Marker For Human Hepatocellular Carcinoma Research Articles

TRIM21 is critical in regulating hepatocellular carcinoma growth and response to therapy by altering the MST1/YAP pathway.

Liver cancer is the sixth most common cancer and the third leading cause of cancer-related death globally. Despite efforts being made in last two decades in cancer diagnosis and treatment, the 5-year survival rate of liver cancer remains extremely low. TRIM21 participates in cancer metabolism, glycolysis, immunity, chemosensitivity and metastasis by targeting various substrates for ubiquitination. TRIM21 serves as a prognosis marker for human hepatocellular carcinoma (HCC), but the mechanism by which TRIM21 regulates HCC tumorigenesis and progression remains elusive. In this study, we demonstrated that TRIM21 protein levels were elevated in human HCC. Elevated TRIM21 expression was associated with HCC progression and poor survival. Knockdown of TRIM21 in HCC cell lines significantly impaired cell growth and metastasis and enhanced sorafenib-induced toxicity. Mechanistically, we found that knockdown of TRIM21 resulted in cytosolic translocation and inactivation of YAP. At the molecular level, we further identified that TRIM21 interacted and induced ubiquitination of MST1, which resulted in MST1 degradation and YAP activation. Knockdown of MST1 or overexpression of YAP reversed TRIM21 knockdown-induced impairment of HCC growth and chemosensitivity. Taken together, the current study demonstrates a novel mechanism that regulates the Hippo pathway and reveals TRM21 as a critical factor that promotes growth and chemoresistance in human HCC.

FBXO28 suppresses liver cancer invasion and metastasis by promoting PKA-dependent SNAI2 degradation

FBXO28 is a member of F-box proteins that are the substrate receptors of SCF (SKP1, CULLIN1, F-box protein) ubiquitin ligase complexes. Despite the implications of its role in cancer, the function of FBXO28 in epithelial-mesenchymal transition (EMT) process and metastasis for cancer remains largely unknown. Here, we report that FBXO28 is a critical negative regulator of migration, invasion and metastasis in human hepatocellular carcinoma (HCC) in vitro and in vivo. FBXO28 expression is upregulated in human epithelial cancer cell lines relative to mesenchymal counterparts. Mechanistically, by directly binding to SNAI2, FBXO28 functions as an E3 ubiquitin ligase that targets the substrate for degradation via ubiquitin proteasome system. Importantly, we establish a cooperative function for PKA in FBXO28-mediated SNAI2 degradation. In clinical HCC specimens, FBXO28 protein levels positively whereas negatively correlate with PKAα and SNAI2 levels, respectively. Low FBXO28 or PRKACA expression is associated with poor prognosis of HCC patients. Together, these findings elucidate the novel function of FBXO28 as a critical inhibitor of EMT and metastasis in cancer and provide a mechanistic rationale for its candidacy as a new prognostic marker and/or therapeutic target in human aggressive HCC.

CDCA7 serves as a novel prognostic marker in human hepatocellular carcinoma

ABSTRACT c-Myc oncogene plays an important role in tumorigenesis, cell division cycle associated 7 (CDCA7), recently found that it is a direct target gene of c-Myc, is upregulated in many tumors, but its role in tumor progression is still poorly understood. CDCA7 expression and prognosis were analyzed in hepatocellular carcinoma using TIMER2.0 and Kaplan–Meier databases, while genomic changes were studied using cbioportal. LinkedOmics identified relevant genes and WebGestalt analyzed the associated pathways. Protein interaction networks were explored using the STRING database, and the core PPI network was analyzed with the MCODE plugin of Cytoscape. CDCA7 expression was detected in 30 paired HCC specimens by real-time PCR, and its effect on HCC cell proliferation was determined in vitro. CDCA7 expression was frequently up-regulated in human hepatocellular carcinoma (HCC), and its expression was positively correlated with prognosis. The TIMER2.0 database showed that CDCA7 was differentially expressed in hepatocellular carcinoma, with high expression in tumor tissues and low expression in normal tissues. The Kaplan-Meier database shows that high CDCA7 expression has a worse prognosis. The cBioportal database showed that the genomic change rate of CDCA7 in hepatocellular carcinoma was 2.15%, including mutations, amplifications, and deep deletions. Pathway analysis of related genes showed that CDCA7-related genes were mainly focused on cell division-related pathways. The experimental results also validate our study. CDCA7 could contribute to HCC progression and raise the possibility that CDCA7 is a potential new therapeutic target for HCC treatment.

