Clinicopathological features of hepatocellular carcinoma with fatty change: Tumors with macrovesicular steatosis have better prognosis and aberrant expression patterns of perilipin and adipophilin

2020 ◽  
Vol 70 (4) ◽  
pp. 199-209 ◽  
Author(s):  
Naoto Kubota ◽  
Hidenori Ojima ◽  
Mami Hatano ◽  
Ken Yamazaki ◽  
Yohei Masugi ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Expression Patterns ◽  
Clinicopathological Features ◽  
Fatty Change ◽  
Aberrant Expression ◽  
Macrovesicular Steatosis

scholarly journals DEPDC1 promotes cell proliferation and suppresses sensitivity to chemotherapy in human hepatocellular carcinoma

2019 ◽  
Vol 39 (7) ◽  
Author(s):  
Chao Zhou ◽  
Pu Wang ◽  
Mengtian Tu ◽  
Yi Huang ◽  
Fei Xiong ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cell Proliferation ◽  
Overall Survival ◽  
Cell Viability ◽  
Cell Apoptosis ◽  
Molecular Mechanisms ◽  
Expression Patterns ◽  
Mechanistic Studies ◽  
Aberrant Expression ◽  
Xenograft Models

Abstract Background: Hepatocellular carcinoma (HCC) is one of the major causes of tumor-related morbidity and mortality worldwide. Accumulating evidence has revealed that aberrant expression of crucial cancer-related genes contributes to hepatocellular carcinogenesis. This study aimed to characterize the biological role of DEP domain containing 1 (DEPDC1), a novel cancer-related gene, in HCC and illuminate the potential molecular mechanisms involved. Materials and methods: Quantitative real-time PCR (qRT-PCR), Western blotting and immunohistochemical (IHC) staining were used to characterize the expression patterns of DEPDC1 in tumorous tissues and adjacent normal tissues. Kaplan–Meier survival analysis was launched to evaluate the relationship between DEPDC1 expression and overall survival. CCK8 assay, colony formation and flow cytometry were performed to investigate the effects of DEPDC1 on HCC cell viability, clonogenic capability and cell apoptosis. Murine xenograft models were established to determine the effect of DEPDC1 on tumor growth in vivo. SP600125, a JNK specific inhibitor, was applied to carriy out mechanistic studies. Results: DEPDC1 was significantly up-regulated in HCC tissues compared with para-cancerous tissues. Besides, patients with high DEPDC1 expression experienced a significantly shorter overall survival. Functional investigations demonstrated that DEPDC1 overexpression facilitated HCC cell proliferation and suppressed cell apoptosis, whereas DEPDC1 depletion inhibited cell proliferation and promoted cell apoptosis. Furthermore, DEPDC1 ablation suppressed tumorigenecity of HCC cells in murine xenograft models. Mechanistic studies uncovered that JNK signaling pathway mediated the promoting effects of DEPDC1 on HCC cell viability and chemotherapy resistance. Conclusion: Collectively, our data may provide some evidence for DEPDC1 as a candidate therapeutic target for HCC.

scholarly journals Histone deacetylase (HDAC) 9: versatile biological functions and emerging roles in human cancer

2021 ◽  
Author(s):  
Chun Yang ◽  
Stéphane Croteau ◽  
Pierre Hardy
Keyword(s):  
Histone Deacetylase ◽  
Posttranslational Modifications ◽  
Histone Deacetylases ◽  
Muscle Development ◽  
Target Genes ◽  
Human Cancer ◽  
Expression Patterns ◽  
Aberrant Expression ◽  
Physiological Processes ◽  
Cancer Pathogenesis

