Downregulation of CYP39A1 Serves as a Novel Biomarker in Hepatocellular Carcinoma with Worse Clinical Outcome

Background. CYP39A1 is a poorly characterized metabolic enzyme that has been investigated in a few tumors. However, the role of CYP39A1 in hepatocellular carcinoma (HCC) has not yet been clarified. In this study, the expression and clinical significance of CYP39A1 in HCC were explored. Methods. CYP39A1 protein expression was detected in Akt/c-Met-induced HCC mice and 14 paired fresh HCC samples as well as another 159 HCC and matched noncancerous tissues. Meanwhile, the mRNA expression was analyzed by GEO and TCGA analysis and validated in 14 paired fresh HCC tissues. Furthermore, the relationships between CYP39A1 expression and clinicopathologic features as well as prognosis were analyzed. HCC cell growth changes were analyzed by cell viability assays after CYP39A1 overexpression and then validated after CYP39A1 knockout by DepMap database analysis. Results. CYP39A1 protein expression was lower expressed in HCC mouse models, and its mRNA and protein expression were also downregulated in HCC compared with noncancerous liver tissues. Higher CYP39A1 expression was associated with well differentiation. Moreover, survival analysis indicated that lower CYP39A1 expression was associated with poorer overall survival. In addition, HepG2 and SMMC-7721 cell viability were inhibited after CYP39A1 overexpression. Genome-wide CRISPR/Cas9 proliferation screening indicated that knockout of CYP39A1 could promote HCC cell growth. Likewise, p-NF-κB and Nrf2 were suppressed after CYP39A1 overexpression. It is worth mentioning that total bile acid, total bilirubin, and direct bilirubin were significantly increased in the patients with low CYP39A1 expression. Conclusions. Downregulation of CYP39A1 is associated with HCC carcinogenesis, tumor differentiation, and poor overall survival, suggesting that CYP39A1 may serve as a tumor suppressor gene and novel biomarker for HCC patients.

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High Expression of LTBP2 Contributes to Poor Prognosis in Colorectal Cancer Patients and Correlates with the Mesenchymal Colorectal Cancer Subtype

Disease Markers ◽

10.1155/2019/5231269 ◽

2019 ◽

Vol 2019 ◽

pp. 1-9 ◽

Cited By ~ 1

Author(s):

Ying Huang ◽

Guihua Wang ◽

Chunmei Zhao ◽

Rong Geng ◽

Shu Zhang ◽

...

Keyword(s):

Colorectal Cancer ◽

Overall Survival ◽

Protein Expression ◽

Mrna Expression ◽

Cell Lines ◽

Critical Role ◽

Prognostic Significance ◽

Poor Overall Survival ◽

Expression Levels ◽

Mrna And Protein Expression

Colorectal cancer (CRC) is a complex and heterogeneous disease with four consensus molecular subtypes (CMS1-4). LTBP2 is a member of the fibrillin/LTBP super family and plays a critical role in tumorigenesis by activating TGF-β in the CMS4 CRC subtype. So far, the expression and prognostic significance of LTBP2 in CRC remains obscure. In this study, we aimed to analyze the mRNA and protein expression levels of LTBP2 in CRC tissues and then estimate their values as a potential prognostic biomarker. We detected the mRNA expression of LTBP2 in 28 cases of fresh CRC tissues and 4 CRC cell lines and the protein expression of LTBP2 in 483 samples of CRC tissues, matched tumor-adjacent tissues, and benign colorectal diseases. LTBP2 protein expression was then correlated to patients’ clinical features and overall survival. Both LTBP2 mRNA and protein expression levels in CRC tissues were remarkably superior to those in adjacent normal colorectal tissues (P=0.0071 and P<0.001, respectively), according to TCGA dataset of CRC. High LTBP2 protein expression was correlated with TNM stage (P<0.001), T stage (P<0.001), N stage (P<0.001), and M stage (P<0.001). High LTBP2 protein expression was related to poor overall survival in CRC patients and was an independent prognostic factor for CRC. LTBP2 mRNA expression was especially higher in the CMS4 subtype (P<0.001), which was confirmed in CRC cell lines. Our data suggested that LTBP2 may act as an oncogene in the development of colorectal cancer and have important significance in predicting CRC prognosis. LTBP2 could be a novel biomarker and potential therapeutic target for mesenchymal colorectal cancer and can improve the outcome of high-risk CRC.