Potential Value of the Motor Protein Family KIF as a Diagnostic & Prognostic Marker for Human Hepatocellular Carcinoma: A Prospective Research

Potential Value of the Motor Protein Family KIF as a Diagnostic & Prognostic Marker for Human Hepatocellular Carcinoma: A Prospective Research

Lymphopenia predicts reduced survival in canine hepatocellular carcinoma.

Platelet to lymphocyte ratio (PLR) is a prognostic marker in human hepatocellular carcinoma (HCC) however, its utility in canine HCC has not been explored. The aim of the study was to determine if PLR could predict survival outcomes in 42 dogs with HCC. PLR was not a significant predictive factor (p = 0.15) but lymphopenia alone was significantly correlated with a reduced probability of survival (p = 0.024). Further studies are needed to evaluate if peripheral lymphocyte count mirrors that of the tumor microenvironment in canine HCC.

Reduced Klotho expression and its prognostic significance in canine hepatocellular carcinoma.

Klotho is an anti-ageing gene and is known to act as a tumour suppressor in human hepatocellular carcinoma (HCC). According to a previous study, Klotho is present in normal canine mammary glands, and down-expression in tumours is positively associated with negative prognosis. However, the presence and significance of Klotho in canine HCC has not yet been reported. This study aimed to confirm Klotho expression in normal canine liver tissues using western blotting and immunohistochemistry, and whether the expression differed in non-neoplastic liver disease and HCC. Furthermore, correlation between clinicopathologic features and expression of Klotho was evaluated. All of the normal liver tissues showed the presence of Klotho, and Klotho expression was significantly decreased in the HCC tissue as compared to the non-neoplastic hepatic tissue. Additionally, Klotho expression was significantly associated with tumour size (P=.045), liver enzyme (alanine aminotransferase (ALT)) (P=.018), and metastasis (P=.024). Analysis of the survival curve revealed that reduced Klotho expression was significantly associated with poor disease-free survival (P=.041) in HCC. These results show that Klotho expression is present in normal canine liver tissue and that reduced Klotho expression is associated with poor prognosis in canine HCC. Thus, Klotho was presumed to be a potential clinical prognostic marker for canine HCC.

Serum level of cytokeratin 19 as a diagnostic and prognostic marker in patients with HCV-related hepatocellular carcinoma

BackgroundThe heterogeneous nature of human hepatocellular carcinoma (HCC) impedes both treatment strategies and prognostic predictions. Several markers have been proposed for the diagnosis of HCC. Cytoskeleton-associated proteins have been known as cellular integrators in neoplasm formation. Hepatic progenitor cells are thought to express alpha-fetoprotein (AFP) and hematopoietic as well as biliary markers such as cytokeratin 19 (CK 19) and cytokeratin 7. The aim of this study was to verify the role of serum CK 19 alone or in combination with AFP as a diagnostic marker of HCC and to assess the changes in its levels after ablation of HCV-related HCC to evaluate its role as a predictor marker for recurrence of HCC after ablation. The study was conducted on 102 HCV-related cirrhotic patients categorized into three different groups according to the clinical, laboratory, and radiological evaluation: group I—62 patients with early or intermediate HCC who underwent locoregional intervention, group II—20 patients with advanced HCC not fit for any intervention apart from best supportive treatment, and group III—20 cirrhotic patients with no evidence of HCC as proved by two imaging techniques.ResultsThe mean serum levels of CK 19 were 6.5 ± 5.7, 10.5 ± 12.5, and 6.8 ± 2.8 ng/ml in groups I, II, and III, respectively, with no significant difference between groups. Sensitivity, specificity, positive, and negative predictive values of combined AFP and human CK 19 at cutoff levels of 25.5 ng/ml and 6.25 ng/ml were 93.9%, 45%, 87.5%, and 64.3%, respectively. In group I patients, CK 19 levels were comparable in patients with ablated focal lesion and those who did not at baseline; then, it was significantly higher in ablated patients than in patients with residual tumor 1 and 6 months after the intervention.ConclusionsCombination of both AFP and CK 19 levels could increase the diagnostic accuracy of suspected HCCs. CK 19 levels are good predictors of ablation/recurrence in patients who underwent interventional procedures minimizing the need for follow-up imaging modalities.

