Galectin-3 not Galectin-9 as a candidate prognosis marker for hepatocellular carcinoma

Background Galectins (Gal) are a family of protein that bind to the β-galactoside of glycoproteins. It modulates a variety of biological functions, such as tumor growth, angiogenesis and tumor metastasis. A series of experimental and clinical evidences have been reported to support a correlation between galectin expressions and neoplastic transformation, progression and prognosis. The objective of this study was to estimate the expression of Gal-3 and Gal-9 in order to evaluate their relation to hepatocellular carcinoma (HCC) -related clinical features and their prognostic values. Methods We evaluated Gal-3 and Gal-9 expression in 247 HCC patients by a tissue microarray immunohistochemistry method, then analyzed the relationship between expression levels of Gal-3 and Gal-9 protein and tumor parameters or clinical outcomes. Results The Gal-3 expression was significantly higher in tumor tissues compared with adjacent non-tumor tissues (P < 0.001), while no significant differences of Gal-9 was detected (P = 0.222). A higher Gal-3 expression was significantly associated with lymph-vascular invasion (P = 0.049), poor histological differentiation (P = 0.016), and no cirrhosis (P = 0.040). In contrast, a lower Gal-9 expression was related to lymph-vascular invasion (P = 0.012) and poor histological differentiation (P = 0.002). Survival analysis showed that patients with higher Gal-3 expression had worse overall survival (P = 0.012) , however no correlation was found between Gal-9 expression and survival (P = 0.185). Multivariate analysis showed that multiple tumor (HR = 1.94, 95% CI [1.36–2.78]), tumor size ≥ 5 cm (HR = 1.51, 95% CI [1.07–2.12]), Lymph-vascular invasion (HR = 1.45, 95% CI [1.00–2.10]) and Gal-3 expression (HR = 1.57, 95% CI [1.06–2.33]) were independent influencing factors of prognosis in patients with hepatocellular carcinoma. Conclusion Gal-3 was expected to serve as a novel prognostic marker of hepatocellular carcinoma, while Gal-9 expression was only related to tumor progression.

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Expression and clinical significance of CMTM1 in hepatocellular carcinoma

Open Medicine ◽

10.1515/med-2021-0221 ◽

2021 ◽

Vol 16 (1) ◽

pp. 217-223

Author(s):

Xin Song ◽

Shidong Zhang ◽

Run Tian ◽

Chuanjun Zheng ◽

Yuge Xu ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Transmembrane Domain ◽

Disease Free Survival ◽

Clinicopathological Characteristics ◽

The Cancer Genome Atlas ◽

High Expression ◽

Chi Square ◽

Tumor Tissues ◽

The Relationship ◽

Low Expression

Abstract Background CKLF Like Marvel Transmembrane Domain Containing 1 (CMTM1) plays a role in breast cancer and lung cancer, but studies on the occurrence and development of CMTM1 in hepatocellular carcinoma (HCC) have not been reported. Methods The Cancer Genome Atlas (TCGA) database and immunohistochemistry (IHC) were used to detect CMTM1 expression in HCC tissues. The relationship between CMTM1 expression and the clinicopathological characteristics of HCC patients was analyzed by chi-square test, and the relationship between CMTM1 expression and the prognosis of HCC patients was tested by the Kaplan–Meier model. Results Bioinformatics analysis showed that the mRNA expression of CMTM1 was upregulated in HCC tissues, and low expression of CMTM1 is associated with longer disease-free survival in patients with HCC. Similarly, the survival time of HCC patients in CMTM1 high expression group was significantly shorter than that in CMTM1 low expression group. IHC detection indicated that CMTM1 protein was highly expressed in both HCC and adjacent non-tumor tissues, with a positive expression in 84% (63/75) of HCC tissues and 89.3% (67/75) of adjacent non-tumor tissues. Moreover, CMTM1 expression was related to family history and TNM stage of HCC patients (P < 0.05), but had no relationship with other clinicopathological characteristics. The survival analysis based on IHC results showed that the prognosis of HCC patients in CMTM1 negative group was significantly poorer than that in CMTM1 positive group (P < 0.05). Conclusion CMTM1 has a high expression in HCC tissues and is related to the prognosis of HCC patients.

