scholarly journals BAP31 Promotes Tumor Cell Proliferation by Stabilizing SERPINE2 in Hepatocellular Carcinoma

2020 ◽  
Vol 8 ◽  
Author(s):  
Xiyang Zhang ◽  
Dongbo Jiang ◽  
Shuya Yang ◽  
Yuanjie Sun ◽  
Yang Liu ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cell Proliferation ◽  
Tumor Growth ◽  
Tumor Cell ◽  
Colony Formation ◽  
Clinical Stage ◽  
Tumor Cell Proliferation ◽  
Ki 67 ◽  
Hcc Cells

Hepatocellular carcinoma (HCC) patients are mostly diagnosed at an advanced stage, resulting in systemic therapy and poor prognosis. Therefore, the identification of a novel treatment target for HCC is important. B-cell receptor-associated protein 31 (BAP31) has been identified as a cancer/testis antigen; however, BAP31 function and mechanism of action in HCC remain unclear. In this study, BAP31 was demonstrated to be upregulated in HCC and correlated with the clinical stage. BAP31 overexpression promoted HCC cell proliferation and colony formation in vitro and tumor growth in vivo. RNA-sequence (RNA-seq) analysis demonstrated that serpin family E member 2 (SERPINE2) was downregulated in BAP31-knockdown HCC cells. Coimmunoprecipitation and immunofluorescence assays demonstrated that BAP31 directly binds to SERPINE2. The inhibition of SERPINE2 significantly decreased the BAP31-induced cell proliferation and colony formation of HCC cells and phosphorylation of Erk1/2 and p38. Moreover, multiplex immunohistochemistry staining of the HCC tissue microarray showed positive associations between the expression levels of BAP31, SERPINE2, its downstream gene LRP1, and a tumor proliferation marker, Ki-67. The administration of anti-BAP31 antibody significantly inhibited HCC cell xenograft tumor growth in vivo. Thus, these findings suggest that BAP31 promotes tumor cell proliferation by stabilizing SERPINE2 and can serve as a promising candidate therapeutic target for HCC.

Expression of β-Catenin in Hepatocellular Carcinoma

2001 ◽  
Vol 71 (3) ◽  
pp. 116-125
Author(s):  
Norina Basa ◽  
Daniela Lazar ◽  
Remus Cornea ◽  
Sorina Taban ◽  
Melania Ardelean ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cell Proliferation ◽  
Tumor Cell ◽  
Mitotic Index ◽  
Histological Grade ◽  
Proliferation Index ◽  
Tumor Cell Proliferation ◽  
Ki 67 ◽  
B Virus ◽  
Development And Evolution

Alteration of β-catenin expression is involved in the development and evolution of hepatocellular carcinoma (HCC); β-catenin is able to influence tumor cell proliferation. We analyzed the immunohistochemical (IHC) expression of β-catenin on a group of 32 patients diagnosed with HCC using the anti-β-catenin monoclonal antibody (clone E247). We correlated the expression of β-catenin with the proliferation index of Ki-67 (PI Ki-67), the mitotic index (MI) and other clinical and pathological features. We observed an altered β-catenin expression in 58.38% of all HCC cases. This expression was insignificantly correlated with tumor size (]5 cm) (p = 0.683), histological grade G1-G2 (p = 0.307), vascular invasion (p = 0.299) and advanced pT stage (p = 0.453); we obtained a significantly higher MI in HCC with altered β-catenin expression (p = 0.018), as compared to HCC without overexpression (1.66 � 1.37) (p = 0.038) and a PI Ki-67 of 22.49 � 20.1 and 28.24 � 18.2, respectively in tumors with altered β-catenin expression with insignificant differences compared to HCC without overexpression (25.95 � 15.2) (p = 0.682 and p = 0.731, respectively). According to the results we obtained, aberrant β-catenin expression in HCC was correlated with a high mitotic index, therefore playing an important role in tumor progression by stimulating tumor cell proliferation; non-nuclear β-catenin overexpression can have a pathological significance in HCC, especially in cases of HCC associated with hepatitis B virus (HBV) infection.

scholarly journals KLF7/VPS35 axis contributes to hepatocellular carcinoma progression through CCDC85C-activated β-catenin pathway

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Yarong Guo ◽  
Bao Chai ◽  
Junmei Jia ◽  
Mudan Yang ◽  
Yanjun Li ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cell Proliferation ◽  
Tumor Growth ◽  
Luciferase Reporter ◽  
Aberrant Expression ◽  
Proliferation And Invasion ◽  
Hcc Cells

