The correlations of pretreatment serum concentrations of proinflammatory cytokines such as interleukin (IL)‐1β, IL‐6, and tumor necrosis factor‐α (TNFα) with the clinicopathologic features and progression of colorectal cancer (CRC) were investigated. The pretreatment serum levels of IL‐1β, IL‐6, and TNFα 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‐1β ≥10 pg/mL; IL‐6 ≥ 10 pg/mL; and TNFα ≥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‐1β, IL‐6, and TNFα serum levels may help identify early cancer progression among patients with CRP <5 mg/L in routine practice.

MicroRNA-21 (miR-21) is one of the most frequently upregulated miRNAs in liver diseases such as nonalcoholic fatty liver disease (NAFLD) and hepatocellular carcinoma (HCC). However, mechanistic pathways that connect NAFLD and HCC remain elusive. We developed a doxycycline (Dox)-inducible transgenic zebrafish model (LmiR21) which exhibited an upregulation of miR-21 in the liver, which in turn induced the full spectrum of NAFLD, including steatosis, inflammation, fibrosis, and HCC, in the LmiR21 fish. Diethylnitrosamine (DEN) treatment led to accelerated liver tumor formation and exacerbated their aggressiveness. Moreover, prolonged miR-21 expression for up to ten months induced nonalcoholic steatohepatitis (NASH)-related HCC (NAHCC). Immunoblotting and immunostaining confirmed the presence of miR-21 regulatory proteins (i.e., PTEN, SMAD7, p-AKT, p-SMAD3, and p-STAT3) in human nonviral HCC tissues and LmiR21 models. Thus, we demonstrated that miR-21 can induce NAHCC via at least three mechanisms: First, the occurrence of hepatic steatosis increases with the decrease of ptenb, pparaa, and activation of the PI3K/AKT pathway; second, miR-21 induces hepatic inflammation (or NASH) through an increase in inflammatory gene expression via STAT3 signaling pathways, and induces liver fibrosis through hepatic stellate cell (HSC) activation and collagen deposition via TGF-β/Smad3/Smad7 signaling pathways; finally, oncogenic activation of Smad3/Stat3 signaling pathways induces HCC. Our LmiR21 models showed similar molecular pathology to the human cancer samples in terms of initiation of lipid metabolism disorder, inflammation, fibrosis and activation of the PI3K/AKT, TGF-β/SMADs and STAT3 (PTS) oncogenic signaling pathways. Our findings indicate that miR-21 plays critical roles in the mechanistic perspectives of NAHCC development via the PTS signaling networks.

The correlations of serum interleukin-6 and soluble interleukin-6 receptor concentrations with clinicopathological features and survival of patients with colorectal cancer were studied. We measured the serum levels of interleukin-6 and soluble interleukin-6 receptor in 99 colorectal cancer patients at the Chang Gung Memorial Hospital, Taiwan. The interleukin-6 and soluble interleukin-6 receptor levels were tested for their association with each other, and with the clinical parameters and outcomes. Both interleukin-6 and soluble interleukin-6 receptor concentrations were significantly higher in colorectal cancer patients than in normal individuals. Unlike patients with serum interleukin-6 levels >10 pg/ml, who have increased carcinoembryonic antigen levels and shorter survival, serum soluble interleukin-6 receptor levels >800 pg/ml were found in patients with stages I–II and no regional lymph nodal invasion and appeared to be a positive prognostic factor for improved survival. Especially, patients with serum interleukin-6 800 pg/ml lived significantly longer. Nonetheless, the multivariate analysis showed that only tumor-node metastasis stage, metastatic status and serum interleukin-6 level were independent prognostic factors, whereas the serum soluble interleukin-6 receptor level became marginally important for survival. We suggest the clinical relevance of interleukin-6 and soluble interleukin-6 receptor for the survival of colorectal cancer patients. From a practical point of view, detection of the serum interleukin-6 level alone, rather than combined measurement of interleukin-6 and soluble interleukin-6 receptor, may be sufficient to independently predict survival in colorectal cancer patients.

Colorectal cancer (CRC) is a leading cause of cancer-related mortality worldwide. Patients with inflammatory bowel disease (IBD) have a high risk of developing CRC. Inflammatory cytokines are regulated by complex gene networks and regulatory RNAs, especially microRNAs. MicroRNA-21 (miR-21) is amongst the most frequently upregulated microRNAs in inflammatory responses and cancer development. miR-21 has become a target for genetic and pharmacological regulation in various diseases. However, the association between inflammation and tumorigenesis in the gut is largely unknown. Hence, in this study, we generated a zebrafish model (ImiR-21) with inducible overexpression of miR-21 in the intestine. The results demonstrate that miR-21 can induce CRC or colitis-associated cancer (CAC) in ImiR-21 through the PI3K/AKT, PDCD4/TNF-α, and IL-6/STAT3 signaling network. miR-21 activated the PI3K/AKT and NF-κB signaling pathways, leading to initial inflammation; thereafter, miR-21 and TNF-α repressed PDCD4 and its tumor suppression activity. Eventually, active STAT3 stimulated a strong inflammatory response and activated the invasion/metastasis process of tumor cells. Hence, our findings indicate that miR-21 is critical for the development of CRC/CAC via the PI3K/AKT, STAT3, and PDCD4/TNF-α signaling networks.