ABSTRACT
As a rate-limiting enzyme of the hexosamine biosynthesis pathway (HBP), which is responsible for glycosylation, Glutamine fructose-6-phosphate amidotransferase 2 (GFPT2) is involved in human breast and lung tumorigenesis. However, whether GFTP2 is associated with tumor metastasis remains unclear. Here, we found that GFPT2 promoted the proliferation, migration, invasion and metastasis of colorectal cancer (CRC) cells. Mechanically, p65 acted as an upstream transcription factor of GFPT2 and regulated its expression and function. In turn, GFPT2 enhanced the glycosylation of p65, which led to the nuclear translocation of p65 and then activated NF-κB pathway. Thus, GFTP2 and p65 formed a positive feedback loop to promote the progression of CRC. In addition, GFPT2 was up-regulated in CRC tissues and closely related with liver metastasis (P<0.0001) and tumor stage (P=0.0184). High expression of GFPT2 predicted poor prognosis for CRC patients. Moreover, GFTP2 expression was positively linked with O-linked N-acetylglucosamine transferase in CRC tissues. Our study reveals a new mechanism of GFPT2 in CRC metastasis and provides a new target therapeutic target to deter metastasis.
ABSTRACT
Cancer-derived exosomes are considered a major driver of cancer-induced pre-metastatic niche formation at foreign sites, but the mechanisms remain unclear. Here, we show that miR-25-3p, a metastasis-promoting miRNA of colorectal cancer (CRC), can be transferred from CRC cells to endothelial cells via exosomes. Exosomal miR-25-3p regulates the expression of VEGFR2, ZO-1, occludin and Claudin5 in endothelial cells by targeting KLF2 and KLF4, consequently promotes vascular permeability and angiogenesis. In addition, exosomal miR-25-3p from CRC cells dramatically induces vascular leakiness and enhances CRC metastasis in liver and lung of mice. Moreover, the expression level of miR-25-3p from circulating exosomes is significantly higher in CRC patients with metastasis than those without metastasis. Our work suggests that exosomal miR-25-3p is involved in pre-metastatic niche formation and may be used as a blood-based biomarker for CRC metastasis.
Subject(s)
Capillary Permeability , Colorectal Neoplasms/metabolism , Endothelial Cells/metabolism , MicroRNAs/metabolism , Neovascularization, Pathologic , Animals , Biomarkers, Tumor/blood , Exosomes/metabolism , Gene Expression Regulation, Neoplastic , HCT116 Cells , HEK293 Cells , Human Umbilical Vein Endothelial Cells , Humans , Kruppel-Like Factor 4 , Kruppel-Like Transcription Factors/metabolism , Mice, Nude , Neoplasm Metastasis , Tumor MicroenvironmentABSTRACT
Bone metastasis (BM) is the advanced complication of breast cancer, while bone marrow-derived mesenchymal stem cells (BMSCs) in the microenvironment unclearly contribute to cancer metastasis. This study investigated potential roles of transforming growth factor- (TGF-) α in the interaction between breast cancer and BMSCs in BM. Clinical cases of breast cancer with bone metastasis (BMBC), breast cancer without bone metastasis (Non-BM-BC), and benign fibroadenoma (Benign) were enlisted in a retrospective study. TGF-α was found obviously overexpressed in BM lesion of BMBC compared to primary lesion of both BMBC and Non-BM-BC (P < 0.01), and TGF-α was higher in primary lesion of both BMBC and Non-BM-BC (P < 0.01) than Benign group. Interestingly, TGF-α in nontumor tissues of both BMBC and Non-BM-BC was at a higher level than Benign group (P < 0.01), and numbers of macrophages in nontumor tissues of both BMBC and Non-BM-BC (P < 0.01) were higher than Benign group. Furthermore, in cultured human BMSCs, TGF-α stimulated production of procancer cytokines including IL-6, VEGF, FGF10, FGF17, and TGF-ß1 in a dose-dependent manner. Thus, TGF-α in BC could potentially be an important signal of carcinogenesis and metastasis. Macrophages in the nontumor tissue of BC may not be protective but could promote cancer metastasis.
