The continuing quest to comprehend genomic imprinting

The discovery of the phenomenon of genomic imprinting in mammals showed that the parental genomes are functionally non-equivalent. Considerable advances have occurred in the field over the past 20 years, which has resulted in the identification and functional analysis of a number of imprinted genes the expression of which is determined by their parental origin. These genes belong to many diverse categories and they have been shown to regulate growth, complex aspects of mammalian physiology and behavior. Many aspects of the mechanism of imprinting have also been elucidated. However, the reasons for the evolution of genomic imprinting remain enigmatic. Further research is needed to determine if there is any relationship between the apparently diverse functions of imprinted genes in mammals, and their role in human diseases. It also remains to be seen what common features exist amongst the diverse imprinting control elements. The mechanisms involved in the erasure and re-establishment of imprints should provide deeper insights into epigenetic mechanisms of wide general interest.     

The O-GlcNAcylation and its promotion to hepatocellular carcinoma

O-GlcNAcylation is a posttranslational modification that attaches O-linked β-N-acetylglucosamine (O-GlcNAc) to the serine and threonine residues of proteins. Such a glycosylation would alter the activities, stabilities, and interactions of target proteins that are functional in a wide range of biological processes and diseases. Accumulating evidence indicates that O-GlcNAcylation is tightly associated with hepatocellular carcinoma (HCC) in its onset, growth, invasion and metastasis, drug resistance, and stemness. Here we summarize the discoveries of the role of O-GlcNAcylation in HCC and its function mechanism, aiming to deepen our understanding of HCC pathology, generate more biomarkers for its diagnosis and prognosis, and offer novel molecular targets for its treatment.     

二甲双胍与肝细胞癌

二甲双胍作为一种口服降糖药,已被用于2型糖尿病的一线治疗,有报道指出其可以预防和控制多种癌症的发展。肝细胞癌(肝癌)是原发性肝癌的最常见形式,也是最常见的恶性肿瘤之一。目前,流行病学显示二甲双胍可以降低肝细胞癌的发生风险或改善肝癌患者的预后,实验室研究也证实二甲双胍可抑制肝癌细胞生长。因此文章将探讨二甲双胍抑制肝癌生长的相关机制。     

Gaba and hepatocellular carcinoma

Data derived from models of hepatic regeneration indicate that transient, recipricol changes in polyamines, potent growth promoters, and gamma aminobutyric acid (GABA), an amino acid neurotransmitter with growth inhibitory properties, play important roles in enhancing and inhibiting respectively regulated hepatocyte proliferation. Based on these findings and supportive data derived from studies of human carcinoma tissues and malignant cell lines we propose that permanent increases in polyamine and decreases in GABAergic activity act in concert to contribute to the pathogenesis of hepatocellular carcinoma.     

Giant cell hepatocellular carcinoma

A terminal case of giant cell hepatocellular carcinoma, subsequent to Hepatitis B-associated macronodular cirrhosis is presented, illustrated and discussed. The uncommon finding of malignant ascites, in itself atypical of hepatocellular carcinoma, with an almost exclusive content of giant cells as the cellular component, was a feature of this unusual variant of hepatocellular carcinoma.     

Obesity linking to hepatocellular carcinoma: A global view

Hepatocellular carcinoma (HCC) is the commonest primary liver cancer and the second leading cause of cancer death worldwide. Obesity is rapidly becoming pandemic and associated with increased carcinogenesis. In this review, we describe the obesity-related factors that influence the development of HCC. We provide evidence of strong links between neural regulation, endocrine and HCC in obesity. We discuss recent advances in our understanding of how adipose tissue alters hepatic metabolism and immune response in HCC development through inter-organ communication. Taken together, our review aims to provides a concise and up-to date summary about the connection between obesity and HCC, with emphasis on the opportunities for effective strategies in preventing the development of HCC in obese individuals.     

