Hepatocellular Carcinoma Differentiation: Research Progress in Mechanism and Treatment

Hepatocellular carcinoma (HCC) is the most common primary malignant tumor of the liver. Although progress has been made in diagnosis and treatment, morbidity and mortality continue to rise. Chronic liver disease and liver cirrhosis are still the most important risk factors for liver cancer. Although there are many treatments, it can only be cured by orthotopic liver transplantation (OLT) or surgical resection. And the worse the degree of differentiation, the worse the prognosis of patients with liver cancer. Then it can be considered that restoring a better state of differentiation may improve the prognosis. The differentiation treatment of liver cancer is to reverse the dedifferentiation process of hepatocytes to liver cancer cells by means of drugs, improve the differentiation state of the tumor, and restore the normal liver characteristics, so as to improve the prognosis. Understanding the mechanism of dedifferentiation of liver cancer can provide ideas for drug design. Liver enrichment of transcription factors, imbalance of signal pathway and changes of tumor microenvironment can promote the occurrence and development of liver cancer, and restoring its normal level can inhibit the malignant behavior of tumor. At present, some drugs have been proved to be effective, but more clinical data are needed to support the effectiveness and reliability of drugs. The differentiation treatment of liver cancer is expected to become an important part of the treatment of liver cancer in the future.

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Downexpression of HSD17B6 correlates with clinical prognosis and tumor immune infiltrates in hepatocellular carcinoma

Cancer Cell International ◽

10.1186/s12935-020-01298-5 ◽

2020 ◽

Vol 20 (1) ◽

Cited By ~ 1

Author(s):

Lei Lv ◽

Yujia Zhao ◽

Qinqin Wei ◽

Ye Zhao ◽

Qiyi Yi

Keyword(s):

Hepatocellular Carcinoma ◽

Liver Cancer ◽

Immune Responses ◽

Cancer Cells ◽

Negative Regulator ◽

Functional Enrichment ◽

Migration And Invasion ◽

Relative Reduction ◽

Clinical Prognosis ◽

Liver Cancer Cells

Abstract Background Hydroxysteroid 17-Beta Dehydrogenase 6 (HSD17B6), a key protein involved in synthetizing dihydrotestosterone, is abundant in the liver. Previous studies have suggested a role for dihydrotestosterone in modulating progress of various malignancies, and HSD17B6 dysfunction was associated with lung cancer and prostate cancer. However, little is known about the detailed role of HSD17B6 in hepatocellular carcinoma (HCC). Methods Clinical implication and survival data related to HSD17B6 expression in patients with HCC were obtained through TCGA, ICGC, ONCOMINE, GEO and HPA databases. Survival analysis plots were drawn with Kaplan–Meier Plotter. The ChIP-seq data were obtained from Cistrome DB. Protein–Protein Interaction and gene functional enrichment analyses were performed in STRING database. The correlations between HSD17B6 and tumor immune infiltrates was investigated via TIMER and xCell. The proliferation, migration and invasion of liver cancer cells transfected with HSD17B6 were evaluated by the CCK8 assay, wound healing test and transwell assay respectively. Expression of HSD17B6, TGFB1 and PD-L1 were assessed by quantitative RT-PCR. Results HSD17B6 expression was lower in HCC compared to normal liver and correlated with tumor stage and grade. Lower expression of HSD17B6 was associated with worse OS, PFS, RFS and DSS in HCC patients. HNF4A bound to enhancer and promoter regions of HSD17B6 gene, activating its transcription, and DNA methylation of HSD17B6 promoter negatively controlled the expression. HSD17B6 and its interaction partners were involved in androgen metabolism and biosynthesis in liver. HSD17B6 inhibited tumor cell proliferation, migration and invasion in liver cancer cells and low expression of HSD17B6 correlated with high immune cells infiltration, relative reduction of immune responses and multiple immune checkpoint genes expression in HCC, probably by regulating the expression of TGFB1. Conclusions This study indicate that HSD17B6 could be a new biomarker for the prognosis of HCC and an important negative regulator of immune responses in HCC.

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Current Research Progress on Long Noncoding RNAs Associated with Hepatocellular Carcinoma

Analytical Cellular Pathology ◽

10.1155/2019/1534607 ◽

2019 ◽

Vol 2019 ◽

pp. 1-8 ◽

Cited By ~ 3

Author(s):

Haihong Shi ◽

Yuxin Xu ◽

Xin Yi ◽

Dandan Fang ◽

Xia Hou

Keyword(s):

Hepatocellular Carcinoma ◽

Cell Proliferation ◽

Liver Cancer ◽

Biological Activities ◽

Noncoding Rnas ◽

Long Noncoding Rnas ◽

Research Progress ◽

Invasion And Metastasis ◽

Complex Processes ◽

And Function

Hepatocellular carcinoma (HCC) is the second leading cause of mortality among cancers. It has been found that long noncoding RNAs (lncRNAs) are involved in many human cancers, including liver cancer. It has been identified that carcinogenic and tumor-suppressing lncRNAs are associated with complex processes in liver cancer. These lncRNAs may participate in a variety of pathological and biological activities, such as cell proliferation, apoptosis, invasion, and metastasis. Here, we review the regulation and function of lncRNA in liver cancer and evaluate the potential of lncRNA as a new goal for liver cancer.