Abstract Background HDAC9 (histone deacetylase 9) belongs to the class IIa family of histone deacetylases. This enzyme can shuttle freely between the nucleus and cytoplasm and promotes tissue-specific transcriptional regulation by interacting with histone and non-histone substrates. HDAC9 plays an essential role in diverse physiological processes including cardiac muscle development, bone formation, adipocyte differentiation and innate immunity. HDAC9 inhibition or activation is therefore a promising avenue for therapeutic intervention in several diseases. HDAC9 overexpression is also common in cancer cells, where HDAC9 alters the expression and activity of numerous relevant proteins involved in carcinogenesis. Conclusions This review summarizes the most recent discoveries regarding HDAC9 as a crucial regulator of specific physiological systems and, more importantly, highlights the diverse spectrum of HDAC9-mediated posttranslational modifications and their contributions to cancer pathogenesis. HDAC9 is a potential novel therapeutic target, and the restoration of aberrant expression patterns observed among HDAC9 target genes and their related signaling pathways may provide opportunities to the design of novel anticancer therapeutic strategies.

scholarly journals Prognostic and clinicopathological significance of hypoxia-inducible factors 1α and 2α in hepatocellular carcinoma: a systematic review with meta-analysis

2021 ◽  
Vol 13 ◽  
pp. 175883592098707
Author(s):  
Carolina Méndez-Blanco ◽  
Paula Fernández-Palanca ◽  
Flavia Fondevila ◽  
Javier González-Gallego ◽  
José L. Mauriz
Keyword(s):  
Hepatocellular Carcinoma ◽  
Subgroup Analysis ◽  
Tumor Size ◽  
Vasculogenic Mimicry ◽  
Disease Free Survival ◽  
Clinicopathological Features ◽  
Hypoxia Inducible Factors ◽  
Free Survival ◽  
Node Metastasis ◽  
Clinicopathological Significance

Background: Hepatocellular carcinoma (HCC) is a highly recurrent tumor after resection and has been closely related to hypoxia. Hypoxia-inducible factors 1α and 2α (HIF-1α and HIF-2α) have been shown to contribute to tumor progression and therapy resistance in HCC. We evaluated the prognostic and clinicopathological significance of HIF-1α and HIF-2α in HCC patients. Methods: We systematically searched Embase, Cochrane, PubMed, Scopus and Web of Science (WOS) from inception to 1 June 2020 for studies evaluating HIF-1α and/or HIF-2α expression in HCC. Selected articles evaluate at least one factor by immunohistochemistry (IHC) in HCC patients who underwent surgical resection, and its relationship with prognosis and/or clinicopathological features. Study protocol was registered in the International Prospective Register of Systematic Reviews (PROSPERO; CDR42020191977). We meta-analyzed the data extracted or estimated according to the Parmar method employing STATA software. We evaluated the overall effect size for the hazard ratio (HR) and odds ratio (OR) with 95% confidence interval (CI), as well as heterogeneity across studies with the I2 statistic and chi-square-based Q test. Moreover, we conducted subgroup analysis when heterogeneity was substantial. Publication bias was assessed by funnel plot asymmetry and Egger’s test. Results: HIF-1α overexpression was correlated with overall survival (OS), disease-free survival (DFS)/recurrence-free survival (RFS) and clinicopathological features including Barcelona Clinic Liver Cancer (BCLC), capsule infiltration, intrahepatic metastasis, lymph node metastasis, tumor–node–metastasis (TNM), tumor differentiation, tumor number, tumor size (3 cm), vascular invasion and vasculogenic mimicry. We also detected a possible correlation of HIF-1α with alpha-fetoprotein (AFP), cirrhosis, histological grade, tumor size (5 cm) and albumin after subgroup analysis. Initially, only DFS/RFS appeared to be associated with HIF-2α overexpression. Subgroup analysis denoted that HIF-2α overexpression was related to OS and capsule infiltration. Conclusions: HIF-1α and HIF-2α overexpression is related to poor OS, DFS/RFS and some clinicopathological features of HCC patients, suggesting that both factors could be useful HCC biomarkers.

