Small nucleolar RNA 42 promotes the growth of hepatocellular carcinoma through the p53 signaling pathway
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ABSTRACT:
SUBMITTER: Wang G
PROVIDER: S-EPMC8581050 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Hepatocellular carcinoma (HCC) is one of the most prevalent cancers and currently the second leading cause of cancer-related mortality worldwide. One recent study reported that lncRNA-LALR1 promotes liver regeneration, the role and underlying mechanisms of lncRNA-LALR1 in HCC remain largely unknown. In this study, we demonstrated that lncRNA-LALR1 was significantly upregulated in HCC tissues compared with adjacent tissues and high expression of lncRNA-LALR1 was associated with advanced TNM stage, poor differentiation, and distant metastasis. RNA Fluorescence in situ hybridization analysis showed lncRNA-LALR1 was expressed not only in cytoplasm but also in nucleolus. Knockdown of lncRNA-LALR1 obviously inhibited HCC cells growth and invasion in vivo and in vitro. Besides, transcriptomic analysis and subsequent confirmation revealed that lncRNA-LALR1 upregulated small nucleolar RNA SNORD72 via binding with SNORD72 and stabilized ID2 mRNA. SNORD72 was overexpressed in HCC tissues and enhanced HCC cells proliferation, colony formation and invasion. Overexpression of SNORD72 could also stabilize ID2 mRNA and rescue the inhibitory effect of silencing lncRNA-LALR1. In conclusion, lncRNA-LALR1 is highly expressed in HCC and promotes tumor growth and invasion by upregulating SNORD72 to stabilize ID2 mRNA, implying that lncRNA-LALR1 might be a novel target for intervention of HCC.
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Project description:BackgroundEmerging evidence suggests that small nucleolar RNAs (snoRNAs) are involved in tumorigenesis. The roles of small nucleolar RNA 113-1 (SNORD113-1) on the development of hepatocellular carcinoma (HCC) remain unknown.MethodsThe expression of SNORD113-1 was measured in 112 HCC tumor tissues using quantitative RT-PCR and compared with expression levels from with paired non-tumor tissues. The effects of SNORD113-1 on HCC tumorigenesis were investigated in HepG2 and Huh7 cells as well as a xenograft nude mouse model. CpG methylation within the promoter region of the SNORD113-1 gene was identified using Sodium bisulfite sequencing. Cancer pathway reporter investigate the mechanism by which SNORD113-1 suppressed tumorigenesis.ResultsSNORD113-1 expression was significantly downregulated in HCC tumors compared with adjacent non-tumor tissues, and downregulation of SNORD113-1 in HCC tumors was significantly associated with worse survival of patients. In addition, CpG methylation at the promoter region of the SNORD113-1 gene was higher in HCC tumors than adjacent non-tumor tissues. Functionally, SNORD113-1 suppressed cancer cell growth in HepG2 and Huh7 cells and in a xenograft nude mouse model. Furthermore, SNORD113-1 inactivated the phosphorylation of ERK1/2 and SMAD2/3 in MAPK/ERK and TGF-β pathways.ConclusionsSNORD113-1 functions as a tumor suppressor role in HCC and may be important as a potential diagnostic and therapeutic target for HCC.
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Project description:Non-small cell lung cancer (NSCLC) is the leading cause of cancer death, reflecting the need for better understanding the oncogenesis, and developing new diagnostic and therapeutic targets for the malignancy. Emerging evidence suggests that small nucleolar RNAs (snoRNAs) have malfunctioning roles in tumorigenesis. Our recent study demonstrated that small nucleolar RNA 42 (SNORA42) was overexpressed in lung tumors. Here, we investigate the role of SNORA42 in tumorigenesis of NSCLC. We simultaneously assess genomic dosages and expression levels of SNORA42 and its host gene, KIAA0907, in 10 NSCLC cell lines and a human bronchial epithelial cell line. We then determine in vitro functional significance of SNORA42 in lung cancer cell lines through gain- and loss-of-function analyses. We also inoculate cancer cells with SNORA42-siRNA into mice through either tail vein or subcutaneous injection. We finally evaluate expression level of SNORA42 on frozen surgically resected lung tumor tissues of 64 patients with stage I NSCLC by using quantitative reverse transcriptase PCR assay. Genomic amplification and associated high expression of SNORA42 rather than KIAA0907 are frequently observed in lung cancer cells, suggesting that SNORA42 overexpression is activated by its genomic amplification. SNORA42 knockdown in NSCLC cells inhibits in vitro and in vivo tumorigenicity, whereas enforced SNORA42 expression in bronchial epitheliums increases cell growth and colony formation. Such pleiotropy of SNORA42 suppression could be achieved at least partially through increased apoptosis of NSCLC cells in a p53-dependent manner. SNORA42 expression in lung tumor tissue specimens is inversely correlated with survival of NSCLC patients. Therefore, SNORA42 activation could have an oncogenic role in lung tumorigenesis and provide potential diagnostic and therapeutic targets for the malignancy.
