Evaluation on the expression of neurotrophic factor and their associated receptors in hepatocellular carcinoma cell lines

Abstract

Liver cancer ranks the sixth most commonly diagnosed cancer and second cancer killer worldwide. Hepatocellular carcinoma (HCC) contributes to around 85% of all cases of liver cancer. The pathogenesis of HCC remains complicated due to tumor heterogeneity. Limited therapeutic agents are available, resulting in high mortality and recurrent rate in HCC. A wide diversity of physiology contributes to the development of HCC, and families of growth factors were identified to influence HCC progression.

There are evidences demonstrating functions of neurotrophic factors in prostate, ovarian and lung cancers. Previous studies have also proposed the role of nerve growth factors (NGF) and brain-derived neurotrophic factor (BDNF) in HCC progression. In this study, we offer an overview on the expression of members in the three families of neurotrophic factors in eight HCC cell lines, including non-metastatic and metastatic cell lines. NGF and BDNF displayed consistent upregulating expression as described in pervious studies, suggesting their ability in promoting HCC progression. The expression of nerve growth factor receptor (NGFR), also denoted as p75, was down-regulated. This may due to its functions in inducing cell death, which may result in apoptosis of hepatic cancer cells. Glial cell line-derived neurotrophic factors (GDNF) family of ligands was under-expressed in SMMC7721, MHCC97L and MHCCLM3 cell lines, by which the expression of GDNF was reduced in the greatest extent. The expression of ciliary neurotrophic factor was also suppressed in metastatic cell lines.

To determine the potential role of GDNF in hepatocarcinogenesis, clinicopathological correlation was performed and the results indicated HCC patients with GDNF under-expression tended to have poorer prognosis. Under-expression of GNDF was significantly associated with venous invasion and poor disease-free survival. Using HLE cell line, GDNF significantly inhibited the migration of cancer cells at the concentration of 400ng/ml, but displayed no effect in invasion at any concentration tested. As our results suggested GDNF under-expression was associated with advanced HCC, further studies should be performed to investigate other potential inhibitory properties of GDNF that restrict metastasis of HCC.