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 Clinical features and outcomes of combined hepatocellular carcinoma and cholangiocarcinoma versus hepatocellular carcinoma versus cholangiocarcinoma after surgical resection: a propensity score matching analysis

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Chih-Wen Lin ◽  
Tsung-Chin Wu ◽  
Hung-Yu Lin ◽  
Chao-Ming Hung ◽  
Pei-Min Hsieh ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Liver Cancer ◽  
Propensity Score ◽  
Propensity Score Matching ◽  
Surgical Resection ◽  
Disease Free Survival ◽  
Clinicopathological Features ◽  
Free Survival ◽  
Before And After ◽  
Disease Free

Abstract Background Combined hepatocellular carcinoma and cholangiocarcinoma (cHCC-CC) is an infrequent type of primary liver cancer that comprises hepatocellular carcinoma (HCC) and cholangiocarcinoma (CC). This study investigated the clinicopathological features and prognosis among cHCC-CC, HCC, and CC groups. Methods We prospectively collected the data of 608 patients who underwent surgical resection for liver cancer between 2011 and 2018 at E-Da Hospital, I-Shou University, Kaohsiung, Taiwan. Overall, 505 patients with cHCC-CC, HCC, and CC were included, and their clinicopathological features, overall survival (OS), and recurrence were recorded. OS and recurrence rates were analyzed using the Kaplan–Meier analysis. Results In the entire cohort, the median age was 61 years and 80% were men. Thirty-five (7.0%) had cHCC-CC, 419 (82.9%) had HCC, and 51 (10.1%) had CC. The clinicopathological features of the cHCC-CC group were more identical to those of the HCC group than the CC group. OS was significantly lower in the cHCC-CC group than in the HCC group but was not significantly higher in the cHCC-CC group than in the CC group. The median OS of cHCC-CC, HCC, and CC groups was 50.1 months [95% confidence interval (CI): 38.7–61.2], 62.3 months (CI: 42.1–72.9), and 36.2 months (CI: 15.4–56.5), respectively. Cumulative OS rates at 1, 3, and 5 years in cHCC-CC, HCC, and CC groups were 88.5%, 62.2%, and 44.0%; 91.2%, 76.1%, and 68.0%; and 72.0%, 48.1%, and 34.5%, respectively. After propensity score matching (PSM), OS in the cHCC-CC group was not significantly different from that in the HCC or CC group. However, OS was significantly higher in the HCC group than in the CC group before and after PSM. Furthermore, the disease-free survival was not significantly different among cHCC-CC, HCC, and CC groups before and after PSM. Conclusion The clinicopathological features of the cHCC-CC group were more identical to those of the HCC group than the CC group. The OS rate was significantly lower in the cHCC-CC group than the HCC group. However, after PSM, OS and disease-free survival in the cHCC-CC group were not significantly different from those in the HCC or CC group.

scholarly journals USP29-mediated HIF1α stabilization is associated with Sorafenib resistance of hepatocellular carcinoma cells by upregulating glycolysis

Oncogenesis ◽  
2021 ◽  
Vol 10 (7) ◽  
Author(s):  
Ruize Gao ◽  
David Buechel ◽  
Ravi K. R. Kalathur ◽  
Marco F. Morini ◽  
Mairene Coto-Llerena ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Transcriptional Activity ◽  
Kinase Inhibitor ◽  
Aerobic Glycolysis ◽  
Hypoxia Inducible Factor ◽  
Aberrant Expression ◽  
Key Enzyme ◽  
Hcc Cells

