NGFR Increases the Chemosensitivity of Colorectal Cancer Cells by Enhancing the Apoptotic and Autophagic Effects of 5-fluorouracil via the Activation of S100A9

Abstract

Colorectal cancer (CRC) is currently the third leading cause of cancer-related deaths worldwide, and 5-fluorouracil (5-FU)-based chemotherapies serve as important adjuvant therapies before and after surgery for CRC. However, the efficacy of CRC chemotherapy is limited by chemoresistance, and therefore the discovery of novel markers to indicate chemosensitivity is essential. Nerve growth factor receptor (NGFR), a cell surface receptor, is involved in cell death and survival. Our previous study indicated that NGFR acts as a tumor suppressor, and high expression is associated with better outcomes in patients receiving 5-FU-based adjuvant chemotherapy after surgery. The aim of this study was to investigate the effect of NGFR on the chemotherapeutic response in CRC. Chemosensitivity was investigated using DLD1 and HCT8 cells after NGFR transfection. Apoptosis was investigated by flow cytometry. Autophagy was assessed using GFP-LC3B transient transfection. Gene expression was measured using an mRNA microarray. Beclin-1 and Bcl-2 protein expressions were assessed by western blot. NGFR and S100 calcium-binding protein A9 (S100A9) expressions in CRC patients were investigated by immunohistochemistry. The results showed that the half maximal inhibitory concentration of NGFR-transfected cells was lower than that of controls in DLD1 and HCT8 cells after 5-FU treatment, and cell viability was lower than in empty-vector cells. Tumor sizes were also smaller than in empty-vector cells in vivo. The percentages of apoptotic and autophagic cells were higher in NGFR-transfected cells. NGFR elevated the expression of S100A9 after 5-FU treatment. The combination of Bcl-2 and Beclin-1 was significantly suppressed by overexpressed NGFR. Five-year overall and disease-free survival in NGFR+/S100A9+ patients was better than in NGFR−/S100A9− patients. This study’s findings suggest that NGFR may serve as a marker predicting CRC patients’ chemosensitivity.

Resveratrol Induces Autophagy and Apoptosis in Non-Small-Cell Lung Cancer Cells by Activating the NGFR-AMPK-mTOR Pathway

“…The increased NGFR induced autophagy to mitigate renal tubular damage caused by proteinuria [42]. NGFR enhanced chemosensitivity of colorectal cancer cells to 5-fluorouracil and increased 5-fluorouracil-induced apoptosis and autophagy [15]. Different cells responded differently to NGFR based on cell type and cell differentiation status.…”

“…NGFR plays a role in various biological processes, such as cell proliferation, differentiation and death, scar formation, energy expenditure, and hypoxic response [13]. Further studies have revealed that NGFR regulates cell growth, invasion, metastasis, autophagy, and apoptosis in many tumors [13][14][15]. For example, RSV treatment reduced the histone methyltransferase EZH2 significantly, further led to reactivation of neuroblastoma tumor suppressor genes NGFR, and then triggered cellular apoptosis in N-2a cells [16].…”

Identification and validation of novel biomarkers affecting bladder cancer immunotherapy via machine learning and its association with M2 macrophages

“…In pancreatic cancer, the protein named PTHrP (encoded by PTHLH) can drive the growth of primary and metastatic tumors in mice (26). In colon cancer, Chen et al indicated that NGFR could act as a tumor suppressor by activating S100A9, thus leading to the enhanced apoptotic and autophagic effects of 5-fluorouracil (27). Huang et al found that the NGFR-FOXP3 positive feedback loop contributes to ICOTINIB resistance in non-small cell lung cancer (28).…”

“…In colon cancer, Chen et al. indicated that NGFR could act as a tumor suppressor by activating S100A9, thus leading to the enhanced apoptotic and autophagic effects of 5-fluorouracil ( 27 ). Huang et al.…”

Identification of hub genes and key pathways in pediatric Crohn’s disease using next generation sequencing and bioinformatics analysis

“…Signaling pathway include immune system [69], neutrophil degranulation [70], cytokine signaling in immune system [71], extracellular matrix organization [72], post-translational protein phosphorylation [73], biological oxidations [74], metabolism [75] and metabolism of lipids [76] were responsible for progression of CD. CXCL5 [77], CXCL3 [78], PROK2 [79], CXCR1 [80], PYCR1 [81], OSM (oncostatin M) [82], IL15RA [83], LRG1 [84], LCN2 [85], BATF2 [86], CXCL1 [87], S100A9 [88], IFITM1 [89], MYOF (myoferlin) [90], XBP1 [91], MMP3 [92], TAP1 [93], FPR2 [94], CXCL6 [95], C2CD4A [96], IFITM3 [97], IL1B [98], SLC6A14 [99], FPR1 [100], NOS2 [101], CHI3L1 [102], TGM2 [103], MUC4 [104], TREM1 [105], WNT5A [106], HGF (hepatocyte growth factor) [107], CXCL9 [108], GBP1 [109], S100A11 [110], ADM (adrenomedullin) [111], CXCL11 [112], CXCL10 [113], LILRB2 [114], GDF15 [115], IL1RN [116] STAT1 [117], SLAMF7 [105], CYP27B1 [118], NETO2 [119], TFPI2 [120], ZC3H12A [121], MMP1 [122], CSF3 [123], SOCS3 [124], TLR8 [125], HTRA3 [126], CEBPB (CCAAT enhancer binding protein beta) [127], CD55 [128], CXCR2 [129], CCL28 [130], CBR3 [131], CCL3 [132], FCGR2A [48], ACSL1 [133], CCL2 [134], SOD2 [135], CD14 [136], IGFBP2 [137], CD274 [138], DERL3 [139], SERPINE1 [140], IDO1 [141], PDK...…”