TROAP aggravates chemoresistance of colorectal cancer cells via lipogenesis by PI3K/Akt pathway and histone acetylation.

Trophinin-associated protein (TROAP) is a proline-rich cytoplasmic protein exclusively on the apical side of syncytiotrophoblasts and is associated with the microtubular cytoskeleton. We analyzed the expression, promoter methylation, and relevant pathways of TROAP in colorectal cancers (CRCs) using bioinformatics, validated TROAP expression with RT-PCR, western blot and immunohistochemistry, and examined its clinical implications. Its biological processes and molecular mechanisms were investigated by tumor xenograft models, TUNEL, CCK-8, flow cytometry, wound healing and transwell assays, Nile red staining, western blot, proteomic and bioinformatics analysis. TROAP expression was significantly elevated in CRC compared to that in normal mucosa (p < 0.05). TROAP mRNA expression was positively correlated with p53 mutation, poor clinical outcome and favorable prognosis in CRC (p < 0.05). TROAP methylation was inversely correlated with its mRNA expression, lower clinicopathological staging, and non-mutant p53 expression (p < 0.05). TROAP expression was positively associated with younger age, distal metastasis, TNM stage, differentiation, and poor prognosis in CRC patients (p < 0.05). TROAP expression was closely linked to cell cycle, nuclear division, chromatid segregation, calcium and Wnt signaling pathway, ECM regulators and glycoproteins, cell senescence, CPCR-ligand, iron ion and heparin binding in CRCs (p < 0.05). TROAP promoted cell proliferation, resistance to apoptosis and pyroptosis, as well as cell migration, invasion, and epithelial-mesenchymal transition in CRC cells. TROAP aggravated lipid droplet formation and subsequent chemoresistance via de novo lipogenesis via histone acetylation and PI3K/Akt pathway. Aberrant TROAP expression could serve as a biomarker for aggressive behavior and poor prognosis in CRCs, as well as a molecular target for gene therapy.