Linker phosphorylation of Smad3 promotes fibro-carcinogenesis in chronic viral hepatitis of hepatocellular carcinoma

Epidemiological and clinical data point to a close association between chronic hepatitis B virus infection or chronic hepatitis C virus infection and development of hepatocellular carcinoma(HCC).HCC develops over several decades and is associated with fibrosis.This sequence suggests that persistent viral infection and chronic inflammation can synergistically induce liver fibrosis and hepatocarcinogenesis.The transforming growth factor-β(TGF-β) signaling pathway plays a pivotal role in diverse cellular processes and contributes to hepatic fibro-carcinogenesis under inflammatory microenvironments during chronic liver diseases.The biological activities of TGF-β are initiated by the binding of the ligand to TGF-β receptors,which phosphorylate Smad proteins.TGF-β typeⅠreceptor activates Smad3 to create COOH-terminally phosphorylated Smad3(pSmad3C),while pro-inflammatory cytokine-activated kinases phosphorylates Smad3 to create the linker phosphorylated Smad3(pSmad3L).During chronic liver disease progression,virus components,together with pro-inflammatory cytokines and somatic mutations,convert the Smad3 signal from tumor-suppressive pS-mad3C to fibro-carcinogenic pSmad3 L pathways,accelerating liver fibrosis and increasing the risk of HCC.The understanding of Smad3 phosphorylation profiles may provide new opportunities for effective chemoprevention and personalized therapy for patients with hepatitis virus-related HCC in the future.

Smad3 phospho-isoform signaling in hepatitis C virus-related chronic liver diseases

The risk of hepatocellular carcinoma(HCC) development increases as hepatitis virus C(HCV)-related liver diseases progress,especially in patients with active inflammation.Insight into hepatic carcinogenesis have emerged from recent detailed analyses of transforming growth factor-β and c-Jun-N-terminal kinase signaling processes directed by multiple phosphorylated(phospho)-isoforms of a Smad3 mediator.In the course of HCV-related chronic liver diseases,chronic inflammation and host genetic/epigenetic alterations additively shift the hepatocytic Smad3 phospho-isoform signaling from tumor suppression to carcinogenesis,increasing the risk of HCC.Chronic inflammation represents an early carcinogenic step that provides a nonmutagenic tumor-promoting stimulus.After undergoing successful antiviral therapy,patients with chronic hepatitis C could experience a lower risk of HCC as Smad3 phospho-isoform signaling reverses from potential carcinogenesis to tumor suppression.Even after HCV clearance,however,patients with cirrhosis could still develop HCC because of sustained,intense carcinogenic Smad3 phospho-isoform signaling that is possibly caused by genetic or epigenetic alterations.Smad3 phospho-isoforms should assist with evaluating the effectiveness of interventions aimed at reducing human HCC.

Role of phosphorylated Smad3 signal components in intraductal papillary mucinous neoplasm of pancreas

Background:Malignant intraductal papillary mucinous neoplasm(IPMN)has poor prognosis.The carcinogenesis of IPMN is not clear.The aim of this study was to clarify transitions in phosphorylated Smad3 signaling during IPMN carcinogenesis.Methods:By using immunohistochemistry,we examined the expression of pSmad3C and pSmad3L from 51 IPMN surgical specimens resected at our institution between 2010 and 2013.We also examined the expression of Ki-67,c-Myc and p-JNK.Results:The median immunostaining index of pSmad3C was 79.2%in low-grade dysplasia,74.9%in highgrade dysplasia,and 42.0%in invasive carcinoma(P<0.01),whereas that of pSmad3L was 3.4%,4.3%,and 42.4%,respectively(P<0.01).There was a negative relationship between the expression of pSmad3C and c-Myc(P<0.001,r=-0.615)and a positive relationship between the expression of pSmad3L and c-Myc(P<0.001,r=0.696).Negative relationship between the expression of pSmad3C and Ki-67(P<0.01,r=-0.610)and positive relationship between the expression of pSmad3L and Ki-67(P<0.01,r=0.731)were confirmed.p-JNK-positive cells were frequently observed among pSmad3L-positive cancer cells.The median of pSmad3L/pSmad3C ratio in the non-recurrence group and the recurrence group were 0.58(range,0.05–0.93),3.83(range,0.85–5.96),respectively(P=0.02).The median immunostaining index of c-Myc in the non-recurrence group and the recurrence group were 2.91(range,0–36.9)and 82.1(range,46.2–97.1),respectively(P=0.02).The median immunostaining index of Ki-67 in the non-recurrence group and the recurrence group were 12.9(range 5.7–30.8)and 90.9(range 52.9–98.5),respectively(P=0.02).Conclusions:pSmad3L was upregulated in malignant IPMN.pSmad3L/pSmad3C ratio may be a useful prognostic factor in IPMN.