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Serum from Chronic Hepatitis B Patients Promotes Growth and Proliferation via the IGF-II/IGF-IR/MEK/ERK Signaling Pathway in Hepatocellular Carcinoma Cells

Cellular Physiology and Biochemistry ◽

10.1159/000489744 ◽

2018 ◽

Vol 47 (1) ◽

pp. 39-53 ◽

Cited By ~ 5

Author(s):

Yuanyuan Ji ◽

Zhidong Wang ◽

Haiyan Chen ◽

Lei Zhang ◽

Fei Zhuo ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Cell Proliferation ◽

Chronic Hepatitis ◽

Cell Growth ◽

Hepatitis B ◽

Protein Expression ◽

Molecular Mechanisms ◽

Erk Signaling ◽

Mrna And Protein Expression ◽

Hcc Cells

Background/Aims: Chronic hepatitis B virus (HBV) infection (CHB) plays a central role in the etiology of hepatocellular carcinoma (HCC). Emerging evidence implicates insulin-like growth factor (IGF)-II as a major risk factor for the growth and development of HCC. However, the relationship between HBV infection and IGF-II functions remains to be elucidated. Methods: Levels of circulating IGF-II and IGF-I receptor (IGF-IR) in healthy donors (HDs) and CHB patients were tested by ELISA. Human HCC cell lines (HepG-2, SMMC-7721, MHCC97-H) were incubated with serum from HDs and CHB patients at various concentrations for 24, 48, and 72 h. MTT and plate colony formation assays, BrdU ELISA, ELISA, small-interfering RNA (siRNA) transfection, quantitative real-time PCR, and western blot were applied to assess the functional and molecular mechanisms in HCC cell lines. Results: Serum levels of IGF-II and IGF-IR were significantly higher in CHB patients than in HDs. Additionally, serum from CHB patients directly induced cell growth, proliferation, IGF-II secretion, and HDGF-related protein-2 (HRP-2) and nuclear protein 1 (NUPR1) mRNA and protein expression in HCC cells. Moreover, serum from CHB patients increased IGF-II–induced cell growth, proliferation, and HRP-2 and NUPR1 mRNA and protein expression in HCC cells. Blockade of IGF-IR clearly inhibited the above effects. Most importantly, interference with IGF-II function markedly repressed the cell proliferation and HRP-2 and NUPR1 mRNA and protein expression induced by serum from CHB patients. Furthermore, serum from CHB patients induced ERK phosphorylation via IGF-IR, with the MEK inhibitor PD98059 significantly decreasing CHB patient serum-induced IGF-II secretion, cell proliferation, and HRP-2 and NUPR1 mRNA and protein expression. Conclusion: Serum from CHB patients increases cell growth and proliferation and enhances HRP-2 and NUPR1 expression in HCC cells via the IGF-II/IGF-IR/MEK/ERK signaling pathway. These findings help to explain the molecular mechanisms underlying HBV-related HCC and may lead to the development of effective therapies.

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Downregulation of MicroRNA-145 Caused by Hepatitis B Virus X Protein Promotes Expression of CUL5 and Contributes to Pathogenesis of Hepatitis B Virus-Associated Hepatocellular Carcinoma

Cellular Physiology and Biochemistry ◽

10.1159/000438522 ◽

2015 ◽

Vol 37 (4) ◽

pp. 1547-1559 ◽

Cited By ~ 23

Author(s):

Feng Gao ◽

Xiaoyu Sun ◽

Likun Wang ◽

Shunxiong Tang ◽

Changqing Yan

Keyword(s):

