-04-06

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第18175号 / 医博第3895号 / 新制||医||1003(附属図書館) / 31033 / 京都大学大学院医学研究科医学専攻 / (主査)教授 上本 伸二, 教授 武藤 学, 教授 森田 智視 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DGAM

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第19560号 / 医博第4067号 / 新制||医||1013(附属図書館) / 32596 / 京都大学大学院医学研究科医学専攻 / (主査)教授 川口 義弥, 教授 小川 修, 教授 長澤 丘司 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第20055号 / 医博第4163号 / 新制||医||1018(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 山田 泰広, 教授 戸井 雅和, 教授 野田 亮 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第21419号 / 医博第4409号 / 京都大学大学院医学研究科医学専攻 / (主査)教授 武藤 学, 教授 小川 誠司, 教授 万代 昌紀 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

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京都大学 / 新制・課程博士 / 博士(医学) / 甲第24139号 / 医博第4879号 / 新制||医||1060(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 森信 暁雄, 教授 上野 英樹, 教授 金子 新 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

Introduction: Colorectal cancer (CRC) survivors may experience functional deficits due to cancer-associated impairments. However, we do not understand their type and extent of functional deficits and how we could measure the associated cause of functional deficits, such as fatigue. As the survival of CRC survivors improves, the burden of living with functional deficits can be high. Purpose: My research program aims to understand (1) the functional changes and deficits that CRC survivors experience and (2) how to best measure fatigue in this population. Methods: To address the first aim, we used the data from the International Study of the Risk Factors for Gastrointestinal Bleeding and Cardiovascular Events after Gastrointestinal Bleeding to examine individuals’ functional abilities within 1 year of gastrointestinal cancer diagnosis (CRC being the most prevalent type). For the second aim, we conducted a systematic review on fatigue measures in adults with inflammatory bowel disease (IBD) because the causes, severity, and impact of IBD and CRC- related fatigue might be similar. We identified fatigue measures in the IBD population, appraised their psychometric properties, and recommended the most psychometrically robust and feasible measures for clinical and research use, indicating the optimal measures for CRC survivors. Results: After gastrointestinal cancer diagnosis, the majority (~70%) performed fewer functional tasks, mostly in the instrumental activities of daily living; and about 44% had more difficulty walking. Our review identified 16 measures, reviewed the content and psychometric properties, and recommended the Functional Assessment of Cancer Therapy Instrument-Fatigue and the IBD- Fatigue scale for research and clinical use in IBD and CRC populations. Conclusion: We provided a novel understanding of the functional deficits that CRC survivors experience and recommended the optimal measures for assessing CRC-related fatigue. As CRC survivors commonly experience fatigue, fatigue should be measured to understand its role in the functional abilities of CRC survivors. / Thesis / Master of Science Rehabilitation Science (MSc) / More people are living with colorectal cancer (CRC), but may have problems performing their daily activities (i.e. functional problems) due to cancer-associated impairments. However, we do not understand the extent of these impairments and functional problems. We used a sample of people with newly-diagnosed gastrointestinal cancer (CRC being the most common type) to understand their type and extent of functional problems. People were found to participate less in functional activities and particularly have more difficulty walking after a cancer diagnosis. Fatigue is common among those with CRC and may primarily cause functional problems. However, it is not commonly measured, and it is unclear how to best measure fatigue among them. Therefore, we reviewed key qualities of 16 fatigue measures in a similar population (inflammatory bowel disease, IBD) and recommended the Functional Assessment of Cancer Therapy Instrument-Fatigue and the IBD-Fatigue scale (English) as the most promising measures for those with CRC.