Long Non-Coding RNAs: New Insights in Neurodegenerative Diseases.

Neurodegenerative diseases (NDDs), including Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS), are gradually becoming a burden to society. The adverse effects and mortality/morbidity rates associated with these NDDs are a cause of many healthcare concerns. The pathologic alterations of NDDs are related to mitochondrial dysfunction, oxidative stress, and inflammation, which further stimulate the progression of NDDs. Recently, long non-coding RNAs (lncRNAs) have attracted ample attention as critical mediators in the pathology of NDDs. However, there is a significant gap in understanding the biological function, molecular mechanisms, and potential importance of lncRNAs in NDDs. This review documents the current research on lncRNAs and their implications in NDDs. We further summarize the potential implication of lncRNAs to serve as novel therapeutic targets and biomarkers for patients with NDDs.

MUC13 drives cancer aggressiveness and metastasis through the YAP1-dependent pathway.

Anchorage-independent survival after intravasation of cancer cells from the primary tumor site represents a critical step in metastasis. Here, we reveal new insights into how MUC13-mediated anoikis resistance, coupled with survival of colorectal tumor cells, leads to distant metastasis. We found that MUC13 targets a potent transcriptional coactivator, YAP1, and drives its nuclear translocation via forming a novel survival complex, which in turn augments the levels of pro-survival and metastasis-associated genes. High expression of MUC13 is correlated well with extensive macrometastasis of colon cancer cells with elevated nuclear YAP1 in physiologically relevant whole animal model systems. Interestingly, a positive correlation of MUC13 and YAP1 expression was observed in human colorectal cancer tissues. In brief, the results presented here broaden the significance of MCU13 in cancer metastasis via targeting YAP1 for the first time and provide new avenues for developing novel strategies for targeting cancer metastasis.

Clinical Implications of Exosomes: Targeted Drug Delivery for Cancer Treatment.

Exosomes are nanoscale vesicles generated by cells for intercellular communication. Due to their composition, significant research has been conducted to transform these particles into specific delivery systems for various disease states. In this review, we discuss the common isolation and loading methods of exosomes, some of the major roles of exosomes in the tumor microenvironment, as well as discuss recent applications of exosomes as drug delivery vessels and the resulting clinical implications.

Biophysical changes caused by altered MUC13 expression in pancreatic cancer cells.

BACKGROUND: Pancreatic cancer is one of the most lethal cancers in the United States. This is partly due to the difficulty in early detection of this disease as well as poor therapeutic responses to currently available regimens. Our previous reports suggest that mucin 13 (MUC13, a transmembrane mucin common to gastrointestinal cells) is aberrantly expressed in this disease state, and has been implicated with a worsened prognosis and an enhanced metastatic potential in PanCa. However, virtually no information currently exists to describe the biophysical ramifications of this protein. METHODS: To demonstrate the biophysical effect of MUC13 in PanCa, we generated overexpressing and knockdown model cell lines for PanCa and subsequently subjected them to various biophysical experiments using atomic force microscopy (AFM) and cellular aggregation studies. RESULTS: AFM-based nanoindentation data showed significant biophysical effects with MUC13 modulation in PanCa cells. The overexpression of MUC13 in Panc-1 cells led to an expected decrease in modulus, and a corresponding decrease in adhesion. With MUC13 knockdown, HPAF-II cells exhibited an increased modulus and adhesion. These results were confirmed with altered cell-cell adhesion as seen with aggregation assays. CONCLUSIONS: MUC13 led to significant biophysical changes in PanCa cells and which exhibited characteristic phenotypic changes in cells demonstrated in previous work from our lab. This work gives insight into the use of biophysical measurements that could be used to help diagnose or monitor cancers as well as determine the effects of genetic alterations at a mechanical level.

Z Probe, An Efficient Tool for Characterizing Long Non-Coding RNA in FFPE Tissues.

