Gremlin in the pathogenesis of hepatocellular carcinoma complicating chronic hepatitis C: an immunohistochemical and PCR study of human liver biopsies

Abstract

BackgroundThe possible role of secretory products of fibrous tissue in the development of hepatocellular carcinoma (HCC) complicating chronic hepatitis C was investigated. Our hypothesis was that gremlin, secreted by fibroblasts, inhibited bone morphogenic protein (BMP), which mediates stem cell maturation into adult functioning hepatocytes, and thus, arrest stem cell maturation and promoted their proliferation in an immature state possibly culminating into development of HCCs.ResultsProtein expression of cytokeratin 19 (CK19) and fibroblast growth factor 2 (FGF-2), and mRNA expression of gremlin and BMP-7 were studied in 35 cases of chronic hepatitis, cirrhosis and HCC complicating chronic hepatitis C. CK19 expression was higher in cases of cirrhosis (0.004), which correlated with the grade (r = 0.64, p = 0.009) and stage (r = 0.71, p = 0.001). All HCCs were negative for CK19. Stem cell niche activation (as indicated as a ductular reaction) was highest in cases of cirrhosis (p = 0.001) and correlated with CK19 expression (r = 0.42, p = 0.012), the grade(r = 0.56, p = 0.024) and stage (0.66, p = 0.006). FGF-2 expression was highest in HCCs and correlated with the grade (r = 0.6, p = 0.013), stage (0.72, p = 0.002), CK19 expression (r = 0.71, p = 002) and ductular reaction (0.68, p = 0.004) in hepatitis cases. Higher numbers of cirrhosis cases and HCCs (p = 0.009) showed gremlin expression, which correlated with the stage (r = 0.7, p = 0.002). Gremlin expression correlated with that of CK19 (r = 0.699, p = 0.003) and FGF2 (r = 0.75, p = 0.001) in hepatitis cases.ConclusionsFibrosis promotes carcinogenesis by fibroblast-secreted gremlin that blocks BMP function and promotes stem cell activation and proliferation as well as possibly HCC development.

Hyperbaric oxygen attenuates neuropathic pain and reverses inflammatory signaling likely via the Kindlin-1/Wnt-10a signaling pathway in the chronic pain injury model in rats

“…The antinociceptive efficacy of HBO treatment has been proven in many rodent experiments and also human patients [9–11, 13]. In accordance with these findings, our current study demonstrated that five consecutive days of HBO treatment greatly attenuated neuropathic pain by suppressing hypersensitivity in rats following CCI of the sciatic nerve.…”

“…Emerging lines of evidence suggest that HBO therapy can reduce chronic pain in animal models [9–11]. In addition, the use of HBO treatment has been proven to attenuate chronic cluster headaches and [12] idiopathic trigeminal neuralgia in patients [13]. Our previous study indicated that the antinociceptive effects of HBO therapy may be linked to inhibition of astrocyte activation and inflammation in a chronic constriction injury (CCI)-induced neuropathic pain model in rats [10].…”

Action and function of Wnt/β-catenin signaling in the progression from chronic hepatitis C to hepatocellular carcinoma

“…Especially in chronic hepatitis C associated HCC, activation of FGF signaling is observed [128, 129] and increased FGF levels are associated with enhanced HCV replication and release of infectious particles [130]. Cross talk of Wnt and FGF pathways in HCV-related HCC is supported by observations that FGF signaling leads to the release of β-catenin from the β-catenin–E-cadherin complexes because of the phosphorylation of Tyr654 as described above.…”

Hypoxic‐ischemic gene expression profile in the isolated variant of biliary atresia

“…CK19 is used to assess severity of liver disease and fibrosis deposition in some hepatic disorders [47,48]. In this study, CK19 expression was lower in the hiHIF2a and loVEGFR2 subsets.…”