Down-regulation of microRNA-125b-2-3p is a risk factor for a poor prognosis in hepatocellular carcinoma.
Ontology highlight
ABSTRACT:
SUBMITTER: Huang HQ
PROVIDER: S-EPMC8806266 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:Hepatocellular carcinoma (HCC) is one of the most common and lethal cancer types worldwide, especially in Asian countries. Genetic alterations, including hyperactivation of oncogenes and loss of expression of tumor suppressor genes, greatly contribute to the initiation and progression of HCC. Here we report that down-regulation of trophoblast cell surface antigen 2 (TROP-2) was frequently detected in HCC. Transcriptome sequencing of non-tumor and HCC patient samples revealed down-regulation of TROP-2 in tumor tissues. Immunohistochemical staining showed nearly undetectable levels of TROP-2 in HCC tissues but distinct and strong staining of TROP-2 in adjacent non-tumor tissues. The frequent down-regulation of TROP-2 expression was further confirmed in an in-house cohort of 205 pairs of HCC patient samples and in the Cancer Genome Atlas (TCGA) databases. Furthermore, the down-regulation of TROP-2 was associated with poor overall survival of HCC patients, severe adjacent organ invasion, and poor differentiation of HCC. Using bisulfite genomic sequencing and methylation-specific polymerase chain reaction analyses, we show that higher levels of promoter methylation were detected in the DNA samples of HCC tissues (low TROP-2 expression) than that of the non-tumor tissues (high TROP-2 expression). Conclusion: Taken together, our data suggest that promoter hypermethylation contributes to the frequent down-regulation of TROP-2 in HCC, and that TROP-2 down-regulation predicts poor prognosis of HCC patients.
| S-EPMC6211329 | biostudies-literature
Project description:microRNAs (miRNAs) are a class of small noncoding RNAs that can regulate gene expression by translation repression or mRNA degradation. Our aim was to evaluate the role of aberrantly expressed miRNAs in hepatocellular cancer (HCC).miRNA expression in HCC tissues and cells was evaluated by qPCR array and Taqman miRNA assay. Cell proliferation, motility, invasion, and the angiogenesis index were quantitated using commercial assays. DNA methylation status, matrix metalloproteinases (MMPs) mRNA expression was quantitated by real-time PCR analysis.miRNA profiling identified a decrease in miR-125b expression in HCC tumor tissues and cell lines. The expression of miR-125b was significantly increased by the methylation inhibitor 5-aza-2'-deoxycytidine in HCC cells but not in normal controls, suggesting that the expression of miR-125b could be epigenetically modulated. Methylation-specific PCR revealed hypermethylation status of miR-125b in HCC cells compared to non-malignant controls. Cell proliferation, anchorage-independent growth, cell migration, invasion, and angiogenesis were significantly decreased by the introduction of miR-125b precursor in HCC cell lines. Placenta growth factor was identified as a target of miR-125b by bioinformatics analysis and experimentally verified using luciferase reporter constructs. Overexpression of miR-125b in HCC cells decreased PIGF expression, and altered the angiogenesis index. Furthermore, modulation of miR-125b also distorted expression of MMP-2 and -9, the mediators of enzymatic degradation of the extracellular matrix.Our studies showing epigenetic silencing of miR-125b contributes to an invasive phenotype provide novel mechanistic insights and identify a potential target mechanism that could be manipulated for therapeutic benefit in HCC.
| S-EPMC3184370 | biostudies-literature
Project description:BackgroundSirtuin 3 (Sirt3), one of the seven Sirtuins family members, plays critical roles in the progression of multiple cancer types. However, its role in the prognosis of hepatocellular carcinoma (HCC) has not yet been investigated systematically.MethodsThe correlation of Sirtuins expression with prognosis of HCC was determined by immunohistochemistry (IHC) in a large HCC patient cohort (n = 342). Expression of Sirt3 in tumoral and peritumoral tissues of HCC patients were further determined by western blotting (WB).ResultsIHC and WB studies both showed a decreased expression of Sirt3 in tumoral tissues compared with peritumoral tissues (P = 0.003 for IHC, P = 0.0042 for WB). Decreased expression of Sirt3 in both tumoral and peritumoral tissues was associated with increased recurrence probability and decreased overall survival rate by univariate analyses (intratumoral Sirt3: P = 0.011 for TTR, P = 0.001 for OS; peritumoral Sirt3: P = 0.017 for TTR, P = 0.023 for OS), the prognostic value was strengthened by multivariate analyses (intratumoral Sirt3: P = 0.031 for TTR, P = 0.001 for OS; peritumoral Sirt3: P = 0.047 for TTR, P = 0.031 for OS). Intratumoral Sirt3 also showed a favorable prognostic value in patients with BCLC stage A (TTR, P = 0.011; OS, P < 0.001). In addition, we found that IHC studies of other sirtuin members showed a decreased expression of Sirt2, Sirt4 and Sirt5 and an increased expression of Sirt1, Sirt6 and Sirt7 in intratumoral tissues compared with peritumoral tissues. In contrast to Sirt3, other members did not showed a remarkable correlation with HCC prognosis.ConclusionsDown-regulation of intratumoral and peritumoral Sirt3 were both associated with poor outcome in HCC, moreover, intratumoral Sirt3 was a favorable prognostic predictor in early stage patients.