Abstract Objective Dysregulation of KLF7 participates in the development of various cancers, but it is unclear whether there is a link between HCC and aberrant expression of KLF7. The aim of this study was to investigate the role of KLF7 in proliferation and migration of hepatocellular carcinoma (HCC) cells. Methods CCK8, colony growth, transwell, cell cycle analysis and apoptosis detection were performed to explore the effect of KLF7, VPS35 and Ccdc85c on cell function in vitro. Xenografted tumor growth was used to assess in vivo role of KLF7. Chip-qPCR and luciferase reporter assays were applied to check whether KLF7 regulated VPS35 at transcriptional manner. Co-IP assay was performed to detect the interaction between VPS35 and Ccdc85c. Immunohistochemical staining and qRT-PCR analysis were performed in human HCC sampels to study the clinical significance of KLF7, VPS35 and β-catenin. Results Firstly, KLF7 was highly expressed in human HCC samples and correlated with patients’ differentiation and metastasis status. KLF7 overexpression contributed to cell proliferation and invasion of HCC cells in vitro and in vivo. KLF7 transcriptional activation of VPS35 was necessary for HCC tumor growth and metastasis. Further, co-IP studies revealed that VPS35 could interact with Ccdc85c in HCC cells. Rescue assay confirmed that overexpression of VPS35 and knockdown of Ccdc85c abolished the VPS35-medicated promotion effect on cell proliferation and invasion. Finally, KLF7/VPS35 axis regulated Ccdc85c, which involved in activation of β-catenin signaling pathway, confirmed using β-catenin inhibitor, GK974. Functional studies suggested that downregulation of Ccdc85c partly reversed the capacity of cell proliferation and invasion in HCC cells, which was regulated by VPS35 upregulation. Lastly, there was a positive correlation among KLF7, VPS35 and active-β-catenin in human HCC patients. Conclusion We demonstrated that KLF7/VPS35 axis promoted HCC cell progression by activating Ccdc85c-medicated β-catenin pathway. Targeting this signal axis might be a potential treatment strategy for HCC.

scholarly journals ACTN1 Supports Tumor Growth by Inhibiting Hippo Signaling in Hepatocellular Carcinoma

2020 ◽  
Author(s):  
Qian Chen ◽  
Xiao-Wei Zhou ◽  
Ai-Jun Zhang ◽  
Kang He
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cell Proliferation ◽  
Tumor Growth ◽  
Expression Pattern ◽  
Cytoskeletal Proteins ◽  
Gene Set Enrichment Analysis ◽  
Hippo Signaling ◽  
Hcc Cells

Abstract Background: Alpha actinins (ACTNs) are major cytoskeletal proteins and exhibit many non-muscle functions. Emerging evidence have uncovered the regulatory role of ACTNs in tumorigenesis, however, the expression pattern, biological functions, and underlying mechanism of ACTN1 in hepatocellular carcinoma (HCC) remain largely unexplored.Methods: Immunohistochemical analysis of a HCC tissue microarray (n = 157) was performed to determine the expression pattern and prognostic value of ACTN1 in HCC. In vitro loss-of-function study in HCC cells were carried out to investigate ACTN1 knockdown on cell proliferation. In vivo subcutaneous xenograft model and intrahepatic transplantation model were generated to decipher the contribution of ACTN1 in the tumor growth of HCC. Gene set enrichment analysis, quantitative real-time PCR, Co-immunoprecipitation, immunofluorescence and western blotting were performed to identify the underlying molecular mechanism.Results: It was found that ACTN1 was significantly upregulated in HCC tissues and closely related to llpha-fetoprotein level, tumor thrombus, tumor size, TNM stage and patient prognoses. Knockdown of ACTN1 suppressed in vitro cell proliferation and in vivo tumor growth of HCC cells. Mechanistically, knockdown of ACTN1 increased Hippo signaling pathway activity and decrease Rho GTPases activities. Mechanistically, ACTN1 could competitively interact with MOB1 and decrease the phosphorylation of LATS1 and YAP. The growth-promoting effect induced by ACTN1 was significantly abrogated by pharmacological inhibition of YAP with verteporfin or super-TDU.Conclusions: ACTN1 is highly expressed in HCC tissues and acts as a tumor promoter by suppressing Hippo signaling via physical interaction with MOB1. ACTN1 may serve as a potential prognostic marker and therapeutic target for HCC.