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NDRG3 overexpression is associated with a poor prognosis in patients with hepatocellular carcinoma

Bioscience Reports ◽

10.1042/bsr20180907 ◽

2018 ◽

Vol 38 (6) ◽

Cited By ~ 1

Author(s):

Ji-sheng Jing ◽

Hongbo Li ◽

Shun-cai Wang ◽

Jiu-ming Ma ◽

La-qing Yu ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Cox Regression ◽

Survival Curve ◽

Disease Free Survival ◽

Prognostic Indicator ◽

Clinicopathological Characteristics ◽

Pcr Analysis ◽

Kaplan Meier ◽

Tumor Tissues ◽

The Relationship

N-myc downstream-regulated gene 3 (NDRG3), an important member of the NDRG family, is involved in cell proliferation, differentiation, and other biological processes. The present study analyzed NDRG3 expression in hepatocellular carcinoma (HCC) and explored the relationship between expression of NDRG3 in HCC patients and their clinicopathological characteristics. We performed quantitative real-time reverse-transcription polymerase chain reaction (qRT-PCR) analysis and immunohistochemistry (IHC) analyses on HCC tissues to elucidate NDRG3 expression characteristics in HCC patients. Kaplan–Meier survival curve and Cox regression analyses were used to evaluate the prognoses of 102 patients with HCC. The results revealed that compared with non-tumor tissues, HCC tissues showed significantly higher NDRG3 expression. In addition, our analyses showed that NDRG3 expression was statistically associated with tumor size (P=0.048) and pathological grade (P=0.001). Survival analysis and Kaplan–Meier curves revealed that NDRG3 expression is an independent prognostic indicator for disease-free survival (P=0.002) and overall survival (P=0.005) in HCC patients. The data indicate that NDRG3 expression may be considered as a oncogenic biomarker and a novel predictor for HCC prognosis.

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Fecal Galectin-3: A New Promising Biomarker for Severity and Progression of Colorectal Carcinoma

Mediators of Inflammation ◽

10.1155/2018/8031328 ◽

2018 ◽

Vol 2018 ◽

pp. 1-11 ◽

Cited By ~ 5

Author(s):

Milan Jovanovic ◽

Nevena Gajovic ◽

Natasa Zdravkovic ◽

Marina Jovanovic ◽

Milena Jurisevic ◽

...

Keyword(s):

Inflammatory Cytokines ◽

Tumor Tissue ◽

Tnm Stage ◽

Nuclear Grade ◽

Blood Vessel Invasion ◽

Histological Differentiation ◽

Galectin 3 ◽

Valuable Marker ◽

Anti Inflammatory ◽

The Relationship

Background and Objectives. The aim of the study was to determine systemic and fecal values of galectin-3 and pro- and anti-inflammatory cytokines in patients with CRC and the relationship with clinicopathological aspects. Methods. Concentrations of galectin-3, TNF-α, TGF-β, IL-10, and IL-1β were analyzed in samples of blood and stool of 60 patients with CRC. Results. Systemic concentration of TNF-α was significantly lower in patients with severe diseases (advanced TNM stage, nuclear grade, and poor histological differentiation) as in patients with more progressive CRC (lymph and blood vessel invasion, presence of metastasis). Fecal values of anti-inflammatory cytokines TGF-β and IL-10 were increased in patients with severe stadium of CRC. Fecal concentration of Gal-3 was enhanced in CRC patients with higher nuclear grade, poor tumor tissue differentiation, advanced TNM stage, and metastatic disease. Gal-3/TNF-α ratio in sera and feces had a higher trend in patients with severe and advanced diseases. Positive correlation between fecal Gal-3 and disease severity, tumor progression, and biomarkers AFP and CEA, respectively, was also observed. Conclusions. Predomination of Gal-3 in patients with advanced diseases may implicate on its role in limiting ongoing proinflammatory processes. The fecal values of Gal-3 can be used as a valuable marker for CRC severity and progression.

