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
External Project ID:MOST106-2314-B182-019
Status | Finished |
---|---|
Effective start/end date | 01/08/17 → 31/07/18 |
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