Andrew Fesler

Clinical Significance of Long Intergenic Noncoding RNA-p21 in Colorectal Cancer

BACKGROUND Long intergenic noncoding RNAs (lincRNAs) have been shown to be novel regulators for both transcription and posttranscriptional/translation. One of them, lincRNA-p21, was regulated by p53 and contributed to apoptosis in mouse embryonic fibroblasts. However, the impact of such regulation on colorectal cancer (CRC) remains to be determined. METHODS Total RNA was extracted from CRC cell lines and snap fresh frozen CRC samples from 2 CRC patient cohorts. The expression of lincRNA-p21 was quantified by quantitative real-time polymerase chain reaction analysis. RESULTS We discovered that the expression level of lincRNA-p21 was increased by elevated wild-type p53 induced by nutlin-3 in HCT-116 colon cancer cells. The expression level of lincRNA-p21 was significantly (P = .0208) lower in CRC tumor tissue when compared with the paired normal tissue from the same patient. There was no significant correlation of lincRNA-p21 with p53 status (wild-type vs. mutant). Tumors in the rectum showed a higher level of lincRNA-p21 than tumors in the colon (P = .00005). In addition, lincRNA-p21 in patients with stage III tumors was significantly higher than in those with stage I tumors (P = .007). Elevated levels of lincRNA-p21 were significantly associated with higher pT (P = .037 between pT 2 and 3) and vascular invasion (P = .017). CONCLUSIONS These results indicate that lincRNA-p21 may contribute to CRC disease progression.

MicroRNA: a third dimension in autophagy.

Autophagy is a catabolic process that allows cellular macromolecules to be broken down and recycled into metabolic precursors. It is a highly conserved, critical process, allowing cells to gain survival advantages under various stress situations due to growth and environmental changes. In the past few years, mounting evidence indicates that the post-transcriptional and translational controls mediated by non-coding miRNAs contribute significantly to autophagy in cancer. Such acute modulation of protein synthesis mediated by miRNAs provides cells with advantages in response to starvation, genotoxic stress and hypoxia. In this review, we highlight some of the important discoveries and molecular insights of miRNAs in regulating autophagy based on various cancer models.Autophagy is a catabolic process that allows cellular macromolecules to be broken down and recycled into metabolic precursors. It is a highly conserved, critical process, allowing cells to gain survival advantages under various stress situations due to growth and environmental changes. In the past few years, mounting evidence indicates that the post-transcriptional and translational controls mediated by non-coding miRNAs contribute significantly to autophagy in cancer. Such acute modulation of protein synthesis mediated by miRNAs provides cells with advantages in response to starvation, genotoxic stress and hypoxia. In this review, we highlight some of the important discoveries and molecular insights of miRNAs in regulating autophagy based on various cancer models.

miR-129 as a novel therapeutic target and biomarker in gastrointestinal cancer

In the last decade, cancer research efforts in the field of noncoding microRNA (miRNA) have been growing exponentially. miRNA-based therapeutics have been tested in both preclinical and clinical settings, and miRNA-based cancer diagnostics and prognostics have moved into clinics to help better manage cancer treatment. A growing body of evidence in recent literature suggests miRNA-129 plays important roles in gastrointestinal cancer, including gastric, colorectal, hepatocellular carcinoma, and esophageal cancer. In this review, we focus on accumulating evidence demonstrating the key roles that miRNA-129 plays in tumorigenesis, disease progression, chemoresistance, proliferation, and cell cycle control. Understanding the emerging roles and mechanisms of miRNA-129 in cancer will help us realize the therapeutic and diagnostic/prognostic potential.

Reduction of gastric cancer proliferation and invasion by miR-15a mediated suppression of Bmi-1 translation

B-cell specific moloney leukemia virus insertion site 1 (Bmi-1) gene plays important roles in gastric cancer, but the epigenetic regulatory mechanism by microRNA (miRNA) and the functional significance of Bmi-1 inhibition in gastric cancer remains elusive. In this study, we systematically investigated the functional roles of miRNA mediated Bmi-1 suppression in gastric cancer. Our results show that the expression of miR-15a is significantly reduced in gastric cancer and the protein expression levels of Bmi-1 are inversely correlated with miR-15a (P = 0.034) in gastric cancer patient samples. Functional studies revealed that ectopic expression of miR-15a decreased Bmi-1 in gastric cancer cell lines with reduced proliferation and tumor invasion. High levels of Bmi-1 in gastric cancer patients are significantly associated with better overall survival (P = 0.024) based on the Kaplan-Meier survival analysis.