First evaluation of Neighbor of Punc E11 (NOPE) as a novel marker in human hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is the second most common cause of cancer death worldwide and the search for clinically useful biomarkers is ongoing. Neighbor of Punc E11 (NOPE) is an established biomarker of murine HCC that remains undetectable in normal liver and at preneoplastic stages. The aim of our study was to evaluate the presence of NOPE in human HCC. Histologically confirmed HCC and corresponding non-tumor liver samples from 20 patients were analyzed for expression of NOPE using qRT-PCR and mRNA-in-situ technology in a conserved tissue context. In our cohort, 30% of HCC samples were expressing NOPE which proved particularly useful in non-cirrhotic HCC samples with up to 155-fold higher expression than in adult liver. Using mRNA-in-situ technology, NOPE was clearly identified within epithelial tumor cells of NOPE positive human HCCs. In our analyzed cohort, the combination of AFP with NOPE did not reach more than 40% sensitivity while GPC-3 and NOPE were complementary to each other reaching a combined sensitivity of 85.7%. This is the first characterization of NOPE as a potential biomarker for human HCC. Our results underline the value of NOPE as a complementing biomarker for human HCC.

Functionalizable Antifouling Coatings as Tunable Platforms for the Stress-Driven Manipulation of Living Cell Machinery.

Cells are continuously sensing their microenvironment and subsequently respond to different physicochemical cues by the activation or inhibition of different signaling pathways. To study a very complex cellular response, it is necessary to diminish background environmental influences and highlight the particular event. However, surface-driven nonspecific interactions of the abundant biomolecules from the environment influence the targeted cell response significantly. Yes-associated protein (YAP) translocation may serve as a marker of human hepatocellular carcinoma (Huh7) cell responses to the extracellular matrix and surface-mediated stresses. Here, we propose a platform of tunable functionable antifouling poly(carboxybetain) (pCB)-based brushes to achieve a molecularly clean background for studying arginine, glycine, and aspartic acid (RGD)-induced YAP-connected mechanotransduction. Using two different sets of RGD-functionalized zwitterionic antifouling coatings with varying compositions of the antifouling layer, a clear correlation of YAP distribution with RGD functionalization concentrations was observed. On the other hand, commonly used surface passivation by the oligo(ethylene glycol)-based self-assembled monolayer (SAM) shows no potential to induce dependency of the YAP distribution on RGD concentrations. The results indicate that the antifouling background is a crucial component of surface-based cellular response studies, and pCB-based zwitterionic antifouling brush architectures may serve as a potential next-generation easily functionable surface platform for the monitoring and quantification of cellular processes.

NT5DC2 is a novel prognostic marker in human hepatocellular carcinoma.