AbstractUnderstanding the mechanisms underlying evasive resistance in cancer is an unmet medical need to improve the efficacy of current therapies. In hepatocellular carcinoma (HCC), aberrant expression of hypoxia-inducible factor 1 α (HIF1α) and increased aerobic glycolysis metabolism are drivers of resistance to therapy with the multi-kinase inhibitor Sorafenib. However, it has remained unknown how HIF1α is activated and how its activity and the subsequent induction of aerobic glycolysis promote Sorafenib resistance in HCC. Here, we report the ubiquitin-specific peptidase USP29 as a new regulator of HIF1α and of aerobic glycolysis during the development of Sorafenib resistance in HCC. In particular, we identified USP29 as a critical deubiquitylase (DUB) of HIF1α, which directly deubiquitylates and stabilizes HIF1α and, thus, promotes its transcriptional activity. Among the transcriptional targets of HIF1α is the gene encoding hexokinase 2 (HK2), a key enzyme of the glycolytic pathway. The absence of USP29, and thus of HIF1α transcriptional activity, reduces the levels of aerobic glycolysis and restores sensitivity to Sorafenib in Sorafenib-resistant HCC cells in vitro and in xenograft transplantation mouse models in vivo. Notably, the absence of USP29 and high HK2 expression levels correlate with the response of HCC patients to Sorafenib therapy. Together, the data demonstrate that, as a DUB of HIF1α, USP29 promotes Sorafenib resistance in HCC cells, in parts by upregulating glycolysis, thereby opening new avenues for therapeutically targeting Sorafenib-resistant HCC in patients.

scholarly journals Cysteine Cathepsins and Their Prognostic and Therapeutic Relevance in Leukemia

2021 ◽  
Author(s):  
Mohit Arora ◽  
Garima Pandey ◽  
Shyam S. Chauhan
Keyword(s):  
Antigen Processing ◽  
Hematological Malignancies ◽  
Expression Patterns ◽  
Aberrant Expression ◽  
Hematopoietic Stem ◽  
Cysteine Cathepsins ◽  
Expression Activity ◽  
Available Information ◽  
Antigen Processing And Presentation ◽  
Selection Of

AbstractCysteine cathepsins are lysosomal proteases that require Cys-His ion pair in their catalytic site for enzymatic activity. While their aberrant expression and oncogenic functions have been widely reported in solid tumors, recent findings suggest that these proteases also play an important role in the pathogenesis of hematological malignancies. In this review, we summarize the potential clinical implications of cysteine cathepsins as diagnostic and prognostic markers in leukemia, and present evidences which supports the utility of these proteases as potential therapeutic targets in hematological malignancies. We also highlight the available information on the expression patterns, regulation, and potential functions of cysteine cathepsins in normal hematopoiesis and hematological malignancies. In hematopoiesis, cysteine cathepsins play a variety of physiological roles including regulation of hematopoietic stem cell adhesion in the bone marrow, trafficking, and maturation. They are also involved in several functions of immune cells which include the selection of lymphocytes in the thymus, antigen processing, and presentation. However, the expression of cysteine cathepsins is dysregulated in hematological malignancies where they have been shown to play diverse functions. Interestingly, several pieces of evidence over the past few years have demonstrated overexpression of cathepsins in leukemia and their association with worst survival outcomes in patients. Strategies aimed at altering the expression, activity, and subcellular localization of these cathepsins are emerging as potential therapeutic modalaties in the management of hematological malignancies. Recent findings also suggest the involvement of these proteases in modulating the immune response in leukemia and lymphomas.

Serum Amyloid A-Positive Hepatocellular Neoplasm: A New Type of Tumor Arising in Patients with Advanced Alcoholic Disease

2015 ◽  
Vol 33 (5) ◽  
pp. 648-654 ◽  
Author(s):  
Motoko Sasaki ◽  
Yasuni Nakanuma
Keyword(s):  
Hepatocellular Carcinoma ◽  
Liver Disease ◽  
Serum Amyloid A ◽  
Hepatocellular Adenoma ◽  
Clinicopathological Features ◽  
Serum Amyloid ◽  
Amyloid A ◽  
New Type ◽  
Strong Immunoreactivity ◽  
Alcoholic Disease

This chapter reviews a new type of hepatocellular neoplasm, serum amyloid A-positive hepatocellular neoplasm (SAA-HN), which arises in patients with advanced alcoholic liver disease such as cirrhosis. SAA-HNs share histological and immunohistochemical features with inflammatory hepatocellular adenoma, for example, a strong immunoreactivity for SAA. Clinicopathological features and issues regarding SAA-HN are reviewed with emphasis regarding its potential to develop into hepatocellular carcinoma.

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