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HULC and H19 Played Different Roles in Overall and Disease-Free Survival from Hepatocellular Carcinoma after Curative Hepatectomy: A Preliminary Analysis from Gene Expression Omnibus

Disease Markers ◽

10.1155/2015/191029 ◽

2015 ◽

Vol 2015 ◽

pp. 1-9 ◽

Cited By ~ 37

Author(s):

Zongguo Yang ◽

Yunfei Lu ◽

Qingnian Xu ◽

Bozong Tang ◽

Cheol-Keun Park ◽

...

Keyword(s):

Gene Expression ◽

Risk Factors ◽

Hepatocellular Carcinoma ◽

Vascular Invasion ◽

Disease Free Survival ◽

Gene Expression Omnibus ◽

Free Survival ◽

Cox Regression Analysis ◽

Tumor Tissues ◽

Disease Free

Objective. This study aimed to evaluate the relationships between long noncoding RNAs (lncRNAs) in tumor tissues and hepatocellular carcinoma (HCC) aggressiveness and survival.Methods. We correlated the lncRNAs in tumor tissues with HCC survival and clinicopathological features based on Gene Expression Omnibus expression profile GSE36376.Results. Eight lncRNAs and 240 HCC patients were included. Cox regression analysis indicated that HULC was a positive factor for HCC overall survival (HR = 0.885, 95% CI = 0.797–0.983, andP=0.023) and disease-free survival time (HR = 0.913, 95% CI = 0.835–0.998, andP=0.045). H19 and UCA1 were both demonstrated to be risk factors of HCC disease-free survival in multivariate Cox model (HR = 1.071, 95% CI = 1.01–1.137, andP=0.022and HR = 2.4, 95% CI = 1.092–5.273, andP=0.029, resp.). But Kaplan-Meier method showed no significant association between UCA1 and HCC disease-free survival (log rankP=0.616). Logistic regression demonstrated that H19 was overexpressed in HBV-infected patients (OR = 1.14, 95% CI = 1.008–1.29, andP=0.037). HULC had a significant association with vascular invasion (OR = 0.648, 95% CI = 0.523–0.803, andP<0.001). H19 and MEG3 were both considered to be risk factors for high AFP level (OR = 1.45, 95% CI = 1.277–1.646, andP<0.001and OR = 1.613, 95% CI = 1.1–2.365, andP=0.014, resp.).Conclusions. Contributing to decreased susceptibility to vascular invasion, upregulation of HULC in tumor tissues was positively associated with HCC survival. In contrast, H19 overexpression might be risk factor for HCC aggressiveness and poor outcomes.

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Cancer-Associated Fibroblasts Promote Vascular Invasion of Hepatocellular Carcinoma via Downregulating Decorin-integrin β1 Signaling

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.678670 ◽

2021 ◽

Vol 9 ◽

Author(s):

Xiaobo Zheng ◽

Peng Wang ◽

Li Li ◽

Jing Yu ◽

Chune Yu ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Vascular Invasion ◽

