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Study of the hedgehog signaling pathway in colorectal cancer: Association with wild type RAS status
Background
EGFR antibodies are efficient in the treatment of patients with RAS wild type metastatic colorectal cancer (mCRC). However, 25% of those patients resist to this therapy. This could be explained by other genetic alterations. Hedgehog (Hh) signaling pathway was described in the development and transition to metastatic stages. The aim of this study is to investigate the expression of Gli1, transcription factor of Hh signaling pathway, and PDGFRα, target gene of Hh signaling pathway, in colorectal adenocarcinoma as compared to normal mucosa and to assess their correlation with clinicopathological features and molecular RAS status.
Methods
Our study enrolled 60 formalin fixed and paraffin-embedded (FFPE) samples of mCRC and 11 FFPE samples of normal colon mucosa as controls. We investigated Gli1 and PDGFRα expression by immunohistochemistry and RAS status by Real Time PCR in all mCRC specimens.
Results
Our results showed a cytoplasmic immunostaining for Gli1 and a cytoplasmic and/or membranous immunostaining for PDGFRα. Gli1 and PDGFRα were weakly expressed in normal colonic mucosa as compared to CCR tissues. High expression of Gli1 and of PDGFRα was found respectively in 65,7% and 68.6% of RAS wild type mCRC and in 32% and 24% respectively of mutated RAS (P < 0.01 and P < 0.001 respectively). High co-expression of PDGFRα and Gli1 was significantly associated to RAS wild type status (P < 0.001) and Male Gender (P < 0.041). No association was found between Gli1 and PDGFRα expression and other clinicopathological features.
Conclusions
High expression of Hh pathway members in wild-RAS genes patients could explain the resistance to targeted therapy in this group and may be considered as target to specific therapy to reduce the number of non-responders.
Legal entity responsible for the study
The author.
Funding
This work was supported by the Tunisian Ministry of Public Health, the Tunisian Ministry of Higher Education and Scientific Research (LR16IPT05).
Disclosures
All authors have declared no conflicts of interest.