Expression analysis of microRNA as prognostic biomarkers in colorectal cancer

microRNA (miRNA) based biomarkers have unique advantages due to their critical regulatory function, superior stability, and relatively small number compared to mRNAs. A number of miRNAs play key roles in colon cancer stem cell chemoresistance and have clinical potential as prognostic biomarkers. The purpose of this study is to systematically validate the prognostic potential of miRNAs in colorectal cancer. In this study, we validated the prognostic potential of a panel of miRNAs using 205 stage II, III, and IV colorectal cancer specimens by qRT-PCR analysis. We cross validated our results using The Cancer Genome Atlas (TCGA) database. Many of the miRNAs we investigated have been functionally validated to be important in contributing to chemoresistance to 5-fluorouracil (5-FU) based chemotherapy. We determined that miR-16 is the most consistent miRNA for expression normalization in colorectal cancer. We have validated several miRNAs (miR-15b, miR-215, miR-145, miR-192, let-7g) that are significantly associated with progression free survival (PFS) and/or overall survival (OS) of colorectal cancer patients independent of tumor stage and age at diagnosis. These 5 miRNAs are significantly associated with OS of colorectal cancer even after tumor location (left side vs. right side) is adjusted for. Furthermore, the prognostic value of let-7g for overall survival was independently validated using the RNA-Seq results from TCGA colorectal cancer database. These results, taken together, establish a solid foundation towards miRNA based precision management of colorectal cancer.microRNA (miRNA) based biomarkers have unique advantages due to their critical regulatory function, superior stability, and relatively small number compared to mRNAs. A number of miRNAs play key roles in colon cancer stem cell chemoresistance and have clinical potential as prognostic biomarkers. The purpose of this study is to systematically validate the prognostic potential of miRNAs in colorectal cancer. In this study, we validated the prognostic potential of a panel of miRNAs using 205 stage II, III, and IV colorectal cancer specimens by qRT-PCR analysis. We cross validated our results using The Cancer Genome Atlas (TCGA) database. Many of the miRNAs we investigated have been functionally validated to be important in contributing to chemoresistance to 5-fluorouracil (5-FU) based chemotherapy. We determined that miR-16 is the most consistent miRNA for expression normalization in colorectal cancer. We have validated several miRNAs (miR-15b, miR-215, miR-145, miR-192, let-7g) that are significantly associated with progression free survival (PFS) and/or overall survival (OS) of colorectal cancer patients independent of tumor stage and age at diagnosis. These 5 miRNAs are significantly associated with OS of colorectal cancer even after tumor location (left side vs. right side) is adjusted for. Furthermore, the prognostic value of let-7g for overall survival was independently validated using the RNA-Seq results from TCGA colorectal cancer database. These results, taken together, establish a solid foundation towards miRNA based precision management of colorectal cancer.

Modified miR-15a has therapeutic potential for improving treatment of advanced stage colorectal cancer through inhibition of BCL2, BMI1, YAP1 and DCLK1

Despite advances in colon cancer treatments, resistance and recurrence remain a significant challenge in treating patients. Novel therapeutic strategies are in urgent need to overcome resistance and improve patient outcomes. MicroRNA based therapeutics have potential to help combat resistance. In this study, we have shown that low miR-15a expression correlates with poor patient prognosis. We have demonstrated the therapeutic potential of miR-15a in colon cancer. miR-15a inhibits several important genes (BCL2, BMI1, YAP1 and DCLK1), decreasing cancer progression and resistance. Additionally, by replacing uracil in miR-15a with 5-fluorouracil, we created a novel miR-15a mimic with enhanced therapeutic potential. This mimic maintains target specificity and is more potent than unmodified miR-15a in vitro and inhibits colon tumor metastasis in vivo. This mimic has great potential for therapeutic development for treating colon cancer patients. This novel modification has potential to advance the development of other microRNA based therapeutics beyond miR-15a.

The expanding regulatory universe of p53 in gastrointestinal cancer

Tumor suppresser gene TP53 is one of the most frequently deleted or mutated genes in gastrointestinal cancers. As a transcription factor, p53 regulates a number of important protein coding genes to control cell cycle, cell death, DNA damage/repair, stemness, differentiation and other key cellular functions. In addition, p53 is also able to activate the expression of a number of small non-coding microRNAs (miRNAs) through direct binding to the promoter region of these miRNAs. Many miRNAs have been identified to be potential tumor suppressors by regulating key effecter target mRNAs. Our understanding of the regulatory network of p53 has recently expanded to include long non-coding RNAs (lncRNAs). Like miRNA, lncRNAs have been found to play important roles in cancer biology. With our increased understanding of the important functions of these non-coding RNAs and their relationship with p53, we are gaining exciting new insights into the biology and function of cells in response to various growth environment changes. In this review we summarize the current understanding of the ever expanding involvement of non-coding RNAs in the p53 regulatory network and its implications for our understanding of gastrointestinal cancer.

Autophagy regulated by miRNAs in colorectal cancer progression and resistance

The catabolic process of autophagy is an essential cellular function that allows for the breakdown and recycling of cellular macromolecules. In recent years, the impact of epigenetic regulation of autophagy by noncoding miRNAs has been recognized in human cancer. In colorectal cancer, autophagy plays critical roles in cancer progression as well as resistance to chemotherapy, and recent evidence demonstrates that miRNAs are directly involved in mediating these functions. In this review, we focus on the recent advancements in the field of miRNA regulation of autophagy in colorectal cancer.

Overcoming chemoresistance in cancer stem cells with the help of microRNAs in colorectal cancer

It has been recognized that acute resistance to chemotherapy mediated by post-transcriptional and translational control is crucial to influence response and survival in cancer treatment. Tumor cells are highly heterogeneous and have the ability to adapt a resistance phenotype through epigenetic regulations such as microRNAs. This poses a major challenge to the treatment of advanced stage colon cancer patients. Colon cancer stem cells have been identified as one of the major contributors to resistance of colon cancer to chemotherapy. Through various mechanisms, these cells are able to resist the effects of traditional chemotherapeutics. The challenge posed by these cells is further enhanced by their plastic nature, where cells can transition between non-stem cancer cells and cancer stem cells creating a moving target. In this editorial, we discuss some of the recent advancements in overcoming chemoresistance associated with colon cancer stem cells with the help of microRNAs.

microRNA based prognostic biomarkers in pancreatic Cancer

Despite tremendous research efforts focused on diagnosis and treatment, pancreatic ductal adenocarcinoma remains the third leading cause of cancer-related death in the United States, with a 5-year overall survival rate of less than 5%. Although resistance is rather complex, emerging evidence has demonstrated that epigenetic alterations (e.g. miRNA) have important roles in PDAC progression as well as resistance to therapy. Certain miRNAs have been identified as potential prognostic biomarkers in PDAC. In this review, we summarize the recent developments in miRNA research related to PDAC therapeutic resistance mechanisms and the potential of miRNAs as prognostic biomarkers for future clinical management of PDAC.