Inflammation, Type 2 Diabetes, and Cancer: Identifying Biomarkers Associated with Colorectal Cancer and Type 2 Diabetes, and the Use of microRNA Molecules as a Therapeutic Use for Cancer Treatment

Guillen, Jenni Kimiko
Grandinetti, Andrew
Public Health
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ABSTRACT Chronic disease has been a growing epidemic for the past few decades. Approximately 70% of the world’s population dies from a noncommunicable disease every year. This accounts for over 38 million annual deaths worldwide. Cardiovascular disease, cancer and diabetes account for a large proportion of chronic death cases. The methods for controlling and reducing cases of chronic disease have been focused on the reduction of lifestyle risk factors, such as poor nutrition and a lack of physical activity, and increasing screening, surveillance and treatment. These preventive measures and early surveillance tools are considered more effective at reducing loss and less costly than treating those with later stages of chronic disease. Diagnostic, prognostic, and treatment methods come in a variety of forms. One of the more recent methods is the screening of molecular biomarkers. The field of molecular biomarkers has recently exploded. In 2016, it was reported that over 768,000 papers were directly linked with biomarkers, and that the number of publications have exponentially grown within the last few years. With the overwhelming amount of publications, it has become necessary to systematically review the information so that health care providers, policy makers, researchers and other key public health members can access these novel markers readily. The aim of this dissertation was to focus on early screening for prevention and early detection of colorectal cancer (CRC) and on novel treatment techniques for patients with CRC. Through the implementation of systematic review and meta-analysis approaches, this dissertation had 3 main study objectives: 1) to identify and quantify acylcarnitine and carnitine biomarkers that are upregulated or downregulated in three diabetic conditions (type 1, type 2, and gestational diabetes) and in prediabetes, 2) to explore 5 key microRNA molecules upregulated in CRC patients that have been found to have high sensitivity and specificity percentages (>60%), and 3) to identify microRNA molecules that act as tumor suppressors in patients with CRC and their target gene(s) or gene product(s) whose expression is affected by tumor-suppressing miRNAs. In the first study, the systematic review and meta-analysis of the acylcarnitine and carnitine biomarkers in the prediabetic and diabetic conditions revealed that these biomarkers are, for the most part, upregulated in those with diabetes when compared to non-glycemic participants. An upregulation of acylcarnitine, a short-chain fatty acid, was found in participants diagnosed with gestational diabetes, prediabetes, and type 2 diabetes, but not in type 1 diabetes, an autoimmune disease. In addition, the systematic review found 30 more acylcarnitine/ carnitine molecules were upregulated and 3 were downregulated in patients with type 2 diabetes. The meta-analysis of type 2 diabetes confirmed the findings of the systematic review for 4 acylcarnitine derivates: an upregulation of acylcarnitine, propionylcarnitine, isovalerylcarnitine, and palmitoylcarnitine. However, in contrast to the other diabetic conditions, type 1 diabetes was found to have a downregulation of free carnitine with no other biomarkers clearly upregulated. In the second study, the systematic review of miRNA-1246, miRNA-202, miRNA-532, miRNA- 1229, and miRNA-21 found that all 5 key microRNAs were significantly upregulated (p<0.05) in those with CRC and additionally in patients with colorectal adenoma (CRA), which can develop into colorectal cancer. All of the studies for miRNA-1246, miRNA-202, miRNA-532, miRNA- 1229 and most of the studies for miRNA-21 also reported high sensitivity and specificity percentages (>60%). The meta-analyses of miR-21 supported the systematic review and was found to have significant overall pooled estimate effects for both the odds ratio (OR = 7.37 [2.25, 24.14] with outlier and 4.14 [1.91, 8.98] without outlier) and the overall survival hazard ratio (OS HR = 2.97 [1.73, 5.09] with outlier and 2.13 [1.67, 2.72] without outlier). However the overall pooled disease free survival HR was not significantly different between CRC patients and non-CRC participants, HR = 2.12 (0.94, 4.79), which could be due to the number of included studies (n=3). In the third study, a systematic review of the tumor-suppressing microRNAs that regulate target genes and gene products known to directly affect the development of CRC was conducted. These tumor-suppressing miRNA molecules are irregularly expressed and their downregulation can lead to the overexpression of oncogenic genes. Therefore, recovery or reintroduction of these tumor suppressing miRNAs could be a potential treatment for individuals diagnosed with cancer. The analysis of this study identified 93 microRNAs and 61 target genes. Of the microRNAs and gene targets found, only 5 miRNAs (miR-22, miR-23a, miR-137, miR-375, miR-425-5p) and 4 genes (ZEB2, LGR5, BCL2, CCND1) were reported in more than one study. With the lack of published results on the same miRNAs and target genes, it is difficult to assess whether these biomarkers can be used in a clinical setting. More research needs to be conducted on tumor-suppressing miRNAs and their target genes in order to accurately assess the value of using miRNAs as a treatment for CRC. The development of using biomarkers for diagnostic, prognostic, and therapeutic purposes requires the continuous identification and quantification of these molecules in patients with chronic diseases at various stages. The body’s processes are complex and sometimes not well understood, but with continued research, a better understanding of how these mechanisms work will lead to better prevention, control, and treatment.
Epidemiology, Acylcarnitine, Biomarkers, Colorectal Cancer, Inflammation, microRNA, Type 2 Diabetes
241 pages
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