Overview of microRNA biology

In considering an overview of microRNA biology, it is useful to consider microRNAs as a part of cellular communication. At the simplest level, microRNAs act to decrease the expression of mRNAs that contain stretches of sequence complementary to the microRNA. This function can be likened to the function of endogenous or synthetic short interfering RNA (siRNA). However, microRNA function is more complicated and nuanced than this ‘on-off’ model would suggest. Further, many microRNA targets are themselves non-coding RNAs. In this review, we will discuss the role of microRNAs in shaping the proteome of the cell in a way that is consistent with microRNA involvement in a highly regulated conversation, sensitive to outside influence and internal feedback

Targeting Macrophages to Reduce Colorectal Cancer Metastasis: Diminished Effect in the Alcohol-injured Liver

https://digitalcommons.unmc.edu/surp2022/1012/thumbnail.jp

MicroRNA-200c modulates the expression of MUC4 and MUC16 by directly targeting their coding sequences in human pancreatic cancer.

Transmembrane mucins, MUC4 and MUC16 are associated with tumor progression and metastatic potential in human pancreatic adenocarcinoma. We discovered that miR-200c interacts with specific sequences within the coding sequence of MUC4 and MUC16 mRNAs, and evaluated the regulatory nature of this association. Pancreatic cancer cell lines S2.028 and T3M-4 transfected with miR-200c showed a 4.18 and 8.50 fold down regulation of MUC4 mRNA, and 4.68 and 4.82 fold down regulation of MUC16 mRNA compared to mock-transfected cells, respectively. A significant reduction of glycoprotein expression was also observed. These results indicate that miR-200c overexpression regulates MUC4 and MUC16 mucins in pancreatic cancer cells by directly targeting the mRNA coding sequence of each, resulting in reduced levels of MUC4 and MUC16 mRNA and protein. These data suggest that, in addition to regulating proteins that modulate EMT, miR-200c influences expression of cell surface mucins in pancreatic cancer

MicroRNA Function in Human Diseases

MicroRNAs are emerging as a hot topic in research, and rightfully so. They show great promise as targets of treatment and as markers for common human diseases, such as cancer and metabolic diseases. In this review, we address some of the basic questions regarding micro- RNA function in human disease and the clinical significance of microRNAs. Specifically, micro- RNAs in epigenetics, cancer, and metabolic diseases are discussed, with examples taken from cholangiocarcinoma and nonalcoholic fatty liver disease

MicroRNA Function in Human Diseases

MicroRNAs are emerging as a hot topic in research, and rightfully so. They show great promise as targets of treatment and as markers for common human diseases, such as cancer and metabolic diseases. In this review, we address some of the basic questions regarding micro- RNA function in human disease and the clinical significance of microRNAs. Specifically, micro- RNAs in epigenetics, cancer, and metabolic diseases are discussed, with examples taken from cholangiocarcinoma and nonalcoholic fatty liver disease

MUC1 Regulates Expression of Multiple microRNAs Involved in Pancreatic Tumor Progression, Including the miR-200c/141 Cluster

MUC1 is a transmembrane glycoprotein that modulates transcription via its cytoplasmic domain. We evaluated the capacity of MUC1 to regulate the global transcription of microRNAs in pancreatic cancer cells expressing MUC1. Results indicated that MUC1 regulated expression of at least 103 microRNAs. We evaluated further regulation of the microRNA transcript cluster miR-200c/141, which was among the most highly regulated microRNAs. We found that MUC1 directly interacted with ZEB1, a known transcriptional repressor of the miR-200c/141 cluster, at the promoter of miR-200c/141, and further reduced transcript production. These data indicate that signaling through MUC1 influences cancer progression by regulating transcription of microRNAs that are associated with the process of metastasis

Alcohol Consumption is associated with Increased CEA Levels in Male Patients with Stage IV Colorectal Cancer- A Single-Institution Retrospective Analysis