Reliable biomarkers for the prognosis of hepatocellular carcinoma (HCC) are rare, and novel biomarkers are required for the appropriate management of HCC. 5′-Nucleotidase domain containing 2 (NT5DC2) acts as an oncogene in various tumors, but its functions as a biomarker have not been confirmed. Therefore, the present study aimed to resolve these functions by analyzing the prognostic value of NT5DC2 in patients with HCC. A tissue microarray (TMA) was prepared and NT5DC2 expression was measured via IHC staining in TMA dots. The liver cancer (LIHC) cohort in The Cancer Genome Atlas (TCGA) was enrolled as a secondary cohort. Kaplan-Meier survival analyses and Cox regression models were used for assessment of the prognostic value of NT5DC2. Gene set enrichment analysis (GSEA) was performed in TCGA LIHC cohort. A total of 134 patients with HCC were retrospectively enrolled in the Peking Union Medical College Hospital cohort and clinical data were collected. A total of 359 patients with HCC in TCGA were enrolled as TCGA cohort. NT5DC2 was used as an indicator of overall survival (OS) and relapse-free survival (RFS) in multiple cohorts. In the multivariate Cox regression model, NT5DC2 upregulation was an independent prognostic factor of OS in both cohorts. GSEA indicated the enrichment of a series of survival- and metastasis-related gene-sets, such as LEE_LIVER_CANCER_SURVIVAL_UP and LIAO_METASTASIS. Collectively, it was suggested that NT5DC2 upregulation was associated with poor OS and RFS in HCC, and was a potential predictive marker for HCC stratification.

Identification of FABP5 as an immunometabolic marker in human hepatocellular carcinoma

BackgroundRegulating T-cell metabolism is crucial for their anticancer activity. Therefore, understanding the function and metabolism of human tumor-infiltrating T cells is of broad interest and clinical importance.MethodsCD3+CD45+ T cells were...

MAGEC2 Correlates With Unfavorable Prognosis And Promotes Tumor Development In HCC Via Epithelial-Mesenchymal Transition.

PurposeAlthough MAGEC2 was first cloned from a human hepatocellular carcinoma (HCC) cDNA library by serum screening, the detailed attributes of MAGEC2 in HCC have rarely been elucidated.Patients and methodsIn this study, The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) databases were consulted to analyse the expression of MAGEC2 mRNA in liver cancer. Immunohistochemistry (IHC) analysis was performed to detect MAGEC2 expression in HCC, and the relationship between MAGEC2 expression and the clinicopathological characteristics of HCC patients was evaluated. Then, we employed the short hairpin (sh)RNA-mediated knockdown of MAGEC2 in HCC cell lines to explore the function of MAGEC2 in HCC development. Finally, the expression of epithelial-mesenchymal transition (EMT) markers in HCC xenografts and clinical samples was investigated.ResultsThe results showed a remarkably higher level of MAGEC2 expression in HCC tissues than in noncancerous tissues, and MAGEC2 expression could be used as an independent prognostic factor for overall survival in HCC. Moreover, sh-MAGEC2 inhibited a series of HCC malignant behaviours both in vitro and in vivo. Finally, decreased MAGEC2 expression and low levels of EMT markers were detected in sh-MAGEC2 xenografts, while increased MAGEC2 expression and high levels of EMT markers were observed in invasive and metastatic HCC samples.ConclusionTaken together, our data imply that MAGEC2 is a novel prognostic marker for HCC and that MAGEC2 significantly promotes HCC tumourigenesis by inducing EMT. Targeting MAGEC2 may provide a promising therapeutic strategy for HCC treatment.

Epigenetic silencing of TMEM176A activates ERK signaling in human hepatocellular carcinoma