Poor Prognosis ◽

Cancer Associated Fibroblasts ◽

Integrin Β1 ◽

Primary Tumors ◽

Invasion And Migration ◽

Tumor Tissues ◽

And Migration

Hepatocellular carcinoma (HCC) is a common malignancy worldwide, and the high ratio of recurrence and metastasis remains the main cause of its poor prognosis. Vascular invasion of HCC includes microvascular invasion (MVI) and portal vein tumor thrombosis (PVTT) and is regarded as a common roadmap of intrahepatic metastasis in HCC. However, the molecular mechanism underlying vascular invasion of HCC is largely unknown. Here, we analyzed the transcriptomes of primary tumors, PVTT tissues, and tumor tissues with or without MVI. We found that extracellular matrix-related pathways were involved in vascular invasion of HCC and that decorin secreted by cancer-associated fibroblasts was gradually downregulated from normal to tumor tissues and more so in PVTT tissues. We also established that low-level decorin expression is an independent risk factor for MVI and it is associated with a poor prognosis. Decorin downregulated integrin β1 and consequently inhibited HCC cell invasion and migration in vitro. Co-staining DCN and integrin β1 revealed that DCN dynamically regulated integrin β1 protein expression. Integrin β1 knockdown significantly inhibited HCC invasion and migration, and decorin combined with such knockdown synergistically augmented the anti-metastatic effects. Co-IP assay confirmed the direct interaction of decorin with integrin β1. Our findings showed that targeting cancer-associated fibroblast-related decorin is not only a promising strategy for inhibiting HCC vascular invasion and metastasis but also provides insight into the clinical treatment of patients with PVTT.

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miR-186 Represses Proliferation, Migration, Invasion, and EMT of Hepatocellular Carcinoma via Directly Targeting CDK6

Oncology Research Featuring Preclinical and Clinical Cancer Therapeutics ◽

10.3727/096504020x15954139263808 ◽

2020 ◽

Vol 28 (5) ◽

pp. 509-518

Author(s):

Junfeng Lu ◽

Zhongsong Zhao ◽

Yanhong Ma

Keyword(s):

Hepatocellular Carcinoma ◽

Vascular Invasion ◽

Poor Prognosis ◽

Untranslated Regions ◽

Migration And Invasion ◽

Synergic Effect ◽

Cyclin Dependent Kinase ◽

Biological Functions ◽

Inhibitory Effects ◽

Hcc Cells

The present study aimed to investigate the effect of miR-186 on proliferation, migration, invasion, and epithelialmesenchymal transition (EMT) of hepatocellular carcinoma (HCC). In this work, miR-186 was downregulated in HCC tissues and cells, and low miR-186 level helped predict the occurrence of vascular invasion and poor prognosis in patients with HCC. miR-186 overexpression inhibited cell proliferation and tumor growth in nude mice, repressed migration and invasion abilities, and enhanced apoptosis in HCC cells. miR-186 also retarded progression of EMT. miR-186 directly bound to the 3-untranslated regions of cyclin-dependent kinase 6 (CDK6) to inhibit its expression. Overexpression of CDK6 markedly reversed inhibitory effects of miR-186 on proliferation, apoptosis, migration, and invasion of HCC cells. Conversely, inhibition of CDK6 exerted synergic effect on the biological functions of miR-186. In conclusion, miR-186 represses proliferation, migration, invasion, and EMT, and induces apoptosis through targeting CDK6 in HCC, which may provide a new therapeutic target for HCC.

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Long non-coding RNA FOXP4-AS1 facilitates the biological functions of hepatocellular carcinoma cells via downregulating ZC3H12D by mediating H3K27me3 through recruitment of EZH2

Cell Biology and Toxicology ◽

10.1007/s10565-021-09642-9 ◽

2021 ◽

Author(s):

Junfeng Ye ◽

Yu Fu ◽

Zhongfeng Wang ◽

Jinhai Yu

Keyword(s):

