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Cancer stem cells play critical roles in tumor initiation, progression, and relapse. Since we previously found that GATA6 promotes the stemness in HCT‐116 and HT‐29 human colorectal cancer (CRC) cells, we aimed to identify the downstream mediator(s) of the stemness‐stimulating effect of GATA6 herein. LRH‐1 was found as a direct target of GATA6 and its upregulation promoted the stemness in both HCT‐116 and HT‐29 cells. Subsequently, hypoxia‐inducible factor‐1α (HIF‐1α) was identified as a direct target of LRH‐1 and its expression level and activity were significantly elevated in the LRH‐1‐overexpressing clones established from the aforementioned two CRC lines. Accordingly, the expression levels of several HIF‐1α targets were also markedly increased, resulting in a stronger glycolysis associated with dramatic elevations of the lactate levels in these cells. Strikingly, higher mitochondrial activities were also found in these clones which might be attributed to the increase of PGC‐1α stimulated by the lactate uptaken through the upregulated MCT‐1. Finally, significant increases in the self‐renewal ability, intracellular radical oxygen species levels and mitochondrial mass were detected in the CD133+/CD44+ subpopulations isolated from CRC cells regardless of their LRH‐1 expression levels. Together, our results suggest a novel metabolic symbiosis between different colorectal cancer stem cell subpopulations critical for maintaining their mutual stemness. [ABSTRACT FROM AUTHOR]

The interaction between hyaluronan and CD44, an important cancer stem‐cell marker, stimulates various tumor cell‐specific functions such as the stemness of tumor cells. microRNA‐203 (miR‐203) can be downregulated by this interaction in human colorectal cancer (CRC) cells, which increases their stemness; however, the underlying mechanism is not yet defined. Here, we show that overexpression and sequestration of miR‐203 in HCT‐116 and HT‐29 human CRC cells reduces and enhances their stemness, respectively. We also show that GATA‐binding factor 6 (GATA6) is a direct target of miR‐203. Our results indicate that upregulated expression of this transcription factor not only restores the self‐renewal abilities of miR‐203‐overexpressing HCT‐116 and HT‐29 cells but also promotes the stemness properties of their parental counterparts. More important, we show that silencing the expression of either LRH‐1 or Hes‐1 is sufficient to diminish the stemness‐promoting effects of GATA6 in human CRC cells. Together, our findings delineate the stemness‐inhibitory mechanism of miR‐203 in human CRC cells and suggest that this miR is a potential therapeutic agent for colorectal cancer. [ABSTRACT FROM AUTHOR]

The correlations of pretreatment serum concentrations of proinflammatory cytokines such as interleukin (IL)-1 β, IL-6, and tumor necrosis factor- α (TNF α) with the clinicopathologic features and progression of colorectal cancer (CRC) were investigated. The pretreatment serum levels of IL-1 β, IL-6, and TNF α were measured in 164 CRC patients before treatment. The relationships between changes in proinflammatory cytokine and C-reactive protein (CRP) levels and both clinicopathologic variables and disease progression were examined by univariate and multivariate analysis. Advanced tumor stage was associated with a poorer histologic differentiation, higher CRP level, lower albumin level, and inferior progression-free survival rate (PFSR). Furthermore, high levels of CRP (>5 mg/L) were associated with proinflammatory cytokine intensity, defined according to the number of proinflammatory cytokines with levels above the median level (IL-1 β ≥10 pg/mL; IL-6 ≥ 10 pg/mL; and TNF α ≥55 pg/mL). Under different inflammation states, proinflammatory cytokine intensity, in addition to tumor stage, independently predicted PFSR in patients with CRP <5 mg/L, whereas tumor stage was the only independent predictor of PFSR in patients with CRP ≥5 mg/L. Proinflammatory cytokine intensity and the CRP level are clinically relevant for CRC progression. Measurement of IL-1 β, IL-6, and TNF α serum levels may help identify early cancer progression among patients with CRP <5 mg/L in routine practice. [ABSTRACT FROM AUTHOR]