Dissecting Cellular and Exosomal Transcriptome Regulation Underlying Tumor Progression and Treatment Outcome of Esophageal Squamous Cell Carcinoma( I )

Deep sequencing technologies have unraveled the once uncharted non-coding constituents of the transcriptome, most notably circular RNA (circRNAs) and long non-coding RNAs (lncRNAs). Despite the lack of protein-coding potential, these non-coding RNAs (ncRNAs) have been found to act as critical gene regulatory hubs. Furthermore, owing to their unique expression patterns in tumor specimens or liquid biopsies, they may presumably be exploited for the development of new biomarkers for tumor progression and outcome, as well as of treatment targets. However, only a limited number of cancer-related ncRNAs has been entirely studied, and their mechanistic implications in treatment response have not been substantially resolved. The clinical focus of this program project is esophageal squamous cell carcinoma (ESCC), which is one of the most diagnosed and aggressive malignancies in the world. Despite recent improvement in patient outcome, the treatment of this disease is still challenged by recurrence and chemoresistance, and thus is still in urgent need of valid molecular-based drug target or therapy. Using the deep sequencing platform, we have profiled the non-coding transcriptomes of tumor tissues and exosomes derived from ESCC patients with good/poor response to the concomitant chemo-radiation therapy (CCRT). We (sub-project 1) have preliminarily identified differentially expressed ncRNAs and provided in silico evidence for their cellular networks, linking the antioxidant transcription factor NRF2 as the upstream regulator. These lines of information support the tumorigenic connection of ncRNAs to esophageal cancer and serve as important foundation for the proposed studies, which are aimed to dissect the molecular actions of candidate ncRNAs, particularly in the context of tumor progression and microenvironment. In the first part, via integrating our in-house esophageal cancer RNA sequencing datasets with public data, we will conduct ncRNA expression analysis to comparatively profile distinctions between specimens of different outcomes. We will then identify and verify ncRNA signatures with clinical relevance (in collaboration with sub-project 3). Next, based on molecular co-expression and interactome, the ncRNA-centric regulatory network will be constructed in a comprehensive manner. As a proof of principle, we have identified NRF2 as a key transcriptional regulator of ncRNAs, which will be further characterized for underlying mechanism and tumorigenic consequence (in collaboration with sub-project 2). In the third and final part, a series of cell biology and functional assays will be executed to explore mechanistically the contribution of ncRNA candidates to esophageal cancer malignant progression and microenvironment interaction. Collectively, these integrated studies are expected to provide key insights into the biology of the non-coding transcriptome, facilitate mechanistic understanding of the underlying variability in ESCC treatment outcome, and also have potential value in the development of new personalized medicine.

Project ID:PC10907-1514
External Project ID:MOST109-2320-B182-016