Hepatocellular Carcinoma ◽

Carcinoma Cells ◽

Biological Functions ◽

Forkhead Box ◽

Non Coding Rna ◽

Ezh2 Expression ◽

The Relationship ◽

Long Non Coding Rna ◽

Hcc Cells

Abstract Background Some studies have reported the effect of long non-coding RNA forkhead box P4 antisense RNA 1 (lncRNA FOXP4-AS1) on hepatocellular carcinoma (HCC). Here, we aimed to discuss the effects of FOXP4-AS1/enhancer of zeste homolog 2 (EZH2)/trimethylation of lysine 27 on histone H3 (H3K27me3)/zinc finger CCCH-type containing 12D (ZC3H12D) axis on HCC. Methods The expression of FOXP4-AS1, EZH2, and ZC3H12D, and abundance of H3K27me3 in HCC tissues and cells were tested. The relationship between FOXP4-AS1 expression and prognosis of HCC patients was analyzed. The biological functions of HCC cells were detected via loss- and gain-of-function assays. The tumor weight and volume in vivo were tested. The interaction between FOXP4-AS1 and EZH2 as well as that between EZH2 and H3K27me3 was verified. Results FOXP4-AS1 and EZH2 expression and H3K27me3 abundance were enhanced while ZC3H12D expression was depressed in HCC tissues and cells. Knockdown of FOXP4-AS1 suppressed biological functions of HCC cells as well as the weight and volume of HCC transplanted tumor. Depleting ZC3H12D reversed the effect of downregulated FOXP4-AS1 on HCC cells. FOXP4-AS1 suppressed ZC3H12D expression via mediating H3K27me3 by recruitment of EZH2. Conclusion The key findings of the present study demonstrate that FOXP4-AS1 suppresses ZC3H12D expression via mediating H3K27me3 by recruitment of EZH2, thus promoting the progression of HCC. Graphical abstract

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P300-dependent acetylation of histone H3 is required for EGFR-mediated HMGA2 transcription in hepatocellular carcinoma

10.21203/rs.3.rs-38706/v1 ◽

2020 ◽

Author(s):

Chao Liang ◽

Jie Niu ◽

Xiao Wang ◽

Xin Yao ◽

Ruo-Han Yang ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Tumor Metastasis ◽

Histone H3 ◽

High Mobility ◽

Carcinoma Cells ◽

High Mobility Group Protein ◽

Hepatocellular Carcinoma Cells ◽

Expression Levels ◽

Tumor Tissues ◽

Hcc Cells

Abstract Background High-mobility group protein A2 (HMGA2) is highly expressed in hepatocellular carcinoma cells and contributes to tumor metastasis and poor patient survival. However, the molecular mechanism of HMGA2 transcriptional regulation in hepatocellular carcinoma cells remains largely unclear. Methods Mouse model of lung metastasis was used to evaluate the effects of HMGA2 on hepatocellular carcinoma. DEN-induced rat model of hepatocellular carcinoma was used to measure the expression of HMGA2 and histone H3 acetylation. Immunohistochemistry was used to analyze the expression levels of HMGA2 in 39 matched HCC tissues and adjacent non-tumor tissues. Real-time PCR, Western blotting and Chromatin Immunoprecipitation assay were used to investigate the underlying mechanisms by which HMGA2 overexpression in hepatocellular carcinoma cells. Result Compared with adjacent non-tumour tissues, the expression of HMGA2 was significantly upregulated in human HCC tumor tissues. Moreover, We demonstrated that the expression HMGA2 was upregulated in HCC, and the elevated HMGA2 could promote tumor metastasis. Incubation HCC cells with Epidermal growth factor (EGF) could promote the expression of HMGA2 mRNA and protein. Knockdown of p300 can reverse EGF-induced HMGA2 expression and histone H3-K9 acetylation, while a phosphorylation-mimic p300 S1834D mutant can stimulate HMGA2 expression as well as H3-K9 acetylation in HCC cells. Furthermore, we identified p300-mediated H3-K9 acetylation participates in EGF-induced HMGA2 expression in HCC. In addition, the levels of H3-K9 acetylation positively correlated with the expression levels of HMGA2 in human HCC specimens. Conclusion p300-dependent acetylation of histone H3 is required for EGFR-mediated HMGA2 transcription in hepatocellular carcinoma.

