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GLI1 promotes cancer stemness through intracellular signaling pathway PI3K/Akt/NFκB in colorectal adenocarcinoma

Zhaoting Yang1, Chengye Zhang2, Wenbo Qi1

  • 1Institute for Regenerative Medicine, Yanbian University College of Medicine, Yanji, China; Department of Pathology, Yan bian University College of Medicine, Yanji 133002, Jilin Province, China.

Experimental Cell Research
|October 16, 2018
PubMed

Insights

Glioma-associated oncogene homolog 1 (GLI1) is linked to poor survival in colorectal cancer. Targeting GLI1 and the PI3K/Akt/NFκB pathway may offer new therapeutic strategies for colorectal adenocarcinoma.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Therapeutics

Background:

  • The Hedgehog (HH)/glioma-associated oncogene homolog 1 (GLI1) pathway is implicated in various cancers.
  • Its role and interactions with pathways like PI3K/Akt/NFκB in colorectal adenocarcinoma are under-explored.
  • GLI1's oncogenic potential and cross-talks require further investigation for therapeutic relevance.

Purpose of the Study:

  • To assess GLI1 expression and its correlation with clinical parameters and other cancer markers in colorectal adenocarcinoma.
  • To investigate the effect of GLI1 on cancer stemness, EMT, cell cycle, and its interaction with the PI3K/Akt/NFκB pathway.
  • To evaluate the therapeutic potential of targeting GLI1 and the PI3K/Akt/NFκB pathway in colorectal adenocarcinoma.

Main Methods:

  • Immunohistochemistry was used to analyze GLI1 expression in 100 colorectal adenocarcinoma tissue samples.
  • Correlation analysis was performed with cancer stemness genes, cell cycle markers, EMT markers, PI3K/Akt/NFκB pathway genes, and HIF1α.
  • In vitro studies using colorectal adenocarcinoma cell lines assessed the effects of GLI1 inhibition and combined pathway inhibition.

Main Results:

  • GLI1 expression correlated with advanced clinical stages and distant metastasis, predicting poor overall and disease-free survival.
  • GLI1-expressing cells showed increased cancer stem-like cell markers (SOX9, CD133), HIF1α, and EMT-related genes.
  • GLI1 inhibition reduced CSC markers, clonogenicity, S-phase, migration, and invasion; Akt inhibitor Perifosine reduced pAkt and GLI1; combined GLI1 and NFκB inhibition showed synergistic effects.

Conclusions:

  • GLI1 may serve as a novel stem cell marker in colorectal adenocarcinoma, with cancer stemness activated via the PI3K/Akt/NFκB pathway.
  • GLI1 expression is significantly associated with aggressive clinicopathological features and poor prognosis.
  • Simultaneous co-targeting of GLI1 and PI3K/Akt/NFκB signaling presents a promising therapeutic strategy for colorectal adenocarcinoma.
Keywords:
Colorectal adenocarcinomaEpithelial-to-mesenchymal transitionGlioma-associated oncogene homolog 1PI3K/Akt/NFκB pathwayPrognosis, cancer stem-like cell

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