乙肝相关性肝癌差异表达基因的获得及FOLR1分析

运用基因芯片技术获取以稳定转染HBx基因的肝癌细胞HepG2(HepG2-X)及非转染的肝癌细胞HepG2中差异表达的基因,并对其中一条基因进行的生物信息学分析。采用人肝癌G2细胞(HepG2)细胞系为对照组,以稳定转染HBx的HepG2细胞为实验组,抽取总RNA,经过反转录cDNA,对照组用Cy3实验组用Cy5荧光标记,获得cDNA探针;经杂交、洗涤后,通过ImaGene3.0软件进行分析统计。通过基因芯片筛选,获得643条与乙肝相关性肝细胞性癌相关的基因,其中FOLR1基因差异性表达最显著,HBx显著下调其表达,同源性比较分析结果表明,其碱基序列与已经报道的其他12种哺乳动物的相似率为67%-99%,且符合种属之间的进化关系。基因芯片筛选HBx诱导的HepG2差异表达基因具有样品用量少,高质量,高速度,高敏感等特性。FOLR1可能为HBV相关肝癌的发生、转移的诊断、靶基因治疗和预后评估提供一定的依据。     

Sorafenib sensitizes hepatocellular carcinoma cells to physiological apoptotic stimuli

Sorafenib increases survival rate of patients with advanced hepatocellular carcinoma (HCC). The mechanism underlying this effect is not completely understood. In this work we have analyzed the effects of sorafenib on autocrine proliferation and survival of different human HCC cell lines. Our results indicate that sorafenib in vitro counteracts autocrine growth of different tumor cells (Hep3B, HepG2, PLC-PRF-5, SK-Hep1). Arrest in S/G2/M cell cycle phases were observed coincident with cyclin D1 down-regulation. However, sorafenib's main anti-tumor activity seems to occur through cell death induction which correlated with caspase activation, increase in the percentage of hypodiploid cells, activation of BAX and BAK and cytochrome c release from mitochondria to cytosol. In addition, we observed a rise in mRNA and protein levels of the pro-apoptotic "BH3-domain only" PUMA and BIM, as well as decreased protein levels of the anti-apoptotic MCL1 and survivin. PUMA targeting knock-down, by using specific siRNAs, inhibited sorafenib-induced apoptotic features. Moreover, we obtained evidence suggesting that sorafenib also sensitizes HCC cells to the apoptotic activity of transforming growth factor-β (TGF-β) through the intrinsic pathway and to tumor necrosis factor-α (TNF) through the extrinsic pathway. Interestingly, sensitization to sorafenib-induced apoptosis is characteristic of liver tumor cells, since untransformed hepatocytes did not respond to sorafenib inducing apoptosis, either alone or in combination with TGF-β or TNF. Indeed, sorafenib effectiveness in delaying HCC late progression might be partly related to a selectively sensitization of HCC cells to apoptosis by disrupting autocrine signals that protect them from adverse conditions and pro-apoptotic physiological cytokines.     

Proteome analysis of hepatocellular carcinoma

Development of hepatocellular carcinoma (HCC) is a complex process involving multiple changes in gene expression and usually occurs in the presence of liver cirrhosis. In this research, we observed proteome alterations of three tissue types isolated from livers of HCC patients: normal, cirrhotic, and tumorous tissue. Proteome alterations were observed using two-dimensional polyacrylamide gel electrophoresis and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. Comparing the tissue types with each other, a significant change in expression level was found in 21 proteins. Of these proteins, sarcosine dehydrogenase, liver carboxylesterase, peptidyl-prolyl isomerase A, and lamin B1 are considered novel HCC marker candidates. In particular, lamin B1 may be considered as a marker for cirrhosis, because its expression level changes considerably in cirrhotic tissue compared with normal tissue. The proteins revealed in this experiment can be used in the future for studies pertaining to hepatocarcinogenesis, or as diagnostic markers and therapeutic targets for HCC.     

