Abstract
BackgroundAerobic glycolysis is a typical metabolic reprogramming in tumor cells, which contributes to the survival and proliferation of tumor cells. The underlying mechanisms controlling this metabolic switch in colorectal cancer (CRC), however, remain only partially understood.MethodsThe Cancer Genome Atlas (TCGA) dataset and Gene Expression Omnibus (GEO) (GDS4382, GSE6988, GSE35834) were used to analyzed the mRNA expression of THBS2. 392 paired samples of CRC and adjacent non-cancerous tissues were collected to detect the expression of THBS2 by IHC. The correlation of THBS2 expression with categorical clinical variables in patients with CRC was evaluated using chi-square analysis or Student’s t-test. CCK-8, colony formation, and animal CT scan were used to functional analysis of THBS2 in CRC.ResultsThrombospondin 2 (THBS2) is aberrantly upregulated and linked to a poor prognosis in CRC. Subsequent experiments also showed that THBS2 promotes the proliferation of CRC cells. In terms of mechanism, THBS2 interacted with Toll-like receptor 4 (TLR4), but not with the other toll-like receptors (TLRs), which upregulated the mRNA expression of GLUT1, HK2, ALDOA, PKM2, and LDHA and enhanced glycolytic capacity in CRC cells. Moreover, THBS2/TLR4 axis significantly increased the protein level of HIF-1α and blocking HIF-1α by siRNA reversed the enhanced glycolytic capacity and the upregulated expression of glycolytic enzymes in CRC cells.ConclusionOur findings revealed that the THBS2/TLR4 axis contributes to HIF-1α derived glycolysis and eventually promotes CRC progress.
Highlights
Colorectal cancer (CRC) is one of the most common malignant tumors and ranks third in terms of incidence and mortality associated with human carcinoma [1]
The comprehensive analysis of THBS2 expression in CRC based on TCGA and GEO datasets showed a very significant increase in THBS2 expression in the mRNA level in CRC (Figures 1A–D)
To verify the main function of THBS2 involved in the CRC development, we detected mRNA and protein expression of THBS2 in seven CRC cell lines and selected two cell lines with high expression of THBS2 (RKO and LoVo) and low expression of THBS2 (SW620) (Figure 1E)
Summary
Colorectal cancer (CRC) is one of the most common malignant tumors and ranks third in terms of incidence and mortality associated with human carcinoma [1]. Given the considerable advances in diagnosis and therapy, early-stage CRC, including stage 1 and stage 2, has a relatively good prognosis with a 5-year survival rate. It is essential to explore the mechanism underlying CRC progress to design potential therapeutic strategies. THBS has been reported to be involved in various kinds of malignant tumors, including lung cancer, gastric cancer, colorectal cancer, and liver cancer [3,4,5,6]. Little is known about the mechanism underlying THBS2-mediated CRC progress. The underlying mechanisms controlling this metabolic switch in colorectal cancer (CRC), remain only partially understood
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