Liver cancer has become the sixth most diagnosed cancer and the fourth leading cause of cancer death worldwide. Hepatocellular carcinoma (HCC) is responsible for up to 75–85% of primary liver cancers, and sorafenib is the first targeted drug for advanced HCC treatment. However, sorafenib resistance is common because of the resultant enhancement of aerobic glycolysis and other molecular mechanisms. Aerobic glycolysis was firstly found in HCC, acts as a hallmark of liver cancer and is responsible for the regulation of proliferation, immune evasion, invasion, metastasis, angiogenesis, and drug resistance in HCC. The three rate-limiting enzymes in the glycolytic pathway, including hexokinase 2 (HK2), phosphofructokinase 1 (PFK1), and pyruvate kinases type M2 (PKM2) play an important role in the regulation of aerobic glycolysis in HCC and can be regulated by many mechanisms, such as the AMPK, PI3K/Akt pathway, HIF-1α, c-Myc and noncoding RNAs. Because of the importance of aerobic glycolysis in the progression of HCC, targeting key factors in its pathway such as the inhibition of HK2, PFK or PKM2, represent potential new therapeutic approaches for the treatment of HCC.

/pdf/emerging-roles-and-the-regulation-of-aerobic-glycolysis-in-2ufy554lss.pdf

Emerging roles and the regulation of aerobic glycolysis in hepatocellular carcinoma.

Molecular signaling pathways involved in cancer have been intensively studied due to their crucial role in cancer cell growth and dissemination. Among them, zinc finger E-box binding homeobox-1 (ZEB1) and -2 (ZEB2) are molecules that play vital roles in signaling pathways to ensure the survival of tumor cells, particularly through enhancing cell proliferation, promoting cell migration and invasion, and triggering drug resistance. Importantly, ZEB proteins are regulated by microRNAs (miRs). In this review, we demonstrate the impact that miRs have on cancer therapy, through their targeting of ZEB proteins. MiRs are able to act as onco-suppressor factors and inhibit the malignancy of tumor cells through ZEB1/2 down-regulation. This can lead to an inhibition of epithelial-mesenchymal transition (EMT) mechanism, therefore reducing metastasis. Additionally, miRs are able to inhibit ZEB1/2-mediated drug resistance and immunosuppression. Additionally, we explore the upstream modulators of miRs such as long non-coding RNAs (lncRNAs) and circular RNAs (circRNAs), as these regulators can influence the inhibitory effect of miRs on ZEB proteins and cancer progression.

/pdf/micrornas-and-their-influence-on-the-zeb-family-mechanistic-wafb768l81.pdf

MicroRNAs and Their Influence on the ZEB Family: Mechanistic Aspects and Therapeutic Applications in Cancer Therapy.

Hepatocellular carcinoma (HCC) is among the most frequently observed forms of cancer. MicroRNAs (miRNAs) are increasingly thought to play a key role in regulating the onset and progression of a wide range of cancer types. In the present report, we found that miR-455-5p expression was significantly decreased in both HCC patient tumor tissues and cell lines, and that this reduction in expression was linked to poorer patient outcomes. When we overexpressed miR-455-5p in HCC cell lines (Huh7 and HepG2), this was linked with impaired proliferation, colony formation, migration, and invasion. We further found that this miRNA was able to directly bind the insulin growth factor receptor (IGF-1R) 3'-untranslated region, thereby suppressing IGF-1R expression in HCC cells. Consistent with this, miR-455-5p overexpression was associated with reduced glucose transporter (GLUT) 1 expression, which in turn inhibited HCC cell uptake of glucose, production of lactate, and generation of ATP. Together these results thus indicate that mIR-455-5p is able to suppress tumor functionality via impairing glycolysis in HCC cells, highlighting this miRNA as a potential target for anti-cancer therapeutic interventions.

miR-455-5p suppresses hepatocellular carcinoma cell growth and invasion via IGF-1R/AKT/GLUT1 pathway by targeting IGF-1R.