Viral hepatitis and hepatocellular carcinoma

Background

Hepatocellular carcinoma (HCC) is one of the most common malignant tumors in the world. The incidence of HCC varies considerably with the geographic area because of differences in the major causative factors. Chronic hepatitis B and C, mostly in the cirrhotic stage, are responsible for the great majority of cases of HCC worldwide. The geographic areas at the highest risk are South-East Asia and sub-Saharan Africa, here hepatitis B is highly endemic and is the main cause of HCC. In areas with an intermediate rate of HCC such as Southern Europe and Japan, hepatitis C is the predominant cause, whereas in low rate areas such as Northern Europe and the USA, HCC is often related to other factors as alcoholic liver disease. There is a rising incidence in HCC in developed countries during the last two decades, due to the increasing rate of hepatitis C infection and improvement of the clinical management of cirrhosis.

Methods

This article reviews the literature on hepatitis and hepatocellular carcinoma. The Medline search was carried out using these key words and articles were selected on epidemiology, risk factors, screening, and prevention of hepatocellular carcinoma.

Results

Screening of patients with advanced chronic hepatitis B and C with hepatic ultrasound and determination of serum alfa-fetoprotein may improve the detection of HCC, but further studies are needed whether screening improves clinical outcome. Hepatitis B and C viruses (HBV/HCV) can be implicated in the development of HCC in an indirect way, through induction of chronic inflammation, or directly by means of viral proteins or, in the case of HBV, by creation of mutations by integration into the genome of the hepatocyte.

Conclusion

The most effective tool to prevent HCC is avoidance of the risk factors such as viral infection. For HBV, a very effective vaccine is available. Preliminary data from Taiwan indicate a protective effect of universal vaccination on the development of HCC. Vaccination against HBV should therefore be a health priority. In patients with chronic hepatitis B or C, interferon-alfa treatment in a noncirrhotic stage is protective for HCC development in responders, probably by prevention of cirrhosis development. When cirrhosis is already present, the protective effect is less clear. For cirrhosis due to hepatitis B, a protective effect was demonstrated in Oriental, but not in European patients. For cirrhosis due to hepatitis C, interferon-alfa treatment showed to be protective in some studies, especially in Japan with a high incidence of HCC in untreated patients. Virological, but also merely biochemical response, seems to be associated with a lower risk of development of HCC. As most studies are not randomized controlled trials, no definitive conclusions on the long-term effects of interferon-alfa in HBV or HCV cirrhosis can be established. Especially in hepatitis C, prospective studies should be performed using the more potent reference treatments for cirrhotics, namely the combination of peginterferon and ribavirin.     

Proteome database of hepatocellular carcinoma

Hepatocellular carcinoma (HCC or hepatoma) is the most common primary cancer of the liver. Persistent viral infection by the hepatic B or C virus is probably the most important cause of HCC worldwide. It is responsible for approximately one million deaths each year, predominantly in the underdeveloped and developing countries, but its incidence is also on the rise in the developed countries. For most patients suffering from HCC, long-term survival is rare, as they are presented late and are often unsuitable for curative treatment. Thus there is great interest to identify novel HCC diagnostic markers for early detection of the disease, and tumour specific associated proteins as potential therapeutic targets in the treatment of HCC. Proteome analyses of HCC cell lines and liver tumour tissues should facilitate the screening and discovery of these HCC proteins. The creation of a comprehensive HCC proteome database would be an important first step towards achieving this goal. This review presents an update of the two-dimensional electrophoresis proteome database of the cell line, HCC-M, which is also now freely accessible through the World Wide Web at http://proteome.btc.nus.edu.sg/hccm/.     