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Oncogenic Roles of RAD51AP1 in Tumor Tissues Related to Overall Survival and Disease-Free Survival in Hepatocellular Carcinoma

Cancer Control ◽

10.1177/1073274820977149 ◽

2020 ◽

Vol 27 (1) ◽

pp. 107327482097714

Author(s):

Liping Zhuang ◽

Yuan Zhang ◽

Zhiqiang Meng ◽

Zongguo Yang

Keyword(s):

Hepatocellular Carcinoma ◽

Overall Survival ◽

Liver Fibrosis ◽

Vascular Invasion ◽

Disease Free Survival ◽

Tumor Stage ◽

Intrahepatic Metastasis ◽

Free Survival ◽

Tumor Tissues ◽

Disease Free

Objective: This study aimed to investigate the associations between RAD51AP1 and the outcomes of hepatocellular carcinoma (HCC). Methods: RAD51AP1 expression levels were compared in Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) datasets. The Liver Hepatocellular Carcinoma (TCGA, Provisional) and GSE36376 datasets were used for survival analysis. RAD51AP1 associations with clinicopathological features were determined with the GSE36376 dataset. Results: RAD51AP1 mRNA expression was significantly upregulated in advanced liver fibrosis samples (S3-4 vs. S0-2 and G3-4 vs. G0-2) from hepatitis B virus (HBV)-related liver fibrosis patients and in tumor tissues and peripheral blood mononuclear cells (PBMCs) from HCC patients (all P < 0.05). HCC patients with high RAD51AP1 expression had significantly worse overall survival (OS) and disease-free survival (DFS) than those with low RAD51AP1 expression ( P = 0.0034 and P = 0.0012, respectively) in the TCGA dataset, and these findings were validated with the GSE36376 dataset ( P = 0.0074 and P = 0.0003, respectively). A Cox regression model indicated that RAD51AP1 was a risk factor for OS and DFS in HCC patients in GSE36376 (HR = 1.54, 95% CI = 1.02-2.32, P = 0.04 and HR = 1.71, 95% CI = 1.22-2.39, P = 0.002, respectively). Moreover, RAD51AP1 mRNA expression increased gradually with increasing tumor stage, including stratification by American Joint Committee on Cancer (AJCC) stages, Barcelona Clinic Liver Cancer (BCLC) stages and Edmondson grades. In addition, RAD51AP1 was overexpressed in HCC patients with intrahepatic metastasis, major portal vein invasion, vascular invasion and/or an alpha-fetoprotein (AFP) level > 300 ng/ml. Conclusions: Contributing to an advanced tumor stage, intrahepatic metastasis, vascular invasion and AFP level elevation, RAD51AP1 upregulation was significantly associated with OS and DFS in HCC patients.

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DTU I isolates of Trypanosoma cruzi induce upregulation of Galectin-3 in murine myocarditis and fibrosis

Parasitology ◽

10.1017/s0031182013002254 ◽

2014 ◽

Vol 141 (6) ◽

pp. 849-858 ◽

Cited By ~ 14

Author(s):

MARÍA F. FERRER ◽

CARLA A. PASCUALE ◽

RICARDO M. GOMEZ ◽

MARÍA S. LEGUIZAMÓN

Keyword(s):

Heart Disease ◽

Trypanosoma Cruzi ◽

Smooth Muscle Actin ◽

Biological Properties ◽

Muscle Actin ◽

Public Concern ◽

Galectin 3 ◽

Chagas Heart Disease ◽

Prognosis Marker ◽

The Relationship

SUMMARYChagas heart disease is a major public concern since 30% of infected patients develop cardiac alterations. The relationship between Trypanosoma cruzi discrete typing units (DTUs) and the biological properties exhibited by the parasite population has yet to be elucidated. In this study, we analysed the expression of α-smooth muscle actin (α-SMA) and galectin-3 (Gal-3) associated with cardiac extracellular matrix (ECM) remodelling a murine chronic cardiomyopathy induced by Tc I genotypes. We found the induction of myocarditis was associated with the upregulation of Col I, α-SMA, Gal-3, IFN-γ and IL-13, as analysed by q-PCR. In myocardial areas of fibrosis, the intensity of myocarditis and significant ECM remodelling correlated with the presence of Col I-, Gal-3- and α-SMA-positive cells. These results are promising for the further efforts to evaluate the relevance of Gal-3 in Chagas heart disease, since this galectin was proposed as a prognosis marker in heart failure patients.

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