scholarly journals Kruppel-like factor 6 suppresses growth and invasion of hepatocellular carcinoma cells in vitro and in vivo

2016 ◽  
Vol 29 (4) ◽  
pp. 666-675 ◽  
Author(s):  
Pei-Hao Wen ◽  
Dong-Yu Wang ◽  
Jia-Kai Zhang ◽  
Zhi-Hui Wang ◽  
Jie Pan ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cell Proliferation ◽  
Tumor Growth ◽  
Tumor Model ◽  
Carcinoma Cells ◽  
Tumor Suppressive Function ◽  
Xenograft Tumor Growth ◽  
Hcc Cells

Kruppel-like factor 6 (KLF6) as a novel tumor suppressive gene participates in multiple biological behaviors and plays an important role in regulating tumor cell growth and invasion. However, the functions of KLF6 in hepatocellular carcinoma (HCC) remain poorly understood. The expression level of KLF6 was examined by immunohistochemical assay in human HCC tissues, and KLF6-overexpressed HCC cells (SMCC-7721 and HepG2) were used for evaluating cell proliferation and invasion by MTT and Transwell assays. A subcutaneous HCC tumor model was established for assessing tumor growth in vivo. Our results showed that the expression of KLF6 was significantly downregulated in HCC tissues compared with the adjacent non-cancerous tissues (50.0% vs. 72.0%, P = 0.034) and negatively associated with the lymph-vascular space invasion (LVSI) in HCC patients ( P = 0.003). Furthermore, overexpression of KLF6 reduced cell proliferation and weakened the cell invasive potential followed with the decreased expression of PCNA and MMP-9 in HCC cells. The in vivo experiment indicated that KLF6 overexpression suppressed the xenograft tumor growth. Therefore, our findings show that KLF6 suppresses growth and invasion of HCC cells in vitro and in vivo, suggesting a tumor suppressive function in HCC and provides the potential therapeutic target for the treatment of HCC.

scholarly journals ACTN1 supports tumor growth by inhibiting Hippo signaling in hepatocellular carcinoma 

2021 ◽  
Author(s):  
Qian Chen ◽  
Xiao-Wei Zhou ◽  
Ai-Jun Zhang ◽  
Kang He
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cell Proliferation ◽  
Tumor Growth ◽  
Expression Pattern ◽  
Cytoskeletal Proteins ◽  
Gene Set Enrichment Analysis ◽  
Hippo Signaling ◽  
Hcc Cells

Abstract Background: Alpha actinins (ACTNs) are major cytoskeletal proteins and exhibit many non-muscle functions. Emerging evidence have uncovered the regulatory role of ACTNs in tumorigenesis, however, the expression pattern, biological functions, and underlying mechanism of ACTN1 in hepatocellular carcinoma (HCC) remain largely unexplored. Methods: Immunohistochemical analysis of a HCC tissue microarray (n = 157) was performed to determine the expression pattern and prognostic value of ACTN1 in HCC. In vitro loss-of-function study in HCC cells were carried out to investigate ACTN1 knockdown on cell proliferation. In vivo subcutaneous xenograft model and intrahepatic transplantation model were generated to decipher the contribution of ACTN1 in the tumor growth of HCC. Gene set enrichment analysis, quantitative real-time PCR, Co-immunoprecipitation, immunofluorescence and western blotting were performed to identify the underlying molecular mechanism. Results: It was found that ACTN1 was significantly upregulated in HCC tissues and closely related to llpha-fetoprotein level, tumor thrombus, tumor size, TNM stage and patient prognoses. Knockdown of ACTN1 suppressed in vitro cell proliferation and in vivo tumor growth of HCC cells. Mechanistically, knockdown of ACTN1 increased Hippo signaling pathway activity and decreased Rho GTPases activities. Mechanistically, ACTN1 could competitively interact with MOB1 and decrease the phosphorylation of LATS1 and YAP. The growth-promoting effect induced by ACTN1 was significantly abrogated by pharmacological inhibition of YAP with verteporfin or super-TDU. Conclusions: ACTN1 is highly expressed in HCC tissues and acts as a tumor promoter by suppressing Hippo signaling via physical interaction with MOB1. ACTN1 may serve as a potential prognostic marker and therapeutic target for HCC.