Hepatocellular Carcinoma ◽

Hepatitis B Virus ◽

Cell Growth ◽

Hepatitis B ◽

Protein Expression ◽

Host Cells ◽

Luciferase Reporter ◽

X Protein ◽

B Virus ◽

Mrna And Protein Expression

Background: Hepatitis B viral infection-induced hepatocellular carcinoma (HCC) is a major threat to human health in China. Hepatitis B virus X protein (HBX), an HBV protein, has been reported to be involved in regulating the cellular activities of the host cells and is responsible for HCC oncogenesis. Methods and Results: In this study, we performed real-time PCR in tumor tissue samples collected from 53 HCC patients (25 HBV-positive cases and 28 HBV-negative cases) to screen the candidate miRNAs that have previously been reported to be aberrantly expressed in HBV-associated HCC and found that miR-145 was significantly downregulated. The following computational analysis identified CUL5 and RAB5C as virtual targets of miR-145, whereas only CUL5 was verified as a validated target gene of miR-145 in liver cells via luciferase reporter assay. In line with this result, we found that both the mRNA and protein expression levels of CUL5 were significantly higher in HBV-positive than in HBV-negative HCC. An in vitro experiment demonstrated a significant decrease in the expression of miRNA-145, a substantial increase in the mRNA and protein expression of CUL5, and an enhanced proliferation of HBX over-expressing HepG2 cells compared with the control. In HepG2.2.15, we found significant decreases in both the expression of CUL5 and the cell growth rate of H cells transfected with 60 nM miR-145 mimics compared with the scramble controls. Conclusion: HBV infection promotes cell growth, at least partially, through the HBX-induced downregulation of miRNA-145 expression, which is responsible for the oncogenesis of HBV-associated HCC.

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Clinical significance of high expression of stanniocalcin-2 in hepatocellular carcinoma

Bioscience Reports ◽

10.1042/bsr20182057 ◽

2019 ◽

Vol 39 (4) ◽

Cited By ~ 1

Author(s):

Yuan Wang ◽

Jian Wu ◽

Jiangyan Xu ◽

Shengyou Lin

Keyword(s):

Hepatocellular Carcinoma ◽

Overall Survival ◽

Portal Vein ◽

Protein Expression ◽

High Expression ◽

Tumor Diameter ◽

Tumor Differentiation ◽

Rt Pcr ◽

Mrna And Protein Expression ◽

Stanniocalcin 2

Abstract To investigate the significance of stanniocalcin-2 (STC2) expression in hepatocellular carcinoma (HCC) tissues and adjacent tissues. Levels of STC2 in HCC tissue were detected in 200 HCC patients tissues and adjacent tissues as controls by immunohistochemistry technique (IHC) and reverse transcriptase-PCR (RT-PCR). Single factor analysis was used to study the relationship between expression of STC2 mRNA and protein and clinicopathological features of HCC. Multifactor Cox survival analysis was used to relationship between the expression of STC2 and overall survival of postoperative patients with HCC. IHC staining showed that the expression of STC2 protein rate was 81.00% (163/200). And the positive rate of adjacent tissues was 29.00% (58/200). Western blot showed that the expression of STC2 protein in HCC was significantly higher than that in the adjacent tissues (P<0.05). RT-PCR showed that the positive rates of STC2 mRNA expression in HCC were 75.50% (151/200), which was significantly higher than that in adjacent tissues 14.50% (29/200) (P<0.05). Both STC2 mRNA and protein expression are related to tumor diameter, stage, tumor metastasis, carcinoma emboli in the portal vein and the degree of tumor differentiation in HCC. The HCC patients with higher expression of STC2 had shorter median survival time. STC2 expression, tumor diameter, carcinoma emboli in the portal vein, tumor differentiation degree, and tumor stage were independent factors affecting the overall survival of postoperative patients. The high expression of STC2 mRNA and protein expression in HCC may be associated with the occurrence, development, and prognosis of HCC. STC2 may also be possible to help developing new therapeutic strategies for HCC.

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Hepatoblastoma: glutamine depletion hinders cell viability in the embryonal subtype but high GLUL expression is associated with better overall survival

Journal of Cancer Research and Clinical Oncology ◽

10.1007/s00432-021-03713-4 ◽

2021 ◽

Author(s):

Andreas Schmidt ◽

Angela Armento ◽

Ovidio Bussolati ◽

Martina Chiu ◽

Verena Ellerkamp ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Overall Survival ◽

