Sonic hedgehog pathway inhibitor mitigates mouse hepatocellular carcinoma

Am J Surg. 2015 Sep;210(3):554-60. doi: 10.1016/j.amjsurg.2015.03.001. Epub 2015 May 8.

Abstract

Background: Hepatocellular carcinoma (HCC) is a leading cause of death in Asian countries. Sonic hedgehog (Shh) pathway plays a role in hepatocarcinogenesis. We investigated the treatment effect of mouse HCC with Shh inhibitor GDC-0449.

Methods: Mouse hepatoma ML-1 cells were implanted in B6 mice. Fifteen days later, GDC-0449 (vismodegib), antagonist of smoothened, was used to treat HCC-bearing mice. The tumor size and liver histopathological features were analyzed, as well as gene expression in Shh pathways.

Results: GDC-0449 treatment effectively reduced tumor size and cell infiltration of the HCC in mice. Gene expression of Shh pathway molecules was altered, including upregulated Shh expression and downregulated smoothened expression in tumor fractions after GDC-0449 treatment.

Conclusion: GDC-0449 could effectively mitigate HCC growth in vivo.

Keywords: GDC-0449; Gli-1; Ptch-1; Shh; Smo; Sonic hedgehog pathway.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anilides / pharmacology*
  • Animals
  • Antineoplastic Agents / pharmacology
  • Carcinoma, Hepatocellular / drug therapy*
  • Carcinoma, Hepatocellular / pathology*
  • Down-Regulation
  • Gene Expression
  • Hedgehog Proteins / genetics
  • Hedgehog Proteins / metabolism
  • Liver Neoplasms, Experimental / drug therapy*
  • Liver Neoplasms, Experimental / pathology*
  • Male
  • Mice, Inbred C57BL
  • Patched Receptors
  • Patched-1 Receptor
  • Pyridines / pharmacology*
  • RNA, Messenger / metabolism
  • Random Allocation
  • Receptors, Cell Surface / genetics
  • Receptors, Cell Surface / metabolism
  • Receptors, G-Protein-Coupled / antagonists & inhibitors*
  • Receptors, G-Protein-Coupled / genetics
  • Receptors, G-Protein-Coupled / metabolism
  • Smoothened Receptor
  • Transcription Factors / genetics
  • Transcription Factors / metabolism
  • Up-Regulation
  • Zinc Finger Protein GLI1

Substances

  • Anilides
  • Antineoplastic Agents
  • GLI1 protein, human
  • Hedgehog Proteins
  • HhAntag691
  • PTCH1 protein, human
  • Patched Receptors
  • Patched-1 Receptor
  • Ptch1 protein, mouse
  • Pyridines
  • RNA, Messenger
  • Receptors, Cell Surface
  • Receptors, G-Protein-Coupled
  • Shh protein, mouse
  • Smo protein, mouse
  • Smoothened Receptor
  • Transcription Factors
  • Zinc Finger Protein GLI1