The Role of Long Non-Coding RNA and microRNA Networks in Hepatocellular Carcinoma and Its Tumor Microenvironment
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ABSTRACT:
SUBMITTER: Shi T
PROVIDER: S-EPMC8508708 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Hepatocellular carcinoma (HCC) accounts for about 80-90% of all liver cancers and is found to be the third most common cause of cancer mortality in the Asia-Pacific region. Risk factors include hepatitis B and C virus, cirrhosis, aflatoxin-contaminated food, alcohol, and diabetes. Surgically removing the tumor tissue seems effective but a high chance of recurrence has led to an urgent need to develop novel molecules for the treatment of HCC. Clinical management with sorafenib is found to be effective but it is only able to prolong survival for a few months. Various side effects like gastrointestinal and abdominal pain, hypertension, and hemorrhage are also associated with sorafenib, which calls for the unmet need of effective therapies against HCC. Similarly, the genetic mechanisms behind the occurrence of HCC are still unknown and need to be expounded further for developing newer candidates. Since unearthing the concept of these variants, transcriptomics has revealed the role of noncoding RNAs (ncRNAs) in many cellular, physiological and pathobiological processes. They are also found to be widely associated and abundantly expressed in a variety of cancer. Aberrant expression and mutations are closely related to tumorigenesis and metastasis and hence are classified as novel biomarkers and therapeutic targets for the treatment of cancer, including HCC. Herein, this review summarises the relationship between ncRNAs and hepatocellular carcinoma.
| S-EPMC7403690 | biostudies-literature
Project description:A number of recent studies have focused on the association between long non-coding RNAs (lncRNAs) and cancer. HOX transcript antisense RNA (HOTAIR), an lncRNA that functions as a transcriptional modulator, has been implicated in various fundamental biological activities. HOTAIR mediates the trimethylation of histone H3 at lysine 27 and the demethylation of histone H3 dimethyl Lys4 by recruiting the polycomb repressive complex 2 and the lysine-specific demethylase 1/co-repressor of RE1-silencing transcription factor (coREST)/REST complex to the target gene promoters, which leads to gene silencing. Overexpression of HOTAIR in hepatocellular carcinoma (HCC) is strongly associated with an unfavorable prognosis for patients with HCC. HOTAIR promotes the carcinogenic activity of HCC cells through the suppression of RNA binding motif protein 38, triggering the epithelial-mesenchymal transition, and by interacting with microRNAs that act as tumor suppressors. In the present review, the role of the lncRNA HOTAIR in HCC is examined. The potential use of HOTAIR as a biomarker to achieve more accurate prognostic predictions and as an effective therapeutic target for HCC is then discussed.
| S-EPMC5529952 | biostudies-other
Project description:The long non-coding RNAs (lncRNAs) have been demonstrated to play pivotal roles in a broad range of processes including tumor biology. However, the exact contributions of lncRNAs to hepatocellular carcinoma (HCC) remain poorly defined. In current study, we have unraveled a novel function of AK023948 in HCC. We found that AK023948 was substantially upregulated in tumor tissues. Meanwhile, higher AK023948 expression correlated with poor survival. Upregulation of AK023948 expression can promote HepG2 and Hep3B proliferation and invasion in in vitro experiments. Furthermore, AK023948 also decreased tumor growth in vivo. The tumorigenic role of AK023948 was partially ascribed to PI3K/Akt/mTOR signaling and AK023948 knockdown decreased pathway activation and tumor growth. These data collectively suggest an oncogenic role for AK023948 and may provide potential insight into therapeutic intervention.
| S-EPMC5639403 | biostudies-literature
Project description:Background:Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related deaths worldwide. Although multiple efforts have been made to understand the development of HCC, morbidity, and mortality rates remain high. In this study, we aimed to discover the mRNAs and long non-coding RNAs (lncRNAs) that contribute to the progression of HCC. We constructed a lncRNA-related competitive endogenous RNA (ceRNA) network to elucidate the molecular regulatory mechanism underlying HCC. Methods:A microarray dataset (GSE54238) containing information about both mRNAs and lncRNAs was downloaded from the Gene Expression Omnibus database. Differentially expressed genes (DEGs) and lncRNAs (DElncRNAs) in tumor tissues and non-cancerous tissues were identified using the limma package of the R software. The miRNAs that are targeted by DElncRNAs were predicted using miRcode, while the target mRNAs of miRNAs were retrieved from miRDB, miRTarBas, and TargetScan. Functional annotation and pathway enrichment of DEGs were performed using the EnrichNet website. We constructed a protein-protein interaction (PPI) network of DEGs using STRING, and identified the hub genes using Cytoscape. Survival analysis of the hub genes and DElncRNAs was performed using the gene expression profiling interactive analysis database. The expression of molecules with prognostic values was validated on the UALCAN database. The hepatic expression of hub genes was examined using the Human Protein Atlas. The hub genes and DElncRNAs with prognostic values as well as the predictive miRNAs were selected to construct the ceRNA networks. Results:We found that 10 hub genes (KPNA2, MCM7, CKS2, KIF23, HMGB2, ZWINT, E2F1, MCM4, H2AFX, and EZH2) and four lncRNAs (FAM182B, SNHG6, SNHG1, and SNHG3) with prognostic values were overexpressed in the hepatic tumor samples. We also constructed a network containing 10 lncRNA-miRNA-mRNA pathways, which might be responsible for regulating the biological mechanisms underlying HCC. Conclusion:We found that the 10 significantly overexpressed hub genes and four lncRNAs were negatively correlated with the prognosis of HCC. Further, we suggest that lncRNA SNHG1 and the SNHG3-related ceRNAs can be potential research targets for exploring the molecular mechanisms of HCC.