| S-EPMC4021365 | biostudies-literature
Project description:BackgroundOpioid receptors have become increasingly implicated in cancer progression and long-term patient outcomes. However, the expression and significance of the κ-opioid receptor (KOR) in hepatocellular carcinoma (HCC) remain unclear.MethodsIn this study, KOR mRNA expression was analysed by real-time quantitative PCR in 64 pairs of HCC tumour tissues and adjacent non-tumour tissues, and KOR protein expression was analysed by immunohistochemistry in 174 HCC patients. We investigated the correlation between KOR expression and clinicopathological parameters to illustrate the potential prognostic significance of KOR expression in HCC.ResultsKOR mRNA expression was significantly down-regulated in 79.69% (51 of 64) of the HCC tumour samples, and KOR expression in tumour tissue was significantly lower than that in adjacent non-tumour tissues (P < 0.001). ROC curve analysis showed that KOR mRNA expression yielded AUC of 0.745, for the detection of HCC patients. Low KOR mRNA expression in HCC was correlated with aggressive clinicopathological parameters, such as tumour size (P = 0.015), differentiation grade (P = 0.011), and TNM stage (P = 0.021). Moreover, down-regulation of KOR protein expression in HCC tissues was detected in 174 HCC patients. Similarly, negative KOR protein expression was significantly correlated with aggressive clinicopathological features, such as tumour size (P = 0.002), vascular invasion (P = 0.003), differentiation grade (P = 0.026), and TNM stage (P = 0.030). Furthermore, Kaplan-Meier survival analysis demonstrated that down-regulation of KOR in HCC indicated poor prognosis. KOR deficiency (KORT < N) was correlated to a shorter survival rate and an increased recurrence (both P < 0.001). In univariate and multivariate survival analyses, KOR was identified as a promising independent risk factor for both overall survival (OS, both P < 0.001) and recurrence-free survival (RFS, both P < 0.001).ConclusionsDown-regulation of KOR in HCC tumour tissues has a strong association with poor prognosis and KOR might be a potential tumour suppressor.
| S-EPMC5562986 | biostudies-literature
Project description:BackgroundGiven the role of microRNA in colorectal cancer (CRC) progression, we explored the association between microRNA (miRNA) expression and CRC-related prognosis.MethodsThree types of tissue samples (primary CRC lesions without liver metastasis, primary lesions with liver metastasis, and liver metastatic tissues) were used for miRNA profiling to identify differentially expressed miRNA. Quantitative real-time PCR was used to examine miRNA expression in CRC cells and in tumor tissues.ResultsMiR-132 was significantly down-regulated in primary CRC tissues with liver metastasis and liver metastatic lesions compared to primary lesions without liver metastasis. Multivariate analysis for overall survival indicated that low miR-132 expression was an independent prognostic factor for CRC patients (overall survival P = 0.040, disease-free survival P = 0.015). Ectopic expression of miR-132 significantly inhibited cell proliferation and cell invasion. The luciferase reporter assay revealed that anoctamin 1 (ANO1) was a direct target of miR-132. Kaplan-Meier survival curves showed that high ANO1 expression was a significant prognostic factor for overall survival of patients with CRC (P = 0.0344).ConclusionsDown-regulation of miR-132 is associated with poor prognosis in CRC. ANO1 could be one of the crucial targets of miR-132 in CRC.