Background Hypoxia is an important feature for the progression of hepatocellular carcinoma (HCC). Long noncoding RNA nuclear receptor subfamily 2 group F member 1 antisense RNA 1 (NR2F1-AS1) is dysregulated in HCC. However, the role and mechanism of N2RF1-AS1 in hypoxia-induced glycolysis and migration remain unclear. Materials and methods Tumor tissues and adjacent samples were harvested from 40 HCC patients. HCC cells were treated by hypoxia. The levels of NR2F1-AS1, microRNA (miR)-140, and hexokinase 2 (HK2) were examined via quantitative reverse transcription polymerase chain reaction or Western blot. Glycolysis was analyzed via glucose uptake, lactate production, and adenosine triphosphate (ATP) levels. Cell migration was analyzed via transwell assay. The target association was analyzed via dual-luciferase reporter assay and RNA immunoprecipitation. Results NR2F1-AS1 level was enhanced in HCC tissues and cells. High expression of NR2F1-AS1 indicated poor overall survival. Silence of NR2F1-AS1 repressed hypoxia-induced glycolysis and migration in HCC cells. NR2F1-AS1 could regulate HK2 expression by modulating miR-140. miR-140 down-regulation or HK2 up-regulation mitigated the influence of NR2F1-AS1 silence on hypoxia-induced glycolysis and migration in HCC cells. Conclusion NR2F1-AS1 knockdown restrained hypoxia-induced glycolysis and migration in HCC cells via increasing miR-140 and decreasing HK2.

/pdf/nr2f1-as1-mir-140-hk2-axis-regulates-hypoxia-induced-37enfgpck6.pdf

NR2F1-AS1/miR-140/HK2 Axis Regulates Hypoxia-Induced Glycolysis and Migration in Hepatocellular Carcinoma.

Evidence suggests that microRNAs (miRNAs) regulate the expression of genes involved in bone metabolism. This study aimed to investigate the role of miR-505 in the osteogenic differentiation of MC3T3-E1 cells. We performed miRNA sequencing to identify differentially expressed miRNAs between MC3T3-E1 cells treated with osteogenic induction medium (OIM) and control cells. Bioinformatics analysis was performed by using the TargetScan and miRDB databases. The expression of miR-505 in MC3T3-E1 cells was detected during osteogenic differentiation. After transfection with miR-505 mimic or miR-505 inhibitor, MC3T3-E1 cells were induced to differentiate into osteoblasts, and the expression of osteogenic differentiation markers (Runt-related transcription factor 2 (RUNX2), alkaline phosphatase (ALP), osteopontin (OPN), osteocalcin (OCN), and osterix (OSX)) was detected. miR-505 was the most downregulated miRNA among the differentially expressed miRNAs. The RUNX2 gene was identified as a potential target of miR-505 using the target prediction program. miR-505 expression was downregulated during osteogenic differentiation of MC3T3-E1 cells. The expression of osteogenic marker genes was inhibited in MC3T3-E1 cells after transfection with miR-505. However, the expression of osteogenic marker genes was upregulated after transfection with miR-505 inhibitor. This study is the first to report miR-505 could bind to the RUNX2 gene and thus regulate partly the dysfunction of osteoblasts differentiation, which is expected to be targets for the treatment of osteoporosis.

https://link.springer.com/content/pdf/10.1186/s13018-020-01645-2.pdf

MicroRNA-505 is involved in the regulation of osteogenic differentiation of MC3T3-E1 cells partially by targeting RUNX2

Hepatocellular carcinoma (HCC) is a high-mortality malignant tumor with genetic and phenotypic heterogeneity, making predicting clinical outcomes challenging. The purpose of this investigation was to examine the potential usefulness of lncRNA DDX11 antisense RNA 1 (DDX11-AS1) as a biomarker for diagnosis and prognosis in hepatocellular carcinoma (HCC). The TCGA-LIHC datasets were searched for patients' clinical information and RNA-seq data, which were then collected. Relative expression levels of DDX11-AS1 in HCC tissues were determined by qRT-PCR. In order to test the sensitivity and specificity of the DDX11-AS1 receiver, receiver operating characteristic curves were utilized. The association of DDX11-AS1 expression with clinicopathological factors or prognosis was statistically analyzed. We found that the levels of DDX11-AS1 were higher in HCC specimens than in normal specimens. ROC analysis showed that DDX11-AS1 was a useful marker for discriminating HCC tissues from normal nontumor specimens. According to the results of clinical tests, a high level of DDX11-AS1 expressions was significantly related to the pathologic stage (p=0.015) and the histologic grade (p < 0.001). Survival studies indicated that patients with higher DDX11-AS1 expression had a significantly poorer overall survival (p=0.005) and progression-free interval (p=0.003) than those with lower DDX11-AS1 expression. Multivariate survival analysis verified that DDX11-AS1 expression level was an independent predictor for HCC patients. Overall, DDX11-AS1 may serve as a tumor promotor during HCC progression, and its high level may be a potential marker for HCC patients.