| S-EPMC6827457 | biostudies-literature
Project description:Hepatocellular carcinoma (HCC) is a highly aggressive, solid malignancy that has a poor prognosis. Long non-coding RNAs (lncRNAs) have been found to be dysregulated in various cancers, including HCC. However, the molecular mechanism involving lncRNAs in HCC remains largely unknown. In this study, lncRNAs differentially expressed between HCC and corresponding non-cancerous tissue were identified by microarray analysis. A specific differentially expressed lncRNA UBE2CP3 (ubiquitin conjugating enzyme E2 C pseudogene 3) was identified. LncRNA UBE2CP3 was frequently up-regulated in HCC samples as assessed by quantitative real-time polymerase chain reaction (qRT-PCR) and in situ hybridization (ISH) experiments. Clinical data showed that high levels of lncRNA UBE2CP3 were correlated with poor prognosis in HCC patients. Functional studies demonstrated that over-expression of lncRNA UBE2CP3 promoted cell invasion and migration in vitro and in vivo. Mechanistically, enhanced expression of lncRNA UBE2CP3 increased the expression of Snail1 and N-cadherin, but decreased the expression of E-cadherin, thus promoting the process of epithelial to mesenchymal transition (EMT) and finally inducing cell invasion and migration. Furthermore, serum levels of lncRNA UBE2CP3 were increased in HCC patients and decreased after surgery. Our results suggest that lncRNA UBE2CP3 promotes the metastasis of HCC and that serum lncRNA UBE2CP3 may be a new biomarker for the diagnosis of HCC.
| S-EPMC5630337 | biostudies-literature
Project description:Hepatocellular carcinoma (HCC) accounts for approximately 85%-90% of primary liver cancers. Based on in silico analysis, differentially expressed long non-coding RNA (lncRNA) LINC01224 in HCC, the downstream microRNA (miRNA) miR-330-5p, and its target gene checkpoint kinase 1 (CHEK1) were selected as research subjects. Herein, this study was designed to evaluate their interaction effects on the malignant phenotypes of HCC cells. LINC01224 and CHEK1 were upregulated and miR-330-5p was downregulated in HCC cells. miR-330-5p shared negative correlations with LINC01224 and CHEK1, and LINC01224 shared a positive correlation with CHEK1. Notably, LINC01224 could specifically bind to miR-330-5p, and CHEK1 was identified as a target gene of miR-330-5p. When LINC01224 was silenced or miR-330-5p was elevated, the sphere and colony formation abilities and proliferative, migrative, and invasive potentials of HCC cells were diminished, while cell cycle arrest and apoptosis were enhanced. Moreover, LINC01224 induced HCC progression in vitro and accelerated tumor formation in nude mice by increasing CHEK1 expression. The key findings of the present study demonstrated that silencing LINC01224 could downregulate the expression of CHEK1 by competitively binding to miR-330-5p, thus inhibiting HCC progression. This result highlights the LINC01224/miR-330-5p/CHEK1 axis as a novel molecular mechanism involved in the pathology of HCC.
| S-EPMC6948252 | biostudies-literature
Project description:MicroRNA (miRNA) and long non-coding RNA (lncRNA) have been demonstrated to participate in the progression of many cancers. Hepatocellular carcinoma (HCC) is one of the most common and aggressive malignant tumors worldwide, while the molecular mechanisms underlying HCC tumorigenesis are not completely clear. In this study, we showed that miR-92b was significantly upregulated in tumor tissue and plasma of HCC patients, and its expression level was highly correlated with gender and microvascular invasion. Functionally, miR-92b could promote cell proliferation and metastasis of HCC in vitro and in vivo. Mechanistic investigations suggested that Smad7, which exhibited an inverse relationship with miR-92b expression in HCC, was a direct target of miR-92b and could reverse its effects on HCC tumorigenesis. Furthermore, long non-coding RNA (lncRNA) X-inactive specific transcript (XIST) and miR-92b could directly interact with and repress each other, and XIST could inhibit HCC cell proliferation and metastasis by targeting miR-92b. Taken together, our study not only revealed for the first time the importance of XIST/miR-92b/Smad7 signaling axis in HCC progression but also suggested the potential value of miR-92b as a biomarker in the clinical diagnosis and treatment of HCC.