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Project description:Spindle and kinetochore-related complex subunit 3 (SKA3) is a component of the spindle and kinetochore-related complexes and is essential for accurate timing of late mitosis. However, the relationship between SKA3 and hepatocellular carcinoma (HCC) has not yet been fully elucidated. Gene expression omnibus (GEO) (GSE62232, GSE45436, GSE6764, and GSE36376) and The Cancer Atlas (TCGA) datasets were analyzed to identify differential expression genes. Cell proliferation ability was analyzed using Cell Counting Kit-8 (CCK8) assay and plate clone formation assay, while scratch wound healing assay and transwell assay were used to analyze cell invasion. The role of SKA3 in vivo was explored using subcutaneous xenotransplantation model and lung metastasis model. Bioinformatics analysis found that hepatocellular carcinoma patients with high levels of expression of SKA3 have a poor prognosis. Similarly, immunohistochemical staining of 236 samples of tumors also found higher SKA3 expression in them, than in adjacent normal liver tissues. Significant levels of inhibition of in vivo and in vitro tumor proliferation and invasion result from the downregulation of SKA3. Mechanistically, SKA3 was found to affect tumor progression through the cell cycle and P53 signaling pathway as shown by the gene enrichment analysis (GSEA). G2/M phase arrest and severe apoptosis was also found to result from SKA3 knockdown, as shown by the inhibition of CDK2/p53 phosphorylation together with downregulation of BAX/Bcl-2 expression in HCC cells. Overall, these findings uncover the role of SKA3 in regulating the apoptosis and proliferation of hepatocellular carcinoma cells. This study was able to uncover new information on the tumorigenesis mechanism in hepatocellular carcinoma.
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Project description:Abnormalities in the TP53 gene and overexpression of MDM2, a transcriptional target and negative regulator of p53, are commonly observed in cancers. The MDM2-p53 feedback loop plays an important role in tumor progression and thus, increased understanding of the pathway has the potential to improve clinical outcomes for cancer patients. Hepatocellular carcinoma (HCC) has emerged as one of the most commonly diagnosed forms of human cancer; yet, the current treatment for HCC is less effective than those used against other cancers. We review the current studies of the MDM2-p53 pathway in cancer with a focus on HCC and specifically discuss the impact of p53 mutations along with other alterations of the MDM2-p53 feedback loop in HCC. We also discuss the potential diagnostic and prognostic applications of p53 and MDM2 in malignant tumors as well as therapeutic avenues that are being developed to target the MDM2-p53 pathway.
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Project description:Long non‑coding RNAs (lncRNAs) offer great potential as cancer biomarkers. Owing to the limited sensitivity and specificity of α‑fetoprotein (AFP) for the diagnosis of hepatocellular carcinoma (HCC), the present study used an lncRNA microarray to screen aberrantly expressed lncRNAs in HCC tissues. Subsequently, the expression profile of the target lncRNAs was investigated in plasma from patients with HCC or hepatitis B virus‑positive chronic hepatitis and cirrhosis (HCH), as well as from healthy volunteers. A total of six aberrantly expressed lncRNAs were identified in HCC tissues and corresponding normal tissues, from which only small nucleolar RNA host gene 1 (SNHG1) expression in HCC tissues demonstrated a good correlation with those in plasma from HCC patients. Subsequent analysis revealed that high plasma SNHG1 expression levels were correlated with tumor size, TNM stage and AFP levels. Receiver operating characteristic analysis demonstrated that SNHG1 yields an excellent diagnostic ability to differentiate between patients with HCC and unaffected control patients, which was superior to that of AFP. The combination of SNHG1 with AFP may be able to distinguish HCC from HCH or healthy volunteers with the area under the curve values of 0.86 and 0.97, respectively. In summary, it was demonstrated that plasma SNHG1 has great potential as a sensitive and reliable biomarker for the diagnosis of HCC.
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Project description:Hepatocellular carcinoma (HCC) is the third leading cause of cancer related death worldwide; however, the molecular mechanisms regulating HCC progression remain largely unknown. In this study, we determined the role of DDX39 which a DEAD-box RNA helicase in HCC progression, and found DDX39 was upregulated in HCC tissues and cells, DDX39 expression was positive correlated with advanced clinical stage, survival analysis showed patients with high-DDX39 levels had poor outcome, it was an independent prognostic factor. Functional analysis revealed that DDX39 overexpression promoted HCC cell migration, invasion, growth, and metastasis, DDX39 knockdown inhibited HCC cell migration, invasion, growth, and metastasis. Mechanism analysis suggested DDX39 overexpression increased ?-catenin expression in nucleus and increased Wnt/?-catenin pathway target genes levels, while DDX39 knockdown reduced this effect. Knockdown of Wnt/?-catenin pathway co-activators TCF4 and LEF1 in DDX39 overexpressing HCC cells inhibited Wnt/?-catenin pathway target genes. The invasion ability was also reduced, confirming DDX39 regulates HCC progression by activating Wnt/?-catenin pathway. In conclusion, we found DDX39 is a target and prognostic factor for HCC, and promotes HCC migration, invasion, growth, and metastasis by activating Wnt/?-catenin pathway.