Expression of epidermal growth factor receptor (EGFR) associates with proliferation, apoptosis, and histologically aggressive features in hepatocellular carcinoma

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 14039-14039
Author(s):  
S. Morinaga ◽  
Y. Nakamura ◽  
N. Sugano ◽  
K. Tsuchida ◽  
M. Shiozawa ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cell Proliferation ◽  
Epidermal Growth Factor Receptor ◽  
Tumor Cell ◽  
Growth Factor Receptor ◽  
Tumor Cell Proliferation ◽  
Curative Surgery ◽  
Ki 67 ◽  
Egfr Expression ◽  
Epidermal Growth

14039 Background: Epidermal growth factor receptor (EGFR) is over-expressed in many types of cancers, plays an important role in the tumorigenesis, and is indicated to be a promising target for cancer therapy. Hepatocellular carcinoma (HCC) is a cancer with one of the worst prognosis, and new therapeutic approaches are required. The aim of this study was to clarify a possible role of EGFR expression on clinico-pathology of HCC. Methods: HCC tissues were obtained from 36 HCC patients (23 men and 13 women, range 45–80 years old) who underwent curative surgery. EGFR status of the tumors was assessed by immunohistochemical (IHC) analysis on formalin-fixed paraffin-embedded tissue. The percentage of positive tumor cells was scored as follows: 0+, no positive tumor cells; 1+, 1–10% positive cells; 2+, 10–50% positive cells; 3+, >50% positive cells. The staining intensity of membrane was evaluated as follows: 0+, negative; 1+, weak; 2+, moderate; 3+, strong. A composite score (EGFR score) was obtained by calculating the sum of these two scores. The tumor cell proliferation and apoptosis were assessed with Ki-67 labeling and ssDNA labeling, respectively. Results: EGFR expression was detected in 33 (91.7%) of 36 tumors. EGFR score ranged from 0 to 6. Higher EGFR score was related with poorer histologic grade (P = 0.005 by Kruskal-Wallis) and advanced pathologic stage (P = 0.038 by Kruskal-Wallis). EGFR score correlated positively with Ki-67 labeling indices (r = 0.358 and P = 0.032 by Spearman), and correlated negatively with apoptosis indices (r = −0.388 and P = 0.019 by Spearman). EGFR score did not affect disease free survival (DFS) or over all survival (OS), after curative surgery. Conclusions: Higher expression of EGFR, assessed with IHC, associates with more aggressive pathologic features, increased tumor cell proliferation, and reduced tumor cell apoptosis. However, further examination is needed to clarify its predictive significance. No significant financial relationships to disclose.

scholarly journals Inhibition of Long Noncoding RNA CRNDE Increases Chemosensitivity of Medulloblastoma Cells by Targeting miR-29c-3p

2020 ◽  
Vol 28 (1) ◽  
pp. 95-102 ◽  
Author(s):  
Xiao-hui Sun ◽  
Wen-jie Fan ◽  
Zong-jian An ◽  
Yong Sun
Keyword(s):  
Cell Proliferation ◽  
Tumor Cell ◽  
Long Noncoding Rna ◽  
Colony Formation ◽  
Noncoding Rna ◽  
Rna Binding ◽  
Migration And Invasion ◽  
Tumor Cell Proliferation ◽  
Transcript Levels

Long noncoding RNA CRNDE (CRNDE) recently emerged as a carcinogenic promoter in various cancers including medulloblastoma. However, the functions and molecular mechanisms of CRNDE to the acquired drug resistance of medulloblastoma are still unclear. The transcript levels of CRNDE were examined in four medulloblastoma cell lines exposed to cisplatin treatment, and IC50 values were calculated. Effects of CRNDE knockdown or miR-29c-3p overexpression on cell viability, colony formation, apoptosis, migration, and invasion were assessed using the CCK-8, colony formation assay, flow cytometry, and Transwell assays, respectively. RNA pulldown and RNA-binding protein immunoprecipitation (RIP) were performed to confirm the molecular interactions between CRNDE and miR-29c-3p involved in medulloblastoma cells. The in vivo role of CRNDE knockdown or miR-29c-3p overexpression on tumor growth and apoptosis was evaluated in a xenograft mouse model of human medulloblastoma. The transcript levels of lncRNA CRNDE were significantly higher in cisplatin-treated tumor cells with higher IC50 values. Depletion of CRNDE inhibited tumor cell proliferation and colony formation, induced cell apoptosis, and suppressed migration and invasion in medulloblastoma cells. Moreover, overexpression of miR-29c-3p inhibited tumor cell proliferation and colony formation, migration, and invasion, and enhanced apoptosis and chemosensitivity to cisplatin. In addition, CRNDE was found to act as a miR-29c-3p sponge. Furthermore, in vivo experiments showed the CRNDE/miR-29c-3p interactions involved in medulloblastoma. Our study demonstrates that CRNDE acts as a critical mediator of proliferation, apoptosis, migration, invasion, and resistance to chemotherapeutics via binding to and negatively regulating miR-29c-3p in medulloblastoma cells. These results provide novel molecular targets for treatment of medulloblastoma.