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ILF2 Directly Binds and Stabilizes CREB to Stimulate Malignant Phenotypes of Liver Cancer Cells

Analytical Cellular Pathology ◽

10.1155/2019/1575031 ◽

2019 ◽

Vol 2019 ◽

pp. 1-9 ◽

Cited By ~ 4

Author(s):

Hui Du ◽

Yun Le ◽

Fenyong Sun ◽

Kai Li ◽

Yanfeng Xu

Keyword(s):

Hepatocellular Carcinoma ◽

Liver Cancer ◽

Cancer Cells ◽

Cyclic Adenosine Monophosphate ◽

Adenosine Monophosphate ◽

Camp Response Element Binding ◽

Camp Response Element ◽

Liver Cancer Cells ◽

Binding Factor ◽

Element Binding Protein

Cyclic adenosine monophosphate (cAMP) response element-binding protein (CREB) is overexpressed and has an oncogenic role in hepatocellular carcinoma (HCC). Interleukin enhancer binding factor 2 (ILF2) has become research hotspot in liver cancer recently. However, it is still unclear whether and how CREB and ILF2 interact with each other. And how this interaction exerts its role in occurrence and development of liver cancer is still unclear. Here, we found that ILF2 directly bound with CREB, and this binding was essential for the malignant phenotypes of liver cancer cells. Moreover, we found that ILF2 acted as one of the upstream proteins of CREB and promoted CREB only in the protein level, whereas ILF2 expression was not regulated by CREB. Mechanistically, ILF2 bound to the pKID domain of CREB and stimulated its phosphorylation at Ser133. Taken together, our study finds a novel interaction between CREB and ILF2 in liver cancer, and this interaction might play a role in the diagnosis and remedy of liver cancer.

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A study of structural differences between liver cancer cells and normal liver cells using FTIR spectroscopy

Journal of Molecular Structure ◽

10.1016/j.molstruc.2015.05.054 ◽

2015 ◽

Vol 1099 ◽

pp. 18-23 ◽

Cited By ~ 17

Author(s):

Daping Sheng ◽

Fangcheng Xu ◽

Qiang Yu ◽

Tingting Fang ◽

Junjun Xia ◽

...

Keyword(s):

Liver Cancer ◽

Ftir Spectroscopy ◽

Cancer Cells ◽

Normal Liver ◽

Liver Cells ◽

Liver Cancer Cells ◽

Structural Differences

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Damage effect of Polygonum multiflorum fractions on human normal liver cells L02 and liver cancer cells HepG2

China Journal of Chinese Materia Medica ◽

10.4268/cjcmm20121229 ◽

2012 ◽

Author(s):

ZHANG Ruichen

Keyword(s):

Liver Cancer ◽

Cancer Cells ◽

Normal Liver ◽

Liver Cells ◽

Damage Effect ◽

Polygonum Multiflorum ◽

Liver Cancer Cells

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The role of microRNA-9 in hepatocellular oncogenesis.

Journal of Clinical Oncology ◽

10.1200/jco.2013.31.4_suppl.168 ◽

2013 ◽

Vol 31 (4_suppl) ◽

pp. 168-168

Author(s):

Alexandra Drakaki ◽

Maria Hatziapostolou ◽

Christos Polytarchou ◽

Dimitrios Iliopoulos

Keyword(s):

Liver Cancer ◽

Cancer Cells ◽

Cancer Patients ◽

Expression Analysis ◽

Therapeutic Potential ◽

Normal Liver ◽

Metastatic Potential ◽

Mrna Levels ◽

Matrigel Invasion ◽

Liver Cancer Cells

168 Background: Hepatocellular carcinoma (HCC) is the main type of liver cancer. MicroRNAs are non-coding RNAs that have been involved in the pathogenesis of different cancer types. Our aim was to identify microRNAs that have functional and clinical significance in liver oncogenesis and understand how manipulation of their levels could have a therapeutic potential. Methods: MicroRNA expression analysis was performed in 38 HCC tissues and 25 normal liver tissues. A microRNA library (318 microRNAs) was transfected in SNU-449 liver cancer cells and invasiveness was measured 24 h later by a matrigel invasion assay. Cell growth and matrigel invasion assays were performed in SNU-449 cells that were transfected with miR-9 or antisense-miR-9 (20nM). TargetScan algorithm was used to identify miR-9 direct downstream target genes. The mRNA levels of PPARalpha, and E-cadherin were assessed by real-time PCR 48h after miR-9 overexpression and down-regulation in SNU-449 cells. Results: MicroRNA expression analysis in 38 HCCs and 25 normal liver tissues identified a 25-microRNA signature of HCC. Integration of the library screen and patient data revealed that miR-9 has clinical and functional relevance for liver cancer. Specifically, we found that miR-9 increases 2.7-fold the invasiveness and the growth of SNU-449 cells, 48h post transfection. Bioinformatic analysis revealed that miR-9 has a binding site in the 3’UTR of PPARalpha gene. MiR-9 overexpression inhibited 35% PPARalpha 3’UTR luciferase activity and 60% mRNA levels, while miR-9 down-regulation led to 75% increased PPARalpha mRNA levels. These data suggest that miR-9 targets directly the 3'UTR of PPARalpha and regulates its expression levels in liver cancer cells. In addition, miR-9 overexpression led to 95% suppression of E-cadherin mRNA levels in SNU-449 cells, thus increasing their metastatic potential. Conclusions: We found that miR-9 is highly overexpressed in liver cancer patients and its up-regulation increases the growth and metastatic potential of liver cancer cells. Overall these data suggest that miR-9 is a novel oncogene involved in liver oncogenesis and its suppression could have therapeutic potential in liver cancer patients.

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