Hepatocellular Carcinoma (HCC) is responsible for 70-85% of primary liver cancer cases. Liver cancer is the 2nd leading cause of cancer related deaths worldwide.
HCC models typically involve an initial insult of N-nitrosodiethylamine followed by long term administration of either a fibrotic or steatotic challenge. Commonly, HCC occur at 8-12 months. Here we have shown that steatotic and fibrotic challenges synergize in the liver to produce HCC in 3-5 months.
The dipeptidyl peptidase 4 (DPP4) gene family consists of four atypical serine proteases, DPP4/DPPIV, fibroblast activation protein (FAP), DPP8, and DPP9. FAP is a key protein that is expressed by carcinoma associated fibroblasts (CAFs). FAP is in the CAF’s of 90% of epithelial cancers (El Khoury, Kurban et al. 2014). DPP4 also has roles in tumour progression.
Our lab has previously observed that less liver fibrosis, improved liver histopathology and improved glucose metabolism in DPP4 gko and FAP gko mice. Reduced hepatic lipid has been observed in DPP-IV gko mice and DPP-IV inhibitor – treated animals. In addition, we have reported elevated levels of DPP4, DPP8 and DPP9 mRNA in fibrotic livers from mice.
DPP8/9, DPP4 and FAP enzyme activities decreased during the progression of HCC in our mouse model, however DPP9 protein expression increased in precancerous and cancerous lesions. Furthermore, increased alpha-Smooth Muscle Actin staining in the lesions indicates the increased presence of CAFs in the lesions. Understanding the molecular basis of the pathogenesis of liver cancer is crucial for progress towards its treatment and prevention and the DPP4 family members provide potential new therapeutic targets.