Formalin-fixed paraffin embedded (FFPE) tissues are a valuable resource for biomarker discovery in order to understand the etiology of different cancers and many other diseases. Proteins are the biomarkers of interest with respect to FFPE tissues as RNA degradation is the major challenge in these tissue samples. Recently, non-protein coding transcripts, long non-coding RNAs (lncRNAs), have gained significant attention due to their important biological actions and potential involvement in cancer. RNA sequencing (RNA-seq) or quantitative reverse transcription-polymerase chain reaction (qRT-PCR) are the only validated methods to evaluate and study lncRNA expression and neither of them provides visual representation as immunohistochemistry (IHC) provides for proteins. We have standardized and are reporting a sensitive Z probe based in situ hybridization method to visually identify and quantify lncRNA in FFPE tissues. This assay is highly sensitive and identifies transcripts visible within different cell types and tumors. We have detected a scarcely expressed tumor suppressor lncRNA NRON (non-coding repressor of nuclear factor of activated T-cells (NFAT)), a moderately expressed oncogenic lncRNA UCA1 (urothelial cancer associated 1), and a highly studied and expressed lncRNA MALAT1 (metastasis associated lung adenocarcinoma transcript 1) in different cancers. High MALAT1 staining was found in colorectal, breast and pancreatic cancer. Additionally, we have observed an increase in MALAT1 expression in different stages of colorectal cancer.

Role of lncRNAs in ovarian cancer: defining new biomarkers for therapeutic purposes.

Long noncoding RNAs (lncRNAs) are a class of noncoding RNA, involved in regulation of diverse physiological and pathological processes. Ovarian cancer is the leading cause of death among all gynecological malignancies in the world and its underlying mechanism is still unclear. LncRNAs exhibit multiple biological functions in various stages of ovarian cancer development. We will discuss and summarize the new and important lncRNAs and their involvement in disease, which might represent promising therapeutic targets. Therapeutic intervention based on silencing or functional inhibition of target lncRNAs will be beneficial for ovarian cancer patients.

Protein kinase D1 regulates subcellular localisation and metastatic function of metastasis-associated protein 1.

BACKGROUND: Cancer progression and metastasis is profoundly influenced by protein kinase D1 (PKD1) and metastasis-associated protein 1 (MTA1) in addition to other pathways. However, the nature of regulatory relationship between the PKD1 and MTA1, and its resulting impact on cancer metastasis remains unknown. Here we present evidence to establish that PKD1 is an upstream regulatory kinase of MTA1. METHODS: Protein and mRNA expression of MTA1 in PKD1-overexpressing cells were determined using western blotting and reverse-transcription quantitative real-time PCR. Immunoprecipitation and proximity ligation assay (PLA) were used to determine the interaction between PKD1 and MTA1. PKD1-mediated nucleo-cytoplasmic export and polyubiquitin-dependent proteosomal degradation was determined using immunostaining. The correlation between PKD1 and MTA1 was determined using intra-tibial, subcutaneous xenograft, PTEN-knockout (PTEN-KO) and transgenic adenocarcinoma of mouse prostate (TRAMP) mouse models, as well as human cancer tissues. RESULTS: We found that MTA1 is a PKD1-interacting substrate, and that PKD1 phosphorylates MTA1, supports its nucleus-to-cytoplasmic redistribution and utilises its N-terminal and kinase domains to effectively inhibit the levels of MTA1 via polyubiquitin-dependent proteosomal degradation. PKD1-mediated downregulation of MTA1 was accompanied by a significant suppression of prostate cancer progression and metastasis in physiologically relevant spontaneous tumour models. Accordingly, progression of human prostate tumours to increased invasiveness was also accompanied by decreased and increased levels of PKD1 and MTA1, respectively. CONCLUSIONS: Overall, this study, for the first time, establishes that PKD1 is an upstream regulatory kinase of MTA1 status and its associated metastatic activity, and that the PKD1-MTA1 axis could be targeted for anti-cancer strategies.

miR-145: Revival of a Dragon in Pancreatic Cancer.

Emergence of the role of MicroRNA-145 (miR-145) as a tumor suppressor in pancreatic cancer, offers its potential for novel therapeutic interventions. Our recently published studies demonstrate clinical significance of miR-145 in pancreatic cancer and suggest that the dysregulation of miR-145 in human pancreatic tumors draws in parallel with the aberrant expression of an oncogenic mucin, MUC13. These studies also present a novel therapeutic strategy of restoring the downregulated levels of miR-145 in pancreatic cancer via nanoparticle mediated efficient delivery system.