Introduction: Alcohol use is an independent risk factor for liver metastasis, a major cause of morbidity and mortality in colorectal cancer (CRC) patients. Serum CEA level is an established prognostic indicator in CRC, yet the correlation with behavioral factors such as alcohol use remains to be defined. In a single-center review, we evaluated alcohol use, gender, and CEA levels in predicting advanced disease in CRC patients. Methods: Retrospective analysis of UNMC patients diagnosed with CRC as the primary cancer between 2012-2019, stages I-IV, and age \u3e19 with documentation of alcohol use. Univariable statistics were performed using Chi-Square and non-parametric tests. Associations between stage, gender, and alcohol use (some vs. none) and the log-transformed CEA outcome (either initial or rate of change) were assessed using linear regressions. Results: Alcohol use was found to be reported in 333 of 1243 CRC patients. The cohort was comprised of 192 male and 141 female subjects. Elevated CEA levels at CRC diagnosis were associated with increased all-cause mortality (33.0% for CEA \u3e 3.4ng/ml vs 10.4% for CEA \u3c 3.4ng/ml). Model analysis found that stage IV male alcohol users showed an increase in serial CEA levels compared to males who did not use alcohol, but this pattern was not observed among stage IV females. Conclusions: Males with a history of alcohol use may be at risk for advanced CRC disease suggesting the utility of serial serum CEA monitoring in these patients. A detailed alcohol use history should be obtained in all patients with CRC as it has prognostic value and may allow for early intervention. This analysis was limited by missing alcohol use data for the majority (73.2%) of CRC patients evaluated. A prospective study is warranted to define the implications of alcohol use and risk of CRC liver metastasis

MUC1 Regulates Cyclin D1 Gene Expression Through p120 Catenin and β-catenin

MUC1 interacts with β-catenin and p120 catenin to modulate WNT signaling. We investigated the effect of overexpressing MUC1 on the regulation of cyclin D1, a downstream target for the WNT/β-catenin signaling pathway, in two human pancreatic cancer cell lines, Panc-1 and S2-013. We observed a significant enhancement in the activation of cyclin D1 promoter-reporter activity in poorly differentiated Panc1.MUC1F cells that overexpress recombinant MUC1 relative to Panc-1.NEO cells, which express very low levels of endogenous MUC1. In stark contrast, cyclin D1 promoter activity was not affected in moderately differentiated S2-013.MUC1F cells that overexpressed recombinant MUC1 relative to S2-013.NEO cells that expressed low levels of endogenous MUC1. The S2-013 cell line was recently shown to be deficient in p120 catenin. MUC1 is known to interact with P120 catenin. We show here that re-expression of different isoforms of p120 catenin restored cyclin D1 promoter activity. Further, MUC1 affected subcellular localization of p120 catenin in association with one of the main effectors of P120 catenin, the transcriptional repressor Kaiso, supporting the hypothesis that p120 catenin relieved transcriptional repression by Kaiso. Thus, full activation of cyclin D1 promoter activity requires β-catenin activation of TCF-lef and stabilization of specific p120 catenin isoforms to relieve the repression of KAISO. Our data show MUC1 enhances the activities of both β-catenin and p120 catenin

FoxO3 increases miR-34a to cause palmitate-induced cholangiocyte lipoapoptosis.

Nonalcoholic steatohepatitis (NASH) patients have elevated plasma saturated free fatty acid levels. These toxic fatty acids can induce liver cell death and our recent results demonstrated that the biliary epithelium may be susceptible to lipotoxicity. Here, we explored the molecular mechanisms of cholangiocyte lipoapoptosis in cell culture and in an animal model of NASH. Treatment of cholangiocytes with palmitate (PA) showed increased caspase 3/7 activity and increased levels of cleaved poly (ADP-ribose) polymerase and cleaved caspase 3, demonstrating cholangiocyte lipoapoptosis. Interestingly, treatment with PA significantly increased the levels of microRNA miR-34a, a pro-apoptotic microRNA known to be elevated in NASH. PA induction of miR-34a was abolished in cholangiocytes transduced with forkhead family of transcription factor class O (FoxO)3 shRNA, demonstrating that FoxO3 activation is upstream of miR-34a and suggesting that FoxO3 is a novel transcriptional regulator of miR-34a. Further, anti-miR-34a protected cholangiocytes from PA-induced lipoapoptosis. Direct and indirect targets of miR-34a, such as SIRT1, receptor tyrosine kinase (MET), Kruppel-like factor 4, fibroblast growth factor receptor (FGFR)1, and FGFR4, were all decreased in PA-treated cholangiocytes. SIRT1 and MET were partially rescued by a miR-34a antagonist. Cholangiocyte apoptosis and miR-34a were dramatically increased in the liver of mice with early histologic features of NASH. Our study provides evidence for the pro-apoptotic role of miR-34a in PA-induced cholangiocyte lipoapoptosis in culture and in the liver