BackgroundThe role of TMEM176A in human hepatocellular carcinoma (HCC) is unknown. This study explored the epigenetic regulation and function of TMEM176A in human HCC.Materials and methodsTwelve HCC cell lines and 126 cases of primary cancer were analyzed. Methylation-specific PCR, immunohistochemistry, flow cytometry, and xenograft mouse models were employed.ResultsTMEM176A was highly expressed in SNU387, SNU182, Huh1, and SNU475 cells; reduced expression was observed in HepG2 and PLC/PRF/5 cells; and no expression was found in SNU449, HBXF344, SMMC7721, Huh7, and LM3 cells. Unmethylation of the TMEM176A promoter was detected in SNU387, SNU182, Huh1, and SNU475 cells; partial methylation was observed in HepG2 and PLC/PRF/5 cells; and complete methylation was found in SNU449, HBXF344, SMMC7721, Huh7, and LM3 cells. Upon treatment with 5-Aza-2-deoxycytidine, re-expression of TMEM176A was detected in SNU449, HBXF344, SMMC7721, Huh7, and LM3 cells; increased expression of TMEM176A was observed in HepG2 and PLC/PRF/5 cells; and no expression changes were found in SNU387, SNU182, Huh1, and SNU475 cells. The TMEM176A promoter region was methylated in 75.4% (95/126) of primary human HCC. Reduced expression of TMEM176A was associated with promoter region methylation (P < 0.05). No association was found between TMEM176A promoter methylation and age, gender, HBV infection, liver cirrhosis, tumor size, lymph node metastasis, vessel cancerous embolus, number of lesions, and TNM stage (all P > 0.05). These results demonstrated that the expression of TMEM176A is regulated by promoter region methylation. Methylation of the TMEM176A promoter was significantly associated with tumor cell differentiation (P < 0.05) and was an independent prognostic factor for poor 3-year overall survival (OS, P < 0.05). TMEM176A expression induced cell apoptosis; inhibited cell proliferation, migration, and invasion; suppressed human HCC cell xenograft growth in mice; and inhibited ERK signaling in HCC cells.ConclusionThe promoter region of TMEM176A is frequently methylated in human HCC, and the expression of TMEM176A is regulated by promoter region methylation. Methylation of the TMEM176A promoter may serve as a diagnostic and prognostic marker in HCC. TMEM176A suppresses HCC growth by inhibiting the ERK signaling pathway.

Prognostic significance of sodium-potassium ATPase regulator, FXYD3, in human hepatocellular carcinoma.

The clinical significance of the sodium-potassium ATPase regulator FXYD domain-containing ion transport regulator 3 (FXYD3) has been demonstrated in a number of types of cancer. However, the role of this protein in human hepatocellular carcinoma (HCC) remains to be elucidated. In the present study, 217 HCC tissue samples were analyzed to evaluate the expression and prognostic significance of FXYD3 in HCC. Reverse transcription-quantitative polymerase chain reaction was used to analyze the mRNA expression of FXYD3 in 80 primary HCC specimens and paired non-cancerous liver tissue samples, while western blotting was used to analyze the protein expression level of FXYD3 in another 24 pairs. These analyses demonstrated that the expression level of FXYD3 was significantly increasedb at the mRNA and protein levels in HCC tumor tissues compared with adjacent non-cancerous tissues. Immunohistochemical analysis of 137 paraffin-embedded HCC tissue samples indicated that the expression of FXYD3 was associated with HCC clinicopathological characteristics. Kaplan-Meier analysis demonstrated that patients with high FXYD3 protein expression (n=60) experienced significantly poorer overall survival time compared with patients with low FXYD3 protein expression (n=77) (P<0.001). Multivariate analysis demonstrated that FYXD3 protein expression level (hazard ratio, 2.137; 95% confidence interval, 1.224–3.732; P=0.008) was an independent prognostic factor in patients with HCC. Overall, the results indicated that FXYD3 expression levels were higher in HCC tumor tissues than in adjacent non-cancerous tissues, and that the FXYD3 protein may serve as a prognostic marker for HCC.

MiR-1247-5p functions as a tumor suppressor in human hepatocellular carcinoma by targeting Wnt3.

