The overall goal of this application is to identify and qualify exosomal non-coding RNA based biomarkers in the circulation to detect early stage disease in patients at risk, to predict recurrence after surgery and to monitor response to therapy in patients with hepatocellular cancer (HCC). The incidence of this cancer is increasing and survival remains poor. Early detection of HCC is essential to survival, yet current biomarkers such as AFP lack the sensitivity to sufficiently detect early stage cancer amenable to surgical cure. Our preliminary studies have identified several microRNA and long-non-coding RNA that are selectively enriched within exosomes released from HCC cells. Moreover, we have cloned a novel long non-coding RNA gene, TUC339 that is very highly enriched in exosomes released from HCC cells, and that can be detected in serum from patients with HCC. We hypothesize that tumor specific non-coding RNA that are selectively released within exosomes into the circulation can be detected to provide highly specific biomarkers for HCC. This project will test this hypothesis using a rigorous two phase biomarker development process to evaluate the utility of exosomal TUC339 and to identify other extracellular non-coding RNA (exRNA) as diagnostic and prognostic biomarkers of HCC. The goal of the first phase will be to identify lead candidates and to develop digital PCR based assays for their detection whereas the goals of the second phase will be to validate the clinical utility of promising exRNA candidates by prospectively validating their capability for diagnosis and as biomarkers of recurrence or treatment response. The study design includes (a) evaluation of identified exRNA candidates and further discovery studies for known or novel long non-coding RNA, (b) explicit biospecimen collection and processing, (c) a multi-stage integrated approach with a prospective case control study, comparison with independently obtained case-control reference samples, and an independent multi-center validation study either as part of a planned on-going study (HEDS) or through a new consortium-based study. Additionally, we will prospectively evaluate exRNA as predictors of recurrence or treatment response. Through these efforts, we expect to develop novel analytical assays for circulating exRNA and to identify a clinically relevant biomarker that will be useful as a diagnostic, prognostic or treatment response marker for patients with HCC.
A goal of this project is to identify new RNA markers circulating within exosomes for early diagnosis and improved care of liver cancer, and thereby to improve the care and outcomes from liver diseases. These studies will identify new non-coding RNA that will be clinically useful disease biomarkers, as well as develop novel sensitive assays for their detection. The results will have a broader impact by increasing basic knowledge about non-coding RNA and their detection and use as biomarkers for other diseases.
| Yan, Irene K; Lohray, Rishabh; Patel, Tushar (2018) Droplet Digital PCR for Quantitation of Extracellular RNA. Methods Mol Biol 1740:155-162 |
| Shukla, Neha; Yan, Irene K; Patel, Tushar (2018) Multiplexed Detection and Quantitation of Extracellular Vesicle RNA Expression Using NanoString. Methods Mol Biol 1740:177-185 |
| Yan, Irene K; Berdah, Valentin X; Patel, Tushar (2018) Isolation of Extracellular RNA from Bile. Methods Mol Biol 1740:59-67 |
| Matsuda, Akiko; Patel, Tushar (2018) Milk-derived Extracellular Vesicles for Therapeutic Delivery of Small Interfering RNAs. Methods Mol Biol 1740:187-197 |
| Godoy, Paula M; Bhakta, Nirav R; Barczak, Andrea J et al. (2018) Large Differences in Small RNA Composition Between Human Biofluids. Cell Rep 25:1346-1358 |
| Haga, Hiroaki; Yan, Irene K; Borrelli, David A et al. (2017) Extracellular vesicles from bone marrow-derived mesenchymal stem cells protect against murine hepatic ischemia/reperfusion injury. Liver Transpl 23:791-803 |
| Moirangthem, Anuradha; Patel, Tushar (2017) Mesenchymal stem cell derived extracellular vesicles: a promising new therapeutic approach for hepatic injury. Biotarget 1: |
| Maji, Sayantan; Matsuda, Akiko; Yan, Irene K et al. (2017) Extracellular vesicles in liver diseases. Am J Physiol Gastrointest Liver Physiol 312:G194-G200 |
| Klingenberg, Marcel; Matsuda, Akiko; Diederichs, Sven et al. (2017) Non-coding RNA in hepatocellular carcinoma: Mechanisms, biomarkers and therapeutic targets. J Hepatol 67:603-618 |
| Maji, Sayantan; Yan, Irene K; Parasramka, Mansi et al. (2017) In vitro toxicology studies of extracellular vesicles. J Appl Toxicol 37:310-318 |
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