The role of TGF-β1–miR-21–ROS pathway in bystander responses induced by irradiated non-small-cell lung cancer cells
Springer Science and Business Media LLC -- British Journal of Cancer
DOI 10.1038/bjc.2014.368
Keyword(s)
  1. radiation-induced bystander effects (RIBEs)
  2. TGF-β1 signalling pathway
  3. miR-21
  4. reactive oxygen species (ROS)
  5. lung cancer cells
Abstract(s)

Background:

Many studies have indicated an important implication of radiation-induced bystander effects (RIBEs) in cancer radiotherapy, but the detailed signalling remains unclear.

Methods:

The roles of tumour growth factor-beta1 (TGF-β1) and miR-21 in medium-mediated RIBEs in H1299 non-small-cell lung cancer cells were investigated using DNA damage, changes in proliferation and levels of reactive oxygen species (ROS) as end points. SB431542, a specific inhibitor of TGF-β type 1 receptor kinases, was used to inhibit TGF-β1 pathways in irradiated and bystander cells. Exogenous miR-21 regulation was achieved through inhibitor or mimic transfection.

Results:

Compared with relative sham-radiation-conditioned medium, radiation-conditioned medium (RCM) from irradiated cells 1 h post radiation (1-h RCM) caused an increase in ROS levels and DNA damage in bystander cells, while 18-h RCM induced cell cycle delay and proliferation inhibition. All these effects were eliminated by TGF-βR1 inhibition. One-hour RCM upregulated miR-21 expression in bystander cells, and miR-21 inhibitor abolished bystander oxidative stress and DNA damage. Eighteen-hour RCM downregulated miR-21 of bystander cells, and miR-21 mimic eliminated bystander proliferation inhibition. Furthermore, the dysregulation of miR-21 was attenuated by TGF-βR1 inhibition.

Conclusions:

The TGF-β1–miR-21–ROS pathway of bystander cells has an important mediating role in RIBEs in H1299 cells.