Increasing evidence suggests that aberrant expression of certain microRNAs (miRNAs) may participate in the genesis and progression of tumors. Several studies have indicated that miR-1247-5p plays different roles in various types of cancer cells. The effects of miR-1247-5p on human hepatocellular carcinoma (HCC) cells are elusive. In the present study, we investigated the effects of miR-1247-5p on the progression of HCC. The transcript of miR-1247-5p was markedly downregulated in clinical samples of patients with HCC and HCC cell lines, and ectopic overexpression of miR‑1247-5p markedly inhibited the proliferation and invasion of HepG2 cells, induced cell apoptosis invitro, and suppressed the growth of transplanted tumors invivo. Wnt3 was found to be a potential target of miR-1247-5p and overexpression of miR-1247-5p was able to significantly downregulate the expression of Wnt3 by directly targeting the 3'UTR of this gene, which was verified by luciferase reporter assay and western blotting. Furthermore, we found that the miR-1247-5p gene was hypermethylated in HepG2 cells, and the transcript of miR-1247-5p was increased significantly after treatment with the demethylation drug 5-azacytidine. These findings demonstrated that miR-1247-5p functions as a tumor suppressor in human HCC by targeting Wnt3 and that the expression of miR-1247-5p can be regulated by DNA methylation, which indicates that miR-1247-5p has the potential to be a therapeutic target as well as a diagnostic marker of HCC.

Methylation of S100A8 is a promising diagnosis and prognostic marker in hepatocellular carcinoma.

The abnormality of DNA methylation is one of the major epigenetic alterations in the human hepatocellular carcinoma (HCC). We have assessed the global genomic DNA methylation profiles in human HCC patients by using the Infinium Human Methylation27 BeadChip. A CpG loci of S100A8 was found to be significantly hypomethylated in HCC.Pooled meta-analysis of five validation public datasets demonstrated its methylation level was significantly lower for HCC compared to paired adjacent normal tissues. Quantitative pyrosequencing analysis also showed that the S100A8 methylation level was decreased in cancer tissues (31.90%±13.31%) than that in the paired adjacent normal tissues (65.33%±3.64%, p<0.01). The area under the ROC curve (AUC) value was 0.950 (p<0.01). Kaplan-Meier survival curves revealed that hypomethylation of S100A8 was associated with shortened overall survival (OS) and progression-free survival (PFS) (log rank p<0.05). Multivariate Cox proportional hazards model also indicated significantly shorter OS (HR, 1.709; 95 % CI, 1.127–2.591) and PFS (HR, 1.767; 95 % CI, 1.168–2.974) were observed in the low-methylation-level group compared to the high-methylation-level group. Furthermore, S100A8 overexpression in Huh7 and MHCC-97H hepatoma cell lines led to increased cell proliferation, migration, invasion, and tumor growth. These findings suggested S100A8 methylation to be served as potential diagnosis and prognosis marker for HCC. S100A8 also may play as a tumor promoter in HCC.

PRSS8 is Downregulated and Suppresses Tumour Growth and Metastases in Hepatocellular Carcinoma

Background: Protease serine 8 (PRSS8), a trypsin-like serine peptidase, has been shown to function as a tumour suppressor in various malignancies. The present study aimed to investigate the expression pattern, prognostic value and the biological role of PRSS8 in human hepatocellular carcinoma (HCC). Methods: PRSS8 expression in 106 HCC surgical specimens was examined by Real-time polymerase chain reaction (PCR) and immunohistochemistry, and its clinical significance was analysed. The role of PRSS8 in cell proliferation, apoptosis and invasion were examined in vitro and in vivo. Results: PRSS8 mRNA and protein expression were decreased in most HCC tumours from that in matched adjacent non-tumour tissues. Low intratumoral PRSS8 expression was significantly correlated with poor overall survival (OS) in patients with HCC (P = 0.001). PRSS8 expression was an independent prognostic factor for OS (hazard ratio [HR] = 1.704, P = 0.009). Furthermore, restoring PRSS8 expression in high metastatic HCCLM3 cells significantly inhibited cell proliferation and invasion. In contrast, silencing PRSS8 expression in non-metastatic HepG2 cells significantly enhanced cell growth and invasion. Moreover, our in vivo data revealed that attenuated PRSS8 expression in HepG2 cells greatly promoted tumour growth, while overexpression of PRSS8 remarkably inhibited tumour growth in an HCCLM3 xenograft model. Enhanced cell growth and invasion ability mediated by the loss of PRSS8 expression was associated with downregulation of PTEN, Bax and E-cadherin and an upregulation in Bcl-2, MMP9 and N-cadherin. Conclusions: Our data demonstrate that PRSS8 may serve as a tumour suppressor in HCC progression, and represent a valuable prognostic marker and potential therapeutic target for HCC.

