Role And Mechanism Of HLF In Liver Fibrosis And Hepatocellular Carcinoma

Hepatocellular carcinoma (HCC) is one of the most prevalent cancers globally. There are approximately 700,000 new cases of HCC reported every year, half of which reside in China. High morbidity, high mortality of HCC and lack of effective therapy strategy make it urgent to elucidate the underlying mechanisms of hepatocarcinogeneis and explore novel targets for HCC prevention and therapy. Liver fibrosis per se is a wound-healing respone upon chronic liver injury represented by excessive extracellular matrix (ECM) proteins deposition. As a scarring process, liver fibrosis usually resulted from viral hepatitis, cholestatic/biliary and metabolic diseases including alcoholic steatohepatitis (ASH) and nonalcoholic steatohepatitis (NASH). Liver fiborsis remains mostly asymptomatic in early stages, while progresses, it disrupts the liver architecture and functions by replacing functional parenchyma with scar tissues, ultimately leading to cirrhosis, liver failure, and even hepatocellular carcinoma. Liver fibrosis is reversible once cessation of injury, therefore, antiviral or other causal treatment that removes the underlying cause of liver injury can halt, or even regress liver fibrosis. Nonetheless, to date, no antifibrotic therapies have been approved for liver fibrosis, largely due to various side effects, limited patients’ response to causal treatment, and most importantly, lack of non-invasive and sensitive approaches to diagnose asymptomatic patients and to monitor progression or reversal of fibrosis as well. Recent experimental and preclinical research also has advanced our knowledge of the pathogenesis of this scarring process, and amounts of potential targets have been yielded, part of which have entered clinical trials. However, translation of preclinical progress into clinical practise has been hampered since short of specific targets, which thus emphasizes the urgency of clarifying underlying detailed mechanism of liver fibrosis and identifying novel therapeutic targets for ideal intervention.Hepatic leukemia factor, initially discovered as a fusion partner involved in the chimeric transcript E2A-HLF, was created by the t(17;19)(q22;p13) translocation in pre-B-cell acute lymphoblastic leukemia. At that time, due to detection of HLF mRNA in the liver and absence in normal lymphoid cells, it was named hepatica leukemia factor. Subsequent studies revealed that, HLF together with two other basic leucine-zipper (bzip) transcription factors, thyrotroph embryonic factor (TEF) and albumin promoter d-box binding protein (DBP), belongs to the proline and acidic amino acid-rich (PAR) protein family. Mice simultaneously devoid of HLF, TEF and DBP were prone to cardiovascular disorders, epilepsy and aging with decreased life span. As a bzip PAR transcription factor, HLF was able to form homodimers or heterodimers with other family member to regulate target genes expression. So far, HLF was known to accumulate in certain organs including normal liver, kidney, brain, small intestine, lung, and some malignancies as well. HLF was found to be implicated in regulation of hematopoietic stem cells (HSCs) expansion and behavior, as well as hematopoietic malignancies. Recent studies also showed that HLF might contribute to liver physiology or pathology through modulating detoxification, lipid metabolism, viral replication and expression of factor IX. However, precise expression and role of HLF in liver fibrosis or liver cancer remained vague.In present study, we utilized various models of experimental fibrosis to investigate the potential involvement of HLF in liver fibrosis and found that HLF governed the fibrotic response. Mechanistically, HLF enhaced IL-6/STAT3 signaling in hepatic satallite cells and facilitates the propagation of HSC cells. Clinincal data showed that HLF expression correlated with extent of liver fibrosis. In DEN-induced mouse hepatocellular carcinogenesis, the incidence, tumor number and size was much less in HLFPB/PB mice. High throughput screening suggested that c-Jun was differentially expressed in the liver cancer of HLFPB/PB mice, which was futher validated by western blot assay. In further study, we demonstrated that HLF suppressed the expression of p21 and thus promoted the proliveration of hepatoma cells. Morevoer, HLF repressed PTEN expression and enhanced Akt activation to facilitate liver cancer metastasis. These data suggested that HLF played critical role in HCC progression and migh exert as a novel therapeutic target in HCC treatment. Investigation on HCC specimens revealed that HLF was upregulated in cancer tissues compared with paired pericancerous tissues. Increased HLF level was associated the poor prognosis of HCC patients indicating that HLF could serve as a novel prognositic biomarker in liver cancer.