| S-EPMC5149564 | biostudies-literature
Project description:ObjectivesThe role of heparanase (HPSE) gene in cancers including hepatocellular carcinoma (HCC) is currently controversial. This study was aimed at investigating the impact of genetic alteration and expression change of HPSE on the progression and prognosis of HCC.MethodsThe HPSE gene was studied in three different aspects: (1) loss of heterozygosity (LOH) by a custom SNP microarray and DNA copy number by real-time PCR; (2) mRNA level by qRT-PCR; and (3) protein expression by immunohistochemistry. The clinical significances of allele loss and expression change of HPSE were analyzed.ResultsMicroarray analysis showed that the average LOH frequency for 10 SNPs located within HPSE gene was 31.6%, three of which were significantly correlated with tumor grade, serum HBV-DNA level, and AFP concentration. In agreement with SNP LOH data, DNA copy number loss of HPSE was observed in 38.74% (43/111) of HCC cases. HPSE mRNA level was notably reduced in 74.1% (83/112) of tumor tissues compared with non-tumor liver tissues, which was significantly associated with DNA copy number loss, increased tumor size, and post-operative metastasis. HPSE protein level was also remarkably reduced in 66.3% (53/80) of tumor tissues, which was correlated with tumor grade. Patients with lower expression level of HPSE mRNA or protein had a significantly lower survival rate than those with higher expression. Cox regression analysis suggested that HPSE protein was an independent predictor of overall survival in HCC patients.ConclusionsThe results in this study demonstrate that genetic alteration and reduction of HPSE expression are associated with tumor progression and poor prognosis of HCCs, suggesting that HPSE behaves like a tumor suppressor gene and is a potential prognostic marker for HCC patients.
| S-EPMC3432106 | biostudies-literature
Project description:Recent studies indicated that long noncoding RNAs (lncRNAs) played important regulatory roles in carcinogenesis and cancer progression. However, the contribution of small nucleolar RNA host gene 20 (SNHG20) to cancer development remains largely unknown. The aim of the study is to investigate the expression of SNHG20 and its clinical significance in hepatocellular carcinoma (HCC). Our results showed that the expression of SNHG20 was remarkably up-regulated in HCC tissues compared with adjacent non-tumor liver tissues from 49 fresh HCC samples (cohort 1) detected by quantitative reverse-transcription polymerase chain reaction (qRT-PCR, P = 0.004). The results were confirmed in 144 formalin-fixed, paraffin-embedded HCC tissues (cohort 2) by in situ hybridization (ISH). Meanwhile, the expression of SNHG20 was associated with tumor size (P = 0.027 for cohort 1 and P = 0.046 for cohort 2) and clinical stage (P = 0.027 for cohort 1 and P = 0.028 for cohort 2). Importantly, patients with high expression of SNHG20 had a shorter overall survival (OS, P < 0.001) and disease-free survival (DFS, P < 0.001) than those with low expression of SNHG20. Univatiate and multivariate analysis showed that SNHG20 was a significant and independent prognostic predictor for OS of HCC patients (hazard ratio = 3.985, 95% CI = 1.981-8.017, P < 0.001). In addition, a total of 331 HCC patients' data from the Caner Genome Atlas project (TCGA) were used to validate our findings. Consistently, the results from TCGA HCC cohort demonstrated that SNHG20 were overexpressed in HCC tissues compared with non-tumor liver tissues (P < 0.001). Patients with higher expression levels of SNHG20 had poorer OS (P = 0.021) and DFS (P < 0.001). Functionally, knockdown of SNHG20 in SK-Hep-1 cells significantly inhibited cellular proliferation, migration, and invasion. In conclusion, SNHG20, up-regulated in patients with HCC, may serve as an independent prognostic predictor for HCC patients.
