| Background Liver has the function of metabolism and detoxification.After being partially excised or damaged by toxic substances,the residual liver will regenerate by the action of various factors.When the injury factors continue,it will develop into hepatic fibrosis,and further development will lead to canceration.Hepatocellular carcinoma is one of the most malignant tumors.In the process of occurrence and development of Hepatocellular carcinoma,the metabolism and detoxification function of hepatocytes will change.FM03 is a flavin monooxygenase that plays a major role in adult liver.Intestinal microorganisms can convert choline-containing substances intake into trimethylamine(TMA),which is oxidized to trimethylamine oxide(TMAO)by FM03 in the liverObjective Our laboratory found that the expression of FM03 gene decreased significantly during regeneration and was low in hepatocellular carcinoma by microarray analysis of regenerated samples.Therefore,the role and clinical significance of FM03 and its metabolites in liver regeneration and hepatocellular carcinoma were studied.Method The expression of FM03 in liver regeneration spccimens and liver cancer was studied by qPCR,Western Blot and immunohistochemistry.TMAO was fed to mice to study the effect of TMAO on the regeneration after partial hepatectomy.To study the relationship between FM03 expression and clinicopathological data of patients,and to analyze the correlation between FM03 expression and clinicopathological characteristics and prognosis of patients.FM03 transfected stable transfected cell lines were constructed by virus transfection.The effects of FM03 on proliferation and migration of hepatocellular carcinoma cells were studied by CCK-8,clone formation,Transwell cell migration and subcutaneous tumorigenesis in nude mice.qPCR and Western Blot were used to study the signal mechanism of TMAO affecting liver regeneration and FM03 inhibiting proliferation of hepatoma cells.Results We found that FM03 expression in liver regeneration and hepatocellular carcinoma was significantly decreased.TMAO could significantly inhibit liver regeneration after partial hepatectomy.Immunohistochemistry was performed in 106 cases of hepatocellular carcinoma.Kaplan-Meier survival analysis showed that patients with low FM03 expression had poor overall survival and tumor-free survival.COX multivariate analysis showed that FM03 was an independent risk factor for overall survival and tumor-free survival of hepatocellular carcinoma patients.By overexpression of FM03 protein,we found that PI3K/AKT/mTOR pathway was inhibited and the proliferation capability of HCC cells was weakened when FM03 was overexpressed.Conclusion In conclusion,we found that FM03 was low expressed in liver regeneration,liver injury and liver fibrosis for the first time.TMAO,the metabolite of FM03,could inhibit liver regeneration after partial hepatectomy in many ways.The low expression of FM03 was closely related to poor prognosis of patients with hepatocellular carcinoma after hepatectomy.FM03 could be used as a prognostic indicator for patients with hepatocellular carcinoma after hepatectomy.FMO3 inhibits the proliferation of hepatoma cells through negative regulation of PI3K/AKT/mTOR pathway.Objective CSN6 is a critical subunit of the constitutive photomorphogenesis 9(COP9)signalosome(CSN)that was previously reported to be increased in various cancers;however,its effect in hepatocellular carcinoma(HCC)remains unknown.The aim of this study was to explore the expression and role of CSN6 in HCC.Methods qPCR,Western blot and immunohistochemistry(IHC)were used to examine the expression of CSN6.Kaplan-Meier survival analysis and univariate and multivariate C ox analyses were used to investigate the clinical and prognostic significance of CSN6 expression in HCC patients.Furthermore,the biological function of CSN6 on HCC cell proliferation and migration was investigated through CCK-8,transwell migration and invasion assays.Besides,the associations between CSN6 and epithelial-mesenchymal transition(EMT)were determined.Results CSN6 was increased in HCC tissues,and CSN6 overexpression was associated with poor prognoses for HCC patients.Overexpression of CSN6 promoted HCC cell proliferation,migration,and invasion,while these processes were inhibited when CSN6 was silenced.Additionally,CSN6 was found to promote EMT by inhibiting E-cadherin,which was mediated via upregulation of Snail as a result of MEK/ERK pathway activationConclusions CSN6 up-regulation may play a contributory role in HCC metastasis and poor prognosis via activation of EMT.CSN6 may serve as an independent predictor for HCC prognosis. |
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