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Project description:HCC is a globally high-incidence malignant tumour, and its pathogenesis is still unclear. Recently, STRN3 has been found to be elevated in various tumours, but its expression and biological functions in HCC have not been studied. In the study, clinical correlation analysis was performed on 371 liver cancer patients from TCGA database and liver cancer tissues and normal tissues from the GEO database. qRT-PCR and western blotting were used to detect relevant proteins in cells, and CCK8 and colony formation experiments were performed to analyse cell proliferation ability. Transwell and wound healing experiments were performed to detect cell invasion ability, and flow cytometry was used to detect cell apoptosis. Single-cell sequencing data and multiple immunofluorescence were analysed for the expression abundance and distribution of certain proteins. Immunohistochemistry was used to assess the expression of STRN3 in patients' tumour and adjacent non-cancerous tissues. The results indicated STRN3 was highly expressed in liver tumour tissues and was closely associated with poor prognosis. Knockdown of STRN3 could significantly inhibit cell proliferation and migration ability. At the same time, we found that STRN3 could inhibit the Hippo pathway and promote the entry of YAP protein into the nucleus. Our study first found that STRN3 could promote tumour growth by inhibiting the Hippo pathway. The study of STRN3 can promote the understanding and treatment of the occurrence and development of HCC.
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Project description:Renal cell carcinoma (RCC) is a primary malignant kidney cancer subtype. It has been suggested that long non?coding RNAs (lncRNAs) serve important roles in the progression of kidney cancer. In fact, the lncRNA small nucleolar RNA host gene 12 (SNHG12) was discovered to be overexpressed in various types of cancer. However, to the best of our knowledge, the role of SNHG12 in RCC remains unclear. The present study aimed to investigate the function of SNHG12 and its underlying molecular mechanism of action in RCC. In patient samples and datasets from The Cancer Genome Atlas. Reverse transcription?quantitative PCR, demonstrated that SNHG12 expression levels were upregulated in RCC tumor tissues, but not in normal kidney tissues. SNHG12 upregulation was also observed in RCC cell lines. Kaplan?Meier survival analysis indicated a poor prognosis for those patients with RCC who had upregulated SNHG12 expression levels. Following lentivirus transduction, SNHG12 was successfully knocked down (validated by western blot analysis) and cell migration and invasion assays were performed. SNHG12 knockdown markedly inhibited cell viability and invasion, while increasing apoptosis in both A498 and 786O cell lines. The results of the luciferase reporter assay suggested that SNHG12 exerted its role by sponging microRNA (miR)?200c?5p, which led to the upregulation of its target gene, collagen type XI ?1 chain (COL11A1). This was further validated, as miR?200c?5p inhibition reduced the effects of SNHG12 downregulation on cell viability and apoptosis, without affecting SNHG12 expression levels. Furthermore, the findings indicated that SNHG12 may partially exert its role through COL11A1, which was also upregulated in RCC. In conclusion, the results of the present study suggested that the SNHG12/miR?200c?5p/COL11A1 axis may be crucial for RCC progression, which provided an insight into potential therapeutic strategies for RCC treatment.
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Project description:Increasing evidence suggests that POU domain class 2 transcription factor 1 (POU2F1) participates in carcinogenesis and cancer progression via promotion of cell proliferation and metastasis; however, the functional role of POU2F1 in hepatocellular carcinoma (HCC) is largely unknown. In this study, we determined that POU2F1 was significantly up-regulated in HCC tumor tissue and cell lines. We demonstrated that POU2F1 over-expression promoted HCC cell proliferation, colony formation, migration, and invasion, while silencing of POU2F1 inhibited these malignant phenotypes. In vivo experiments indicated that knockdown of POU2F1 inhibited HCC cell metastasis and xenograft growth, whereas ectopic expression of POU2F1 promoted these cellular functions. Microarray analysis suggests that FAT atypical cadherin 1 (FAT1) can function downstream of POU2F1. Functionally, we demonstrated that POU2F1 knockdown induced growth suppression and metastasis inhibition of HCC cells and inactivated the FAT1 pathway, indicating that POU2F1 is a potential novel therapeutic target in HCC.
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