Abstract
Purpose The epithelial–mesenchymal transition (EMT) is a key hallmark of cancer which promotes malignant progression, especially during the process of cancer invasion. A better understanding of EMT will help elucidate the molecular mechanism underlying colorectal cancer (CRC) metastasis and may provide new insights into the identification of potential biomarkers and therapeutic targets. Methods A series of bioinformatic approaches were combined and identify GLI3 as a potential key regulator in EMT. In vitro experiments were performed to knockdown GLI3 expression in two CRC cell lines and to reveal the oncogenic role of GLI3 in CRC. qRT-PCR and western blot were performed to show the influence of GLI3 in EMT and downstream pathways. The Kaplan-Meier analysis and log-rank test were used to evaluate the prognostic value of GLI3 in CRC patients. Results GLI3 was identified as a key regulator in coexpression and protein-protein interaction (PPI) networks involved in EMT. Bioinformatic analyses indicated that GLI3 had a high correlation with EMT markers in CRC. In vitro experiments showed that GLI3 knockdown attenuated the migratory and invasive capacities of CRC cells via influencing EMT property, especially by regulating phosphorylation of ERK signaling pathway. In addition, higher expression of GLI3 predicts worse prognosis in CRC patients. Conclusions In summary, we presented the first evidence that GLI3 could promote the migratory and invasive capacities of CRC cells by regulating the EMT process. Our study might provide some useful clues to a better understanding of GLI3 in EMT during CRC progression.
Highlights
According to the latest released Global Cancer Statistics, colorectal cancer (CRC) becomes the world’s third most diagnosed cancer, with an annual incidence of over 1.4 million cases [1]
Weighted gene coexpression network analysis (WGCNA) was performed with transcriptome profiling data and epithelial-mesenchymal transition (EMT) Z-scores to construct a scale-free coexpression network
A regulation network composing coexpression genes and protein-protein interaction (PPI) was constructed using CEMiTool, and the key regulators in the EMT module were coloured with different colours according to the roles (Figure 1(f))
Summary
According to the latest released Global Cancer Statistics, colorectal cancer (CRC) becomes the world’s third most diagnosed cancer, with an annual incidence of over 1.4 million cases [1]. There is an urgent need to reveal the mechanism underlying CRC metastasis, which may benefit to identification of novel diagnostic biomarkers and development of therapeutic targets [5, 7]. GLI1, the first member identified of GLI family, has been widely reported and promotes malignant progression in various cancers via influencing the hedgehog signaling pathway. GLI3 affects proliferation and apoptosis in cervical cancer cells and was targeted by miRNA-218 and miRNA506 [13, 14]. These evidences suggested that GLI3 was BioMed Research International involved in the malignant progression in different cancer types.
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