scholarly journals MiR-93 suppresses cell proliferation and invasion by targeting ZNF322 in human hepatocellular carcinoma

2021 ◽  
Author(s):  
Yong Zhang ◽  
Liangsheng Miao ◽  
Huijuan Zhang ◽  
Gang Wu ◽  
Jianrui Lv
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cell Proliferation ◽  
Overall Survival ◽  
Cell Migration ◽  
Tumor Growth ◽  
Colony Formation ◽  
Luciferase Reporter ◽  
Migration And Invasion ◽  
Over Expression

IntroductionThis study aimed to investigate the biological role of microRNA 93 (miR-93), a novel tumor-related miRNA, in human hepatocellular carcinoma (HCC) and elucidate the potential molecular mechanisms involved.Material and methodsQuantitative real-time polymerase chain reaction (qRT-PCR) was conducted to determine the expression of miR-93 in HCC tissues and cell lines. The log-rank test and Kaplan-Meier survival analysis were performed to evaluate the relationship between miR-93 expression and overall survival. MTT assay, colony formation assay, Transwell migration and invasion assays were carried out to exam cell proliferation, colony formation, migration and invasion, respectively. Murine xenograft models were established to the effect of miR-93 on tumor growth in vivo. TargetScan online software was applied to predict the potential target of miR-93. Luciferase reporter assays were used to validate the direct binding of miR-93 and its putative target.ResultsHere we found that miR-93 was significantly down-regulated in HCC tissues and cell lines. Patients with decreased miR-93 expression had a significantly shorter overall survival. Functional investigations demonstrated miR-93 over-expression suppressed HCC cell proliferation, weakened clonogenic ability, and slowed down cell migration and invasion; whereas miR-93 depletion facilitated HCC cell proliferation, colony formation, cell migration and invasion. MiR-93 over-expression retarded tumor growth in vivo. Luciferase reporter assay and rescue assay revealed that zinc finger protein 322 (ZNF322) was a direct target of miR-93 and mediated the inhibitory effects of miR-93 on HCC cell proliferation and motility.ConclusionsOur data may provide some evidence for miR-93/ZNF322 axis a candidate therapeutic target for HCC.

scholarly journals Tumor cell-intrinsic PD-1 receptor is a tumor suppressor and mediates resistance to PD-1 blockade therapy

2020 ◽  
Vol 117 (12) ◽  
pp. 6640-6650 ◽  
Author(s):  
Xiaodong Wang ◽  
Xiaohui Yang ◽  
Chang Zhang ◽  
Yang Wang ◽  
Tianyou Cheng ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Tumor Suppressor ◽  
Tumor Growth ◽  
Tumor Cell ◽  
Tumor Cells ◽  
Colony Formation ◽  
Immune Escape ◽  
Potential Biomarker

The programmed cell death 1 (PD-1) receptor on the surface of immune cells is an immune checkpoint molecule that mediates the immune escape of tumor cells. Consequently, antibodies targeting PD-1 have shown efficacy in enhancing the antitumor activity of T cells in some types of cancers. However, the potential effects of PD-1 on tumor cells remain largely unknown. Here, we show that PD-1 is expressed across a broad range of tumor cells. The silencing of PD-1 or its ligand, PD-1 ligand 1 (PD-L1), promotes cell proliferation and colony formation in vitro and tumor growth in vivo. Conversely, overexpression of PD-1 or PD-L1 inhibits tumor cell proliferation and colony formation. Moreover, blocking antibodies targeting PD-1 or PD-L1 promote tumor growth in cell cultures and xenografts. Mechanistically, the coordination of PD-1 and PD-L1 activates its major downstream signaling pathways including the AKT and ERK1/2 pathways, thus enhancing tumor cell growth. This study demonstrates that PD-1/PD-L1 is a potential tumor suppressor and potentially regulates the response to anti-PD-1/PD-L1 treatments, thus representing a potential biomarker for the optimal cancer immunotherapeutic treatment.

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