Cytokeratin 20-positive hepatocellular carcinoma

The differential diagnosis between hepatocellular carcinoma (HCC), cholangiocarcinoma (CC) and metastatic colorectal adenocarcinoma (MCA) may be difficult when only based on morphology. For this purpose immunohistochemical analyses are often required, utilizing antibodies directed against CK8-18, Hep-Par1, glypican 3, CK7, CK19, CK20. Here we report a case of a 65-year-old man who presented with a clinical picture of decompensated cirrhosis. Ultrasonography revealed two nodular areas in the right liver lobe. Liver needle biopsy revealed micro-macronodular cirrhosis associated with HCC with trabecular and pseudoglandular patterns. Immunohistochemically, tumour cells were diffusely positive for CK8-18 and also diffusely immunostained by glypican 3 and Hep-Par1. Interestingly, a diffuse and strong staining for CK20 was detected in the vast majority of tumor cells, particularly in the areas showing a pseudo-glandular pattern. No immunostaining for CK7 and CK19 was found in the tumor cells. The tumor behaved aggressively, with a rapid diffusion to the whole liver. The patient died from the disease few months after presentation. These findings underline that the interpretation of the expression of CK20 alone in the differential diagnosis among HCC, CC and MCA should be done with caution because a diffuse immunoreactivity for CK20 alone may not rule out the diagnosis of HCC.Key words: hepatocellular carcinoma, cholangiocarcinoma, metastatic colorectal carcinomas, CK20.The differential diagnosis between hepatocellular carcinoma (HCC), cholangiocarcinoma (CC) and metastatic colorectal adenocarcinoma (MCA) may be difficult when only based on morphology (Terracciano et al., 2003).In fact, a subset of extrahepatic adenocarcinomas of different origin may show a solid “hepatoid” pattern virtually indistinguishable from HCC (Porcell et al., 2000). On the other hand, the undifferentiated form of HCC may mimic poorly differentiated tumors of different origin, while its tubular and adenoid variants may be indistinguishable from CC or from MCA.In these cases, immunohistochemical analyses are often required (Stroescu et al., 2006).The panel of antibodies utilized to solve this differential diagnosis includes: CK8-18 (Porcell et al., 2000) Hep-Par1 (Leong et al., 1998) (Zimmerman et al., 2001), glypican 3 (GPC3) (Yamauchi et al., 2005) (Capurro et al., 2003), CK7 (Maeda et al., 1996) (Chu et al., 2000), CK20 (Faa G et al., 1998), CK19, CEA and Alpha-fetoprotein (Onofre et al., 2007) (Lau et al., 2002).Immunoreactivity of tumour cells for CK8-18, Hep-Par 1 and GPC3 is considered suggestive of HCC; a diffuse immunoreactivity for CK7 and CK19 is in favour of the diagnosis of CC; a diffuse positivity for CK20 and negativity for CK7 are normally associated with MCA.Here we report a case of HCC with a peculiar immunohistochemical profile, characterized by the association of the typical immunoreactivity of HCC with a diffuse and strong positivity for CK20, generally considered typical of MCA.     