Upregulation of Long Non-Coding RNA PlncRNA-1 Promotes Metastasis and Induces Epithelial-Mesenchymal Transition in Hepatocellular Carcinoma

Background/Aims: PlncRNA-1 has been demonstrated to promote malignancy in various cancers. The present study aims to investigate the expression pattern, prognosis value and the function of PlncRNA-1 in human hepatocellular carcinoma (HCC). Methods: The expression of PlncRNA-1 in 84 pairs of HCC and their matched normal tissues was examined by quantitative real-time polymerase chain reaction (qRT-PCR). The correlations of PlncRNA-1 expression and clinicopathological characteristics and prognosis were also analyzed. The biological role of PlncRNA-1 in cell proliferation, migration and invasion was examined in vitro and in vivo. Results: The results showed that the level of PlncRNA-1 expression was significantly increased in HCC tissues and significantly correlated with tumor size, vascular invasion and advanced TNM stage. Moreover, patients with high levels of PlncRNA-1 expression had relatively poor prognostic outcomes, serving as an independent prognostic factor for HCC. In vitro functional assays indicated that knockdown of PlncRNA-1 expression significantly reduced cell proliferation, migration and invasion by inhibiting the epithelial-mesenchymal transition (EMT) signaling. Animal model experiments confirmed the ability of PlncRNA-1 to promote tumor growth in vivo. Conclusions: Taken together, our findings suggest that PlncRNA-1 may serve as an oncogene in HCC progression and represent a valuable prognostic marker and potential therapeutic target for HCC.

Wisp1 as an early stage marker of human hepatocellular carcinoma (HCC)?

Microarray analysis of TGF-β treated mouse hepatocytes revealed Wisp1 as the most regulated gene. As TGF-β is upregulated during HCC development and progression, we analyzed Wisp1 expression and function in HCC.

The metabolic gene HAO2 is downregulated in hepatocellular carcinoma and predicts metastasis and poor survival

l-2-Hydroxy acid oxidases are flavin mononucleotide-dependent peroxisomal enzymes, responsible for the oxidation of l-2-hydroxy acids to ketoacids, resulting in the formation of hydrogen peroxide. We investigated the role of HAO2, a member of this family, in rat, mouse and human hepatocarcinogenesis. We evaluated Hao2 expression by qRT-PCR in the following rodent models of hepatocarcinogenesis: the Resistant-Hepatocyte, the CMD and the chronic DENA rat models, and the TCPOBOP/DENA and TCPOBOP only mouse models. Microarray and qRT-PCR analyses were performed on two cohorts of human hepatocellular carcinoma (HCC) patients. Rat HCC cells were transduced by a Hao2 encoding lentiviral vector and grafted in mice. Downregulation of Hao2 was observed in all investigated rodent models of hepatocarcinogenesis. Interestingly, Hao2 mRNA levels were also profoundly downregulated in early preneoplastic lesions. Moreover, HAO2 mRNA levels were strongly downregulated in two distinct series of human HCCs, when compared to both normal and cirrhotic peri-tumoral liver. HAO2 levels were inversely correlated with grading, overall survival and metastatic ability. Finally, exogenous expression of Hao2 in rat cells impaired their tumorigenic ability. Our work identifies for the first time the oncosuppressive role of the metabolic gene Hao2. Indeed, its expression is severely decreased in HCC of different species and etiology, and its reintroduction in HCC cells profoundly impairs tumorigenesis. We also demonstrate that dysregulation of HAO2 is a very early event in the development of HCC and it may represent a useful diagnostic and prognostic marker for human HCC.