/pdf/the-clinical-value-of-long-noncoding-rna-ddx11-as1-as-a-3g5d4tu3.pdf

The Clinical Value of Long Noncoding RNA DDX11-AS1 as a Biomarker for the Diagnosis and Prognosis of Hepatocellular Carcinoma

Abstract Integrin subunit alpha 3 (ITGA3) expression correlates with the development and prognosis of human cancers. This study aimed to investigate the association of ITGA3 expression with pancreatic cancer (PCa) prognosis. The ITGA3 gene expression data were extracted from The Cancer Genome Atlas (TCGA) pancreatic adenocarcinoma (PAAD) cohort and 14 Gene Expression Omnibus microarray datasets. The differences in ITGA3 expression levels between tumor and non-tumor tissues were compared using the Mann–Whitney U test. Cox regression analysis and meta-analysis were performed to detect the association of ITGA3 expression with PCa prognosis. ITGA3 expression was higher in tumors than in controls. Tumors with advanced grades (3/4) had higher ITGA3 levels compared with early-grade tumors (1/2). The meta-analysis of the TCGA PAAD cohort and seven microarray datasets (GSE28735, GSE62452, GSE79668, GSE71729, GSE57495, GSE78229, and GSE21501) showed that ITGA3 was a prognostic biomarker in PCa (hazard ratio (HR) = 1.38, 95% confidence interval (CI) 1.26–1.51, p < 0.00001). Five ITGA3-related genes, including ITGB1 (HR = 1.6), ITGB5 (HR = 1.6), ITGB6 (HR = 1.6), LAMA3 (HR = 2.1), and CD9 (HR = 2.3), correlated with PCa prognosis significantly (p < 0.05). Functional enrichment analysis showed that ITGA3 was related to “hsa04151: PI3K-Akt signaling pathway” and “hsa04510: Focal adhesion.” We concluded that high ITGA3 expression was a potential prognostic biomarker in PCa.

https://www.degruyter.com/document/doi/10.1515/med-2022-0606/pdf

Integrated bioinformatics analysis shows integrin alpha 3 is a prognostic biomarker for pancreatic cancer

Hepatocellular carcinoma (HCC) is one of the most common cancers globally. An increasing body of evidence has demonstrated the critical function of microRNAs (miRNAs) in the initiation and progression of human cancers. Here, we showed that miR-505 was down-regulated in HCC tissues and cell lines. Reduced expression of miR-505 was significantly correlated with the worse prognosis of HCC patients. Overexpression of miR-505 suppressed the proliferation, colony formation and induced apoptosis of both HepG2 and Huh7 cells. Further mechanism study uncovered that miR-505 bound the 3'-untranslated region (3'-UTR) of the insulin growth factor receptor (IGF-1R) and inhibited the expression of IGF-1R in HCC cells. The down-regulation of IGF-1R by miR-505 further suppressed the phosphorylation of AKT at the amino acid S473. Consistently, the abundance of glucose transporter (GLUT) 1 (GLUT1) was reduced with the overexpression of miR-505. Down-regulation of GLUT1 by miR-505 consequently attenuated the glucose uptake, lactate production and ATP generation of HCC cells. Collectively, our results demonstrated the tumor suppressive function of miR-505 possibly via inhibiting the glycolysis of HCC cells. These findings suggested miR-505 as an interesting target for designing anti-cancer strategy in HCC.

/pdf/mir-505-suppressed-the-growth-of-hepatocellular-carcinoma-3932l5fjf8.pdf

MiR-505 suppressed the growth of hepatocellular carcinoma cells via targeting IGF-1R.

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The Clinical Value of Long Noncoding RNA DDX11-AS1 as a Biomarker for the Diagnosis and Prognosis of Hepatocellular Carcinoma

Integrated bioinformatics analysis shows integrin alpha 3 is a prognostic biomarker for pancreatic cancer

MiR-505 suppressed the growth of hepatocellular carcinoma cells via targeting IGF-1R.