Detecting hepatocellular carcinoma in blood

Liquid biopsy is ideal for early diagnosis of cancer and for prognosis upon treatment. Wen et al. describe a methylated CpG tandems amplification and sequencing method to profile hypermethylated CpG islands genome-widely in cell-free DNA, and further identify high performance markers in blood for potential detection of early stage hepatocellular carcinoma.Early diagnosis is key to cancer prevention and treatment. When physiological consequences of cancer are observed it could be too late for the optimal treatment and therapy¹. Traditional biopsy has been widely used for diagnosis; however, it is difficult to frequently perform biopsy. In many cases it is impossible to perform biopsy of solid tumors grown in deep tissues. Cell-free nucleic acids (cfNAs) offer an alternative option. The presence of cfNAs in blood was described in 1948. However, cfNAs such as DNA, mRNA and microRNAs (miRNAs) were not recognized as potential disease biomarkers until recently because of the rapid advance of sequencing technologies^2,3,4. The apoptosis and necrosis of tumor tissues can lead to release of cell-free DNAs (cfDNAs) into the circulating system⁵; these cfDNAs contain crucial genetic and epigenetic information for early diagnosis if sensitive and accurate methods can be developed.Human hepatocellular cancer, one of the most lethal cancers, is characterized by progressive accumulation of epigenetic changes⁶, among which hypermethylation of cancer-associated DNA offers distinct markers for diagnosis. DNA methylation patterns could change throughout the cancer development stages. If the same DNA methylation changes could be monitored in cfDNA released by tumor one could trace the emergence of the cancer, monitor the progression, and predict effects of treatments. Despite these advantages, current cfDNA detection is significantly hampered by the lack of sensitivity because only a very small amount of cfDNA could be obtained from plasma and serum. cfDNA is also heavily fragmented (between 200∼400 bp), adding additional challenges.Faced with these challenges, Wen et al.⁷ invent methylated CpG tandems amplification and sequencing (MCTA-Seq), a method that takes advantage of the fact that CpG tandems are highly enriched in the CpG island-containing promoters of human genome. These CpGs are typically unmethylated but tend to gain hypermethylation in hepatocellular carcinoma (HCC)⁶. The cfDNAs released into circulation carry the same hypermethylation patterns, thereby providing accurate information of the presence of HCC in patients. In their new method, cfDNA is treated with bisulfite, during which non-methylated C (cytosine) is converted to U (uracil) while methylated C remains unaffected. They then use a pair of primers to specifically amplify DNA loci that contain hypermethylated CGCGCGG, a sequence frequently presented in CpG islands and tend to be methylated in cancer tissues. The focus on the CGCGCGG-containing loci may miss other potential markers; however, it offers the sensitivity required for methylation detection in cfDNA. Validation data of MCTA-Seq shows that it is highly reproducible and sensitive, with the detection limit down to as low as 7.5 pg (∼2.5 haploid genome equivalents). Existing biomarkers that are frequently hypermethylated in human cancers⁸, such as VIM, SEPT9, NDRG2 and RASSF1⁸, could be detected with high sensitivity by using MCTA-Seq. The method, although limited by the requirement of the CGCGCGG sequence content, is genome-wide and offers sufficient information about CpG island methylation changes in HCC.Wen et al. applied the new method to detect tumor-specific CGI methylation with plasma samples from HCC patients, cirrhosis patients, and normal individuals. Two types of biomarkers have been identified for early stage HCC diagnosis (Figure 1). Type I markers possess significantly higher methylated CGIs than cancer-free individuals. Type II markers are tissue-specifically methylated CGIs, which tend to be restricted to liver cells under normal circumstances but are released into the blood when malignance occurs. Type II markers dominate in the cfDNA at early stage of HCCs, making them sensitive signs of tumor emergence.Open in a separate windowFigure 1Hypermethylated cfDNA released into the blood can be detected with a new method. Cell-free DNA-containing hypermethylated CpG islands (mCGIs) circulating in the blood of heptocellular carcinoma patients can be detected for early diagnosis. These marker DNAs are released by either tumor cells undergoing apoptosis or necrosis (type I) or adjacent non-cancerous cells affected by tumor growth (type II).The new method and the use of marker combination shown by Wen et al. provide a new strategy for DNA methylation detection from cfDNA. It may have widely applicable potential not only in HCC but also a cohort of other cancer types.     

Animal models for hepatocellular carcinoma

Hepatocellular carcinoma (HCC) represents ~90% of all cases of primary liver cancer and occurs predominantly in patients with underlying chronic liver disease and cirrhosis. Establishing appropriate animal models for HCC is required for basic and translational studies, especially the models that can recapitulate one of the human disease settings. Current animal models can be categorized as chemically-induced, genetically-engineered, xenograft, or a combination of these with each other or with a metabolic insult. A single approach to resemble human HCC in animals is not sufficient. Combining pathogenic insults in animal models may more realistically recapitulate the multiple etiologic agents occurring in humans. Combining chemical injury with metabolic disorder or alcohol consumption in mice reduces the time taken to hepatocarcinogenesis. Genetically-engineering weak activation of HCC-promoting pathways combined with disease-specific injury models will possibly mimic the pathophysiology of human HCC in distinct clinical settings.     

