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FGF14 Functions as a Tumor Suppressor through Inhibiting PI3K/AKT/mTOR Pathway in Colorectal Cancer
Tianhong Su1, Linlin Huang2,3, Ning Zhang2
1Department of Liver Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China.
Abstract:
We identified that Fibroblast Growth Factor 14 (FGF14) was preferentially methylated in colorectal cancer (CRC). In this study, we aimed to investigate the epigenetic regulation, biological function and molecular mechanism of FGF14 in CRC. The expression of FGF14 in CRC cell lines, normal human colon epithelial cell line, CRC tissues and paired adjacent normal tissues was detected by PCR and Western blot. The biological function of FGF14 in CRC was interrogated by cell viability assay, colony formation, flow cytometry, cell invasion and migration assay, as well as in vivo study. We found FGF14 was downregulated or silenced in all (10/10) CRC cell lines, while it was expressed in normal colonic tissues and normal human colon epithelial cell line. The expression of FGF14 was lower in primary CRCs as compared to their adjacent normal tissues. Significant higher methylation of FGF14 was observed in CRCs than that in normal tissues based on the data from TCGA database. The loss of FGF14 gene expression was restored by treatment with DNA methyltransferase inhibitor 5-Aza. Re-expression of FGF14 in CRC cell lines inhibited cell viability and colony formation, and induced cell apoptosis. FGF14 induced mitochondrial apoptosis and inhibited PI3K/AKT/mTOR pathway. In xenograft mouse model, overexpression of FGF14 significantly reduced tumor growth (P<0.001). In conclusion, FGF14 is a novel tumor suppressor, which suppresses cell proliferation and induces cell apoptosis via mediating PI3K/AKT/mTOR pathway.
Insights
Fibroblast Growth Factor 14 (FGF14) is silenced by methylation in colorectal cancer (CRC). Re-expressing FGF14 inhibits CRC cell growth and induces apoptosis, identifying it as a tumor suppressor.
Area of Science:
- Oncology
- Molecular Biology
- Epigenetics
Background:
- Colorectal cancer (CRC) is a major global health concern.
- Epigenetic alterations, including DNA methylation, play a critical role in CRC development.
- Fibroblast Growth Factor 14 (FGF14) has been identified as a potentially methylated gene in CRC.
Purpose of the Study:
- To investigate the epigenetic regulation of FGF14 in CRC.
- To elucidate the biological function and molecular mechanism of FGF14 in CRC.
- To determine the potential of FGF14 as a therapeutic target in CRC.
Main Methods:
- Quantitative PCR and Western blot to assess FGF14 expression in CRC cell lines and tissues.
- DNA methylation analysis using TCGA database and 5-Aza treatment.
- Functional assays including cell viability, colony formation, apoptosis, invasion, and migration assays.
- In vivo studies using a xenograft mouse model.
Main Results:
- FGF14 expression is significantly downregulated or silenced in CRC cell lines and tissues compared to normal controls.
- Increased FGF14 methylation is observed in CRC, and its expression can be restored by DNA methyltransferase inhibition.
- FGF14 re-expression suppresses CRC cell proliferation, colony formation, and induces apoptosis via the mitochondrial pathway.
- FGF14 inhibits the PI3K/AKT/mTOR signaling pathway and reduces tumor growth in vivo.
Conclusions:
- FGF14 acts as a novel tumor suppressor in colorectal cancer.
- FGF14 suppresses tumor progression by inhibiting cell proliferation and inducing apoptosis through the PI3K/AKT/mTOR pathway.
- Targeting FGF14 epigenetic silencing may offer a therapeutic strategy for CRC.
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