Radiation-Induced Exosomal Mirna Mediate Bystander Liver Regeneration

  • Chen, Fang-Hsin (PI)
  • Hong, Ji-Hong (CoPI)
  • Huang, Hsien Da (CoPI)

Project: National Science and Technology CouncilNational Science and Technology Council Academic Grants

Project Details

Abstract

Radiotherapy (RT) has traditionally not been a major treatment modality for liver cancer, but its role has been gradually increased due to the use of stereotactic radiotherapy (SBRT) and particle therapy. RT not only eradicates the tumor, but also inevitably damages the normal liver surrounding the tumor. In clinical follow-up by imaging, we often see the atrophy of liver within high-dose irradiated regions, but the remote normal liver tissues gradually expanded, suggesting liver regeneration; while liver regeneration should be able to compensate the function of the damaged liver tissues. The mechanism of liver regeneration in several types of damages has been extensively investigated. After massive loss of functional liver cells caused by hepatectomy or other types of liver injuries, the residual liver cells will rapidly regenerate to help the recovery of liver function. In addition to numerous growth factors and cytokines that have been identified to be involved in this process, exosome also serves as a mode of intercellular communication in the process of liver repair and regeneration. Compensatory liver hypertrophy in remote, less exposed region has been also stated on patients with hepatocellular carcinoma (HCC) treated with RT, but its mechanism has never been explored. Not like that in hepatectomy, the damages caused by RT are much more complicated and not limited in the hepatocyte damage. Although the pathway of compensatory liver hypertrophy after RT is still unknown, we believe that the radiation-induced bystander effect (RIBE) is the most possible mediator. Among RIBE triggered in liver, exosome might be the major mechanistic pathway of transmitting the signals from irradiated liver cells to the non-irradiated bystander cells, but little is known about the biological functions of these exosomes. In this study we aim to determine if exosomes derived from irradiated hepatocytes contribute to liver hypertrophy and regeneration. We hypothesize that there is a set of differentially expressed miRNAs in the exosomes from irradiated hepatocytes. The miRNAs could modulate gene expression and contribute to hepatocyte proliferation after transferring into non-irradiated hepatocytes. The potential miRNAs will be selected from computational prediction programs and intervened with its inhibitor to investigate the effects on hepatocyte proliferation. In addition, partial liver irradiation will be performed in mice model followed by examination of the serum exosome and its miRNAs. We will investigate how miRNAs in serum exosomes mediate liver regeneration and whether these miRNAs interferer the HCC growth. According to the clinical observation, radiation injury results in slower regeneration and less liver recovery which is contrary to quick and full liver recovery after hepatectomy. The success of this study will contribute to unveil the mechanism of radiation-induced liver regeneration after radiotherapy and to boost or accelerate this process for liver recovery by targeting therapy utilizing miRNA. Specific aims in this study are: 1. To investigate how radiation-induced bystander effect promote hepatocyte proliferation via exosomes. 2. To Identify miRNA profiles in the secretive exosome and investigate the effect of selected miRNA on hepatocyte proliferation. 3. To Identify exosome release after liver irradiation and investigate its effect on liver hypertrophy/ regeneration

Project IDs

Project ID:PC10608-1480
External Project ID:MOST106-2314-B182-019
StatusFinished
Effective start/end date01/08/1731/07/18

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