Adiponectin Antagonizes the Oncogenic Actions of Leptin in Hepatocellular Carcinogenesis

Lafdil

The American Journal of Pathology

et al. 2011

Aberrantly hyperactivated STAT3 has been found in human liver cancers as an oncogene; however, STAT3 has also been shown to exert hepatoprotective effects during liver injury. The balancing act that STAT3 plays between hepatoprotection and liver tumorigenesis remains poorly defined. In this study, the diethylnitrosamine (DEN)-induced liver tumor model and the chronic carbon tetrachloride (CCl 4 )-induced liver fibrosis model were both used to investigate the role of STAT3 in liver tumorigenesis. Hepatocyte-specific STAT3 knockout mice were resistant to liver tumorigenesis induced by a single DEN injection, whose tumorigenesis was associated with minimal chronic liver inflammation, injury, and fibrosis. In contrast, long-term CCl 4 treatment resulted in severe hepatic oxidative damage, inflammation, and fibrosis but rarely induced liver tumor formation in wild-type mice. Despite the oncogenic function of STAT3 in DEN-induced liver tumor, hepatocyte-specific STAT3 knockout mice were more susceptible to liver tumorigenesis after 16 weeks of CCl 4 injection, which was associated with higher levels of liver injury, inflammation, fibrosis, and oxidative DNA damage compared with wild-type mice. These findings suggest that the hepatoprotective feature of STAT3 prevents hepatic damage and fibrosis under the condition of persistent inflammatory stress, consequently suppressing injurydriven liver tumor initiation. Once liver tumor cells have developed, STAT3 likely acts as an oncogenic factor to promote tumor growth.

Section: Stat3 Is a Pro-oncogenic Factor That Promotes Liver Tumorigesupporting

confidence: 90%

Hepatoprotective versus Oncogenic Functions of STAT3 in Liver Tumorigenesis

Lafdil

The American Journal of Pathology

et al. 2011

Cancer Biology &Amp; Medicine

“…As well as its direct effects as a transcription factor, STAT3 is seen to have epigenetic effects on gene expression and also modulates mitochondrial functions 58 . gAcrp and flArcp have both been seen to inhibit STAT3 activation in PrC and HC lines 59,60 .…”

Section: Apn Signallingmentioning

confidence: 97%

Evolving role of adiponectin in cancer-controversies and update

Katira¹,

Tan²

2016

Adiponectin (APN), an adipokine produced by adipocytes, has been shown to have a critical role in the pathogenesis of obesityassociated malignancies. Through its receptor interactions, APN may exert its anti-carcinogenic effects including regulating cell survival, apoptosis and metastasis via a plethora of signalling pathways. Despite the strong evidence supporting this notion, some work may indicate otherwise. Our review addresses all controversies critically. On the whole, hypoadiponectinaemia is associated with increased risk of several malignancies and poor prognosis. In addition, various genetic polymorphisms may predispose individuals to increased risk of obesity-associated malignancies. We also provide an updated summary on therapeutic interventions to increase APN levels that are of key interest in this field. To date efforts to manipulate APN levels have been promising, but much work remains to be done.

“…In this work the odds ratio progressively increased in the patients who have associated metabolic syndrome factors [80] . Obesity is characterized by the excess of adipose tissue and the altered secretion of adipocytokines that correlate with the occurrence of HCC and liver-related death in patients with cirrhosis [81] . In the last decade, it has become evident that obesity-related metabolic inflammation is involved in different aspects of HCC progression and metastatic dissemination, among which: neural regulation, innate immune responses, intestinal immune system and endocrinal regulation.…”

Section: Pathogenesismentioning

confidence: 99%

Fat and hepatocellular carcinoma

Balsano¹,

Porcu²,

Sideri³

et al. 2018

Obesity and diabetes are associated with the onset of hepatocellular carcinoma (HCC). These two illnesses correlate also with the development of non-alcoholic fatty liver disease (NAFLD). Currently, NAFL is considered the leading form of chronic liver disease in the Western industrialized countries. Insulin resistance is the common pathogenic factor among these three pathologies. NAFL is characterized by fat accumulation in the liver that involves greater than 5% of the liver parenchyma with no evidence of hepatocyte injury. However, NAFL may progress toward non-alcoholic steatohepatitis that in turn may lead to advanced fibrosis, cirrhosis and HCC. It is alarming that NAFLD related HCC has been, at present, considered as a growing burden worldwide, and its prevalence is tending to further increase together with the increasing incidence of obesity and diabetes. Worthy of note is that in the presence of chronic accumulation of fat in the liver it has been reported the emergence of HCC during chronic liver disease in absence of liver cirrhosis, usually the major risk factor for the development of HCC. Thus, in the future NAFLD related HCCs will place a growing strain on health-care systems from the need for their management. Unfortunately, most of the NAFLD related HCC patients are diagnosed at advanced stages and are characterized by a poor prognosis, because they are ineligible to radical treatments. Thus, it is urgent to boost up new screening policies to make early diagnoses, as well as to develop preventive-therapeutic strategies.