Incomplete radiofrequency ablation provokes colorectal cancer liver metastases through heat shock response by PKCα/Fra-1 pathway

Objective: Incomplete radiofrequency ablation (ICR) has been proposed as a major cause of recurrence in the treatment of hepatic metastatic tumors. We tried to determine the mechanisms of this progression in colorectal cancer (CRC) liver metastasis (CRLMs).

Methods: We have established a mouse model of radiofrequency ablation (RFA) therapy to demonstrate increased risk of recurrence of CRLMs with ICR. Here we focused on heat shock-induced CRC malignancy. Sub-lethal heat shock (HS) in CRC cell lines provoked cell growth, invasion, and tumor initiation in vitro and in vivo.

Results: We found that Fra-1, which lies downstream of PKCα-ERK1/2 signaling, was significantly increased by HS compared with the untreated CRC cells. Silencing Fra-1 reversed the tumor promoting effects of HS. Furthermore, proliferation and tumor initiation inducer c-Myc, together with tumor invasion inducer matrix-metalloprotase 1 (MMP-1) expression were up-regulated by AP-1/Fra-1 induced genes transcription.

Conclusions: Our study demonstrated that ICR generated HS induces CRC malignancy by targeting Fra-1, which could be a potential prognostic marker and a promising therapeutic strategy to prevent disease recurrence after radiofrequency ablation treatment.