CXCR7 stimulates MAPK signaling to regulate hepatocellular carcinoma progression

The CXCL12/CXCR4 axis has been posited widely to have significant roles in many primary tumors and metastases. It is known that CXCR7 can also be engaged by CXCL12, but the exact function of CXCR7 is controversial. This prompted us to investigate the expression, specific function and signal transduction of CXCR7 in hepatocellular carcinoma (HCC). In this study, CXCR7 and CXCR4 were differentially expressed in nine cell lines of HCC, and that elevated expression of both CXCR7 and CXCL4 were correlated with highly metastatic ability of HCC cells. Moreover, CXCR7 expression was significantly upregulated in metastatic HCC samples compared with the non-metastatic ones by staining of high-density tissue microarrays constructed from a cohort of 48 human HCC specimens. CXCR7 overexpression enhanced cell growth and invasiveness in vitro, and tumorigenicity and lung metastasis in vivo. By contrast, CXCR7 stable knockdown markedly reduced these malignant behaviors. In addition, it was observed that alterations in CXCR7 expression were positively correlated with the phosphorylation levels of mitogen-activated protein kinase (MAPK) pathway proteins. Targeting extracellular regulated kinase pathway by using U0126 inhibitor or using CCX771, a selective CXCR7 antagonist, drastically reduced CXCR7-mediated cell proliferation. Importantly, by using human biotin-based antibody arrays, several differentially expressed proteins were identified in CXCR7-overexpression and depletion groups. Comparative analysis indicated that upstream regulators including TP53 and IL-6 were involved in CXCR7 signal transduction. CXCR7 expression was further proved to regulate expression of vascular endothelial growth factor A and galectin-3, which may contribute to tumor angiogenesis and invasiveness. Consequently, elevated expression of CXCR7 contributes to HCC growth and invasiveness via activation of MAPK and angiogenesis signaling pathways. Targeting CXCR7 may prevent metastasis and provide a potential therapeutic strategy for HCC.Liver cancer is the third most common cause of cancer-related mortality worldwide.¹ Although surgical and medical interventions becomes available, over 70% patients with metastasis or recurrence have little chance of survival.² High rate of tumor metastasis to lung after hepatectomy represents a highly organized and organ-selective process. Emerging evidences indicate that several chemokines and their receptors appear to be directly implicated in mediating the biological cascade of sequential events, leading to tumor formation and metastasis.^3,4Chemokines are small secreted proteins (8–12 kDa) that share structural similarities, and members of this molecular superfamily can be subdivided into four classes, the C-C, C-X-C, C and C-X3-C chemokines, depending on the location of the first two conserved N-terminal cysteine residues that built disulfide bonds to two other cysteine residues within the protein sequence.⁵ To date, about 50 chemokines and ~25 chemokine receptors have been identified, thus some ligands exclusively bind to one receptor, others may interact with several receptors.⁶ Apart from their initially discovered and best-known function in trafficking of leukocytes,⁷ these soluble chemokines also influence organ development and physiological homeostasis via their respective G-protein-coupled receptors (GPCRs).⁸Mounting studies indicate the involvement of chemokines and their respective receptors in tumor biology during the last decade. Malignant cells can express chemokine receptors and respond to chemokine gradients and this may be related to the growth and spread of cancer.⁹ In particular, CXCL12, which is also called stromal-derived factor-1, and its receptor CXCR4 have attracted tremendous interest, owing to their critical role in determining the metastatic destination of breast cancer cells.¹⁰ Shortly thereafter, researches revealed that CXCR4 is one of the most common chemokine receptors that cells from at least 23 different types of cancer express this receptor and respond to its ligand CXCL12.^{11, 12, 13} Since CXCL12/CXCR4 axis has a vital role in embryonic development of the hematopoietic, cardiovascular and nervous systems, the deficiency of this axis leads to perinatal lethality.^{14, 15, 16} This raises questions concerning the feasibility of CXCR4 as the therapeutic target in a range of cancers.For a long time, CXCR4 was thought to be the only receptor for CXCL12, however, recent studies reported that CXCL12 also binds to CXCR7 with 10 times higher affinity than to CXCR4.^17,18 CXCR7 is expressed in zebrafish and frog and is highly conserved in mammals.¹⁹ In the immune system, intracellular expression of CXCR7 has been found in T cells and monocytes,²⁰ and its surface expression on B cells, plasmacytoid DCs, NK cells and basophils.²¹ In addition, very small but functional level of CXCR7 is observed on the surface of T cells, indicating that the intracellular pool of CXCR7 recycles back to the cell membrane and becomes activated.^17,22 CXCR7 plays its important exclusive role in the proper development of the heart, particularly cardiac valves and its expression pattern in brain cells is also documented.^23,24 It is known that CXCR7 is expressed on activated endothelial cells, fetal liver cells and on tumor-associated blood vessels as well as distinct tumor cells, but not on most nontransformed cells.^17,25 Growing evidence has suggested that membrane-associated CXCR7 expression is elevated on many malignant cells, including breast,^18,25 lung,²⁵ prostate,²⁶ pancreatic²⁷ and glial cancer cells.²⁸ Based on current literature, in glioma, CXCR7 is a functional receptor for CXCL12 and mediates anti-apoptotic/survival effects;²⁸ whereas in breast cancer, CXCL12 enhanced CXCR7-mediated tumorigenicity and invasiveness by activating proinflammatory STAT3 signaling.²⁹ Moreover, CXCR7 may also has CXCR4-independent functions as it provides growth and survival advantages even without ligand binding.^18,30,31 How CXCR7 mediates the multiple functions has remained a mystery. Unlike most other CXC chemokine receptors, CXCR7 lacks the specific DRYLAIV motif, hence CXCR7 fails to mobilize Ca²⁺ from intracellular stores or extracellular sources after ligand engagement, which is the hallmark of chemokine receptor activation.¹⁸ Thus our interest is to explore the role and the mechanism of CXCR7 in hepatocellular carcinoma (HCC) progression.     

