Abstract
Colorectal cancer stem cells (CSCs), characterized by self-renewal ability and high expression of proliferative genes, contribute to the chemoresistance of colorectal cancer (CRC). We aimed to identify the molecular mechanisms underlying CRC chemoresistance through comprehensive bioinformatics screenings and experimental confirmation of gene functions. We found that high expression of FGF1 intracellular binding protein (FIBP) was correlated with chemoresistance and poor prognosis in CRC patients. Therefore, the chemoresistant CRC cell line HCT116-CSC with high expression of the stem cell markers CD44 and CD133 was established for further phenotypic tests. FIBP knockdown inhibited proliferation, enhanced chemotherapy effects, and attenuated the stemness markers of CRC cells in vivo and in vitro. Through RNA-seq and gene set enrichment analysis, we identified cyclin D1 as a key downstream target in FIBP-regulated cell cycle progression and proliferation. Moreover, FIBP bound to GSK3β, inhibited its phosphorylation at Tyr216, and activated β-catenin/TCF/cyclin D1 signaling in HCT116-CSCs. Additional GSK3β knockdown reversed the FIBP silencing-induced inhibition of proliferation and decreased stemness marker expression in HCT116-CSCs. Furthermore, DNA methylation profiling suggested that FIBP regulated the stemness of CRC cells via methylation activity that was dependent on GSK3β but independent of β-catenin signaling. Our data illuminate the potential of FIBP as a novel therapeutic target for treating chemoresistant CRC through inhibition of GSK3β-related signaling.
Highlights
Colorectal cancer (CRC) is the second leading cause of cancer-related death in the United States and the fifth in China[1,2]
In combination with our previous proteomic analysis results, a Venn diagram showed that three genes (FIBP, HSFY1, PPM1K) are simultaneously present in both the group of genes with a high hazard risk (HR) and the group of genes downregulated by curcumin (Fig. 1b)
Fibroblast growth factor 1 (FGF1) intracellular binding protein (FIBP) shows a high HR for CRC progression (HR = 2.933, 95% confidence interval (CI) = 1.462–5.884, p = 0.002), little is currently known regarding the association between FIBP and CRC progression
Summary
Colorectal cancer (CRC) is the second leading cause of cancer-related death in the United States and the fifth in China[1,2]. Huang et al Oncogenesis (2018)7:77 higher relapse and lower survival rates[6,7,8]. Our previous studies showed that curcumin, a plant extract with antitumor activity, enhances the effects of irinotecan on CRC cell apoptosis through reactive oxygen species generation, activation of endoplasmic reticulum stress, and autophagy restoration[9,10]. Fibroblast growth factor 1 (FGF1) intracellular binding protein (FIBP) was identified as a potential target molecule of curcumin treatment in irinotecan-induced apoptosis of CRC LOVO cells[11]. FIBP is an intracellular protein that binds selectively to acidic fibroblast growth factor (aFGF), which is mitogenic for a variety of cell types by stimulating mitogenesis or inducing morphological changes and differentiation. FGFs and their chaperone molecules have been reported to participate in cancer development[12,13]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