Growth Inhibition ◽

Cell Viability ◽

Cell Lines ◽

Prognostic Significance ◽

Asparagine Synthetase ◽

Inhibition Of Proliferation ◽

Its Gene ◽

Glutamine Synthesis

Abstract Purpose Glutamine plays an important role in cell viability and growth of various tumors. For the fetal subtype of hepatoblastoma, growth inhibition through glutamine depletion was shown. We studied glutamine depletion in embryonal cell lines of hepatoblastoma carrying different mutations. Since asparagine synthetase was identified as a prognostic factor and potential therapeutic target in adult hepatocellular carcinoma, we investigated the expression of its gene ASNS and of the gene GLUL, encoding for glutamine synthetase, in hepatoblastoma specimens and cell lines and investigated the correlation with overall survival. Methods We correlated GLUL and ASNS expression with overall survival using publicly available microarray and clinical data. We examined GLUL and ASNS expression by RT-qPCR and by Western blot analysis in the embryonal cell lines Huh-6 and HepT1, and in five hepatoblastoma specimens. In the same cell lines, we investigated the effects of glutamine depletion. Hepatoblastoma biopsies were examined for histology and CTNNB1 mutations. Results High GLUL expression was associated with a higher median survival time. Independent of mutations and histology, hepatoblastoma samples showed strong GLUL expression and glutamine synthesis. Glutamine depletion resulted in the inhibition of proliferation and of cell viability in both embryonal hepatoblastoma cell lines. ASNS expression did not correlate with overall survival. Conclusion Growth inhibition resulting from glutamine depletion, as described for the hepatoblastoma fetal subtype, is also detected in established embryonal hepatoblastoma cell lines carrying different mutations. At variance with adult hepatocellular carcinoma, in hepatoblastoma asparagine synthetase has no prognostic significance.

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THU0097 The discrepancy between mrna and protein expression of the tumour-suppressor gene maspin in synovial tissue might contribute to synovial hyperplasia in rheumatoid arthritis (ra)

10.1136/annrheumdis-2001.974 ◽

2001 ◽

Author(s):

J Schedel ◽

E Jeisy Walder ◽

B Simmen ◽

BA Michel ◽

RE Gay ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Protein Expression ◽

Synovial Tissue ◽

Suppressor Gene ◽

Tumour Suppressor Gene ◽

Tumour Suppressor ◽

Synovial Hyperplasia ◽

Mrna And Protein Expression

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Sirt1 deacetylates and stabilizes p62 to promote hepato-carcinogenesis

Cell Death and Disease ◽

10.1038/s41419-021-03666-z ◽

2021 ◽

Vol 12 (4) ◽

Author(s):

Lifeng Feng ◽

Miaoqin Chen ◽

Yiling Li ◽

Muchun Li ◽

Shiman Hu ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Overall Survival ◽

Cell Growth ◽

Knockout Mice ◽

Liver Tumors ◽

Underlying Mechanism ◽

Carcinoma Cells ◽

Conditional Knockout

Abstractp62/SQSTM1 is frequently up-regulated in many cancers including hepatocellular carcinoma. Highly expressed p62 promotes hepato-carcinogenesis by activating many signaling pathways including Nrf2, mTORC1, and NFκB signaling. However, the underlying mechanism for p62 up-regulation in hepatocellular carcinoma remains largely unclear. Herein, we confirmed that p62 was up-regulated in hepatocellular carcinoma and its higher expression was associated with shorter overall survival in patients. The knockdown of p62 in hepatocellular carcinoma cells decreased cell growth in vitro and in vivo. Intriguingly, p62 protein stability could be reduced by its acetylation at lysine 295, which was regulated by deacetylase Sirt1 and acetyltransferase GCN5. Acetylated p62 increased its association with the E3 ligase Keap1, which facilitated its poly-ubiquitination-dependent proteasomal degradation. Moreover, Sirt1 was up-regulated to deacetylate and stabilize p62 in hepatocellular carcinoma. Additionally, Hepatocyte Sirt1 conditional knockout mice developed much fewer liver tumors after Diethynitrosamine treatment, which could be reversed by the re-introduction of exogenous p62. Taken together, Sirt1 deacetylates p62 at lysine 295 to disturb Keap1-mediated p62 poly-ubiquitination, thus up-regulating p62 expression to promote hepato-carcinogenesis. Therefore, targeting Sirt1 or p62 is a reasonable strategy for the treatment of hepatocellular carcinoma.

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