Aberrant upregulation of LRRC1 contributes to human hepatocellular carcinoma

Loss of apico-basal polarity often results in a malignant phenotype in epithelial tissues. Aberrant expression of polarity mediator proteins is closely associated with this process. LRRC1/LANO, a putative cell polarity regulator, was previously screened from our gene expression profiling in which its expression was significantly upregulated in hepatocellular carcinoma (HCC). In the present study, we provide evidences that LRRC1 plays a potential oncogenic function in HCC. Consistent with the microarray data, quantitative real-time PCR results showed LRRC1 was aberrantly upregulated in 37/56 (66.1 %, more than twofolds) of HCC specimens compared with adjacent non-cancerous livers. Furthermore, the cellular expression of LRRC1 in all HCC cell lines examined exhibited much higher level than that in normal adult liver tissue. Functional analyses revealed that overexpression of LRRC1 promoted, while knockdown of LRRC1 by RNA interference inhibited the growth and colony formation of HCC cells. Importantly, enhanced expression of LRRC1 conferred NIH3T3 cells the ability of cell transformation. In a xenograft tumor model, we found LRRC1 overexpression increased the tumorigenicity of HCC cells. Thus, our collective findings suggest that LRRC1 contributes to HCC development, and may be a potential target for therapeutic intervention in this disease.     

Rho GTPases in hepatocellular carcinoma

Rho GTPases are major regulators of signal transduction pathways and play key roles in processes including actin dynamics, cell cycle progression, cell survival and gene expression, whose deregulation may lead to tumorigenesis. A growing number of in vitro and in vivo studies using tumor-derived cell lines, primary tumors and animal cancer models strongly suggest that altered Rho GTPase signaling plays an important role in the initiation as well as in the progression of hepatocellular carcinoma (HCC), one of the deadliest human cancers in the world. These alterations can occur at the level of the GTPases themselves or of one of their regulators or effectors. The participation into the tumorigenic process can occur either through the over-expression of one of these components which presents an oncogenic activity as illustrated with RhoA and C or through the attenuation of the expression of a component presenting tumor suppressor activity as for Cdc42 or the RhoGAP, DLC-1. Consequently, these observations reflect the heterogeneity and the complexity of liver carcinogenesis. Recently, pharmacological approaches targeting Rho GTPase signaling have been used in HCC-derived models with relative success but remain to be validated in more physiologically relevant systems. Therefore, therapeutic approaches targeting Rho GTPase signaling may provide a novel alternative for anti-HCC therapy.