| S-EPMC4820738 | biostudies-literature
Project description:BackgroundHepatocellular carcinoma (HCC) is the second-most lethal cancer worldwide with a complex pathogenesis. RuvB-like 2 (RUVBL2) was previously found to contribute to hepatocarcinogenesis. However, its expression, regulation and clinical significance have not been systematically evaluated in a large number of clinical samples.MethodsHere, we performed a comprehensive analysis of RUVBL2 based on multiple datasets from 371 liver cancer patients of The Cancer Genome Atlas (TCGA) and on immunohistochemical staining in 153 subjects. In addition, the aberrant signaling pathways caused by RUVBL2 overexpression were investigated.ResultsWe demonstrated that promoter hypomethylation, copy number gain, MYC amplification and CTNNB1 mutation were all responsible for RUVBL2 overexpression in HCC. High levels of RUVBL2 mRNA were associated with shorter recurrence-free survival time (RFS) but not overall survival time (OS). Furthermore, RUVBL2 protein was overexpressed in the nucleus and cytoplasm of HCC samples. Univariate and multivariate survival analyses showed that strong nuclear and cytoplasmic staining of RUVBL2 independently predicted worse OS and RFS with a 2.03-fold and a 1.71-fold increase in the hazard ratio, respectively. High levels of RUVBL2 promoted carcinogenesis through the heat shock protein 90 (HSP90)-Cell Division Cycle 37 (CDC37), AKT serine/threonine kinase (AKT) and mitogen-activated protein kinase (ERK/MAPK) pathways.ConclusionThe deregulation of RUVBL2 in HCC is influenced at the genomic, epigenetic and transcriptional levels. Our findings highlight the potential roles of RUVBL2 as a promising prognostic marker as well as a therapeutic target for HCC.
| S-EPMC6764127 | biostudies-literature
Project description:POTE ankyrin domain family, member G (poteg) belongs to POTE family. The POTE family is composed of many proteins which are very closely related and expressed in prostate, ovary, testis, and placenta. Some POTE paralogs are related with some cancers. Here we showed that down-regulation of POTEG was detected in about 60% primary esophageal squamous cell carcinoma (ESCC) tumor tissues. Clinical association studies determined that POTEG down-regulation was significantly correlated with tumor differentiation, lymph nodes metastasis and TNM staging. Kaplan-Meier analysis determined that POTEG down-regulation was associated with poorer clinical outcomes of ESCC patients (P = 0.026). Functional studies showed that POTEG overexpression could suppress tumor cell growth and metastasis capacity in vitro and in vivo. Molecular analyses revealed that POTEG downregulated CDKs, leading to subsequent inhibition of Rb phosphorylation, and consequently arrested Cell Cycle at G1/S Checkpoint. POTEG overexpression induced apoptosis by activating caspases and PARP, and regulating canonical mitochondrial apoptotic pathways. On the other side, POTEG inhibited epithelial-mesenchymal transition and suppressed tumor cell metastasis. In conclusion, our study reveals a functionally important control mechanism of POTEG in esophageal cancer pathogenesis, suggesting potential use in the ESCC intervention and therapeutic strategies.
| S-EPMC6001627 | biostudies-literature
Project description:The aim of the study was to explore the clinical significance of let-7 expression in hepatocellular carcinoma (HCC).A PCR array was conducted to screen for let-7 expression in early-stage HCC. Next, the deregulation of let-7 was confirmed by quantitative real-time RT-PCR (qRT-PCR) in another set of liver tissues, including normal control (NC), chronic hepatitis (CH), liver cirrhosis (LC), HCC, and adjacent nontumor (NT) tissues. In addition, as the potential target mRNA of let-7, alpha 2(I) collagen (COL1A2) mRNA was also quantified in the above liver tissues. Finally, an association study comparing let-7 and COL1A2 and their clinical significance in HCC was conducted.PCR array analysis revealed that the expression levels of let-7a/7b/7c were significantly downregulated in early-stage HCC compared to those in NT tissues. As compared to NC samples, qRT-PCR further confirmed that let-7a/7b/7c/7e were significantly upregulated in CH, LC, and NT tissues, while there were no significant differences in expression between the HCC and NC groups. Although COL1A2 may be the target mRNA of let-7, only let-7c expression was inversely correlated with COL1A2 mRNA expression in CH tissues. In HCC tissues, levels of let-7a/7b/7c/7e were positively correlated with that of COL1A2 mRNA. The clinical significance study revealed that elevated let-7a expression was significantly correlated with serosal and vein invasion, while elevated let-7c expression was significantly correlated with vein invasion and advanced TNM stage. Elevated let-7e expression was significantly correlated with vein invasion in HCC. Significantly shorter postoperative overall survival was observed in HCC patients with high let-7c expression.The results suggest that aberrant expression of let-7a/7b/7c/7e occurs in benign liver diseases and HCC. The upregulation of let-7 expression is associated with the progression and poor prognosis of HCC, and further mechanistic studies are warranted.
| S-EPMC5556237 | biostudies-other