| S-EPMC4855645 | biostudies-literature
Project description:Hepatocellular carcinoma (HCC) poses an increasing threat to humans, due to its poor prognosis. Nuclear‑enriched abundant transcript 1 (NEAT1), a type of long non‑coding (lnc)RNA, has been found to function in a variety of cancer types. However, the role of NEAT1 in HCC is poorly understood. Reverse transcription‑quantitative PCR was used to detect the expression levels of NEAT1, microRNA (miR)‑503 and Smoothened (SMO) mRNA in HCC tissues and cells. MTT and flow cytometry assays were used to investigate cell viability and apoptosis, respectively, while Transwell assays were performed to investigate cell invasion and migration. StarBase and TargetScan were utilized to predict the target sequence between miR‑503 and NEAT1 or SMO, the results of which were verified using a dual‑luciferase reporter assay. The protein expression level of SMO was measured using western blot. The RNA expression level of NEAT1 and SMO was significantly elevated in HCC tissues and cells compared with that in the corresponding healthy tissues and cells, which was contrary to miR‑503 expression level. NEAT1 silencing was found to restrict the viability, migration and invasion of the cells, while simultaneously induced apoptosis in the HCC cell line. Further studies found that miR‑503 expression was negatively correlated with NEAT1 or SMO. It was also confirmed that NEAT1 directly interacted with miR‑503 and miR‑503 could bind to the 3'‑untranslated region of SMO. Furthermore, overexpression of NEAT1 or SMO could reverse the effects of miR‑503‑mediated inhibition on cell viability, invasion, migration and promotion of apoptosis in the HCC cell lines. These results demonstrated that downregulation of NEAT1 impeded the viability, migration, invasion and induced apoptosis through the NEAT1/miR‑503/SMO axis in the HCC cell line.
| S-EPMC7821340 | biostudies-literature
Project description:BackgroundThe hepatocellular carcinoma (HCC) belongs to a common malignancy especially in China. Recent data have clarified important roles of long non-coding RNAs (lncRNAs) in HCC. However, the role of a novel intergenic lncRNA termed TGLC15 is still elusive.MethodsWe screened for novel lncRNAs using lncRNA profiling. TGLC15 expression was quantified by qRT-PCR. In vitro experiments such as migration and viability assays were performed. In vivo implantation experiments were conducted to investigate tumorigenic functions of TGLC15. Combined RNA immunoprecipitation (RIP) and mass spectrometry (MS) were utilized to uncover Sox4 as TGLC15 binding protein.ResultsTGLC15 is significantly overexpressed in tumor tissues and HCC cell lines. Higher TGLC15 levels correlated with advanced malignant characteristics such as TNM stages, tumor size, and metastasis. TGLC15 advanced HCC migration and viability. The in vivo experiments supported that xenograft tumor growth and proliferation were facilitated by TGLC15 overexpression. Mechanistic studies showed that TGLC15 interacted with Sox4 and interaction between TGLC15 and Sox4 could stabilize Sox4 via reduction in proteasome-mediated degradation.ConclusionsCollectively, our data have identified a novel lncRNA TGLC15 during HCC development. The TGLC15-Sox4 signaling might be a potential target for pharmaceutical intervention.
| S-EPMC6977111 | biostudies-literature
Project description:Long non?coding RNAs (lncRNAs) have been shown to contribute to progression and prognosis of hepatocellular carcinoma (HCC). However, expression profiling and interaction of lncRNAs with messenger RNAs (mRNAs) and microRNAs (miRNAs) remain largely unknown in HCC. The expression profiling of lncRNAs, mRNA and miRNAs was obtained using microarray. The Gene Ontology (GO) enrichment and Kyoto Encyclopedia of Genes and Genomes pathway analysis were used to characterize potential functions of differentially expressed mRNAs. Cytoscape was applied to construct an lncRNA?miRNA?mRNA co?expression network and candidate lncRNAs were validated via quantitative PCR in 30 pairs of HCC and adjacent tumor?free tissues. In this study, 1,056 upregulated and 1,288 downregulated lncRNAs were identified, while 2,687 mRNAs and 6 miRNAs were aberrantly expressed in HCC compared with adjacent tumor?free tissues. Potential functions of differentially expressed mRNAs were demonstrated to significantly participate in modulating critical genes in the cell cycle, such as cyclin E1 and cyclin B2. After screening, 95 lncRNAs, 5 miRNAs and 36 mRNAs were recruited for construction of lncRNA?mRNA?miRNA co?expression network in the cell cycle pathway. Subsequently, the top 5 lncRNAs that potentially modulate critical genes in the cell cycle were selected as the candidates for further verification. Kaplan?Meier curves using the Cancer Genome Atlas database showed that 13 targeted mRNAs were associated with overall survival of HCC patients. Finally, three lncRNAs, including ENST00000522221, lnc?HACE1?6:1 and lnc?ICOSLG?11:1, are significantly upregulated in HCC tissues compared with adjacent tumor?free tissues. These findings suggest that lncRNAs play essential roles in the pathogenesis of HCC via regulating coding genes and miRNAs, and may be important targets for diagnosis and treatment of this disease.
| S-EPMC6777664 | biostudies-literature