CD44 promotes hepatocellular carcinoma progression via upregulation of YAP
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ABSTRACT: Supplementary Information
The online version contains supplementary material available at 10.1186/s40164-021-00247-w.
SUBMITTER: Zhang J
PROVIDER: S-EPMC8603576 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundCircular RNAs (circRNAs), which are involved in various human malignancies, have emerged as promising biomarkers. The present study aimed to investigate unique expression profiles of circRNAs in hepatocellular carcinoma (HCC) and identify novel biomarkers associated with HCC development and progression.MethodsCircRNA expression profiles of HCC tissues were jointly analyzed to identify differentially expressed circRNAs. Overexpression plasmid and siRNA targeting candidate circRNAs were used in functional assays in vitro. CircRNA-miRNA interactions were predicted using miRNAs expressed in the miRNA-seq dataset GSE76903. To further screen downstream genes targeted by the miRNAs, survival analysis and qRT-PCR were conducted to evaluate their prognostic role in HCC and construct a ceRNA regulatory network.ResultsThree significantly upregulated circRNAs, hsa_circ_0002003, hsa_circ_0002454, and hsa_circ_0001394, and one significantly downregulated circRNA, hsa_circ_0003239, were identified and validated by qRT-PCR. Our in vitro data indicated that upregulation of hsa_circ_0002003 accelerated cell growth and metastasis. Mechanistically, DTYMK, DAP3, and STMN1, which were targeted by hsa-miR-1343-3p, were significantly downregulated in HCC cells when hsa_circ_0002003 was silenced and were significantly correlated with poor prognosis in patients with HCC.ConclusionHsa_circ_0002003 may play critical roles in HCC pathogenesis and serve as a potential prognostic biomarker for HCC. Targeting the hsa_circ_0002003/hsa-miR-1343-3p/STMN1 regulatory axis could be an effective therapeutic strategy in patients with HCC.
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Project description:Hepatocellular carcinoma (HCC) is a common digestive tumor with high fatality worldwide. Previous studies have shown that Reticulocalbin-2 (RCN2) was a crucial factor for HCC proliferation, but invasion and migration mechanism of RCN2 contributing to HCC is poorly investigated. In this study, we estimated the RCN2 expression in both patient tissues and cell lines by polymerase chain reaction (PCR) and western blotting (WB), as well as the clinical information of HCC patients from public databases. Biological function induced by RCN2 in vitro and vivo was also researched through multiple functional experiments. Upstream and downstream signal of RCN2 was identified by bioinformatics. We found that up-regulated RCN2 was related to poorer prognosis in HCC patients and attached significance to HCC proliferation, invasion and migration. Luciferase reporter assay and chromatin immunoprecipitation validated that YY1 as the upstream transcription factor of RCN2, facilitating the expression of RCN2. Gene set enrichment analysis indicated that HCC progression induced by RCN2 might be related to MYC signaling. Furthermore, we demonstrated RCN2 reduced proteasomal degradation of MYC and lead to HCC progression. The effects of overexpressed RCN2 in HCC were attenuated by MYC silencing. In conclusion, our study highlighted the vital role of RCN2 in tumor progression and the potential benefit for the treatment of HCC.
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Project description:Malignant T-cell-amplified sequence 1 (Mct-1) has been reported as an oncogene in multiple malignant diseases. However, the function of Mct-1 in hepatocellular carcinoma (HCC) and the molecular mechanisms underlying tumor progression have not been explored. In this study, Mct-1 expression levels in HCC tissues and cells were detected by quantitative real-time PCR and western blotting. Mct-1 shRNAs and overexpression vector were transfected into HCC cells to downregulate or upregulate Mct-1 expression. In vitro and in vivo assays were performed to investigate the function of Mct-1 in cell proliferation and apoptosis. RNA sequencing analysis (RNA-seq) was performed to explore differences in gene expression when silenced Mct-1 expression. Mct-1 was upregulated in HCC specimens and cell lines, and higher expression of Mct-1 was predictive of poor survival. Overexpression of Mct-1 was shown to promote cell proliferation and repress cell apoptosis both in vitro and in vivo. The results of RNA-seq indicated that knockdown of Mct-1 suppressed Yap expression, while the results of the luciferase assay also revealed that Mct-1 increases the activity of the Yap promoter. Restoration of Yap expression in Mct-1 knockdown cells partially recovered the promotion of cell proliferation and inhibition of apoptosis. Collectively, these results indicate that Mct-1 acts as a tumor promoter gene in HCC progression by up-regulating Yap expression and, thus, could serve a novel potential diagnostic and prognostic biomarker for HCC.
| S-EPMC7985373 | biostudies-literature
Project description:BackgroundHepatocellular carcinoma (HCC) is the most common type of primary liver cancer and one of the major causes of cancer-related death. Thymidylate synthase (TYMS) catalyzes the methylation of deoxy guanosine to deoxy thymidylate, which is a crucial gene for DNA repair and replication. Thus, TYMS was reported to be closely associated with developing a variety of tumors, but it has been poorly studied in HCC.Materials and methodsWe used the cell counting kit-8 (CCK-8), BrdU, and CFSE assay to measure cell proliferation. The flow cytometry assay and the TUNEL assay were used for assessing cell apoptosis. The flow cytometry assay was used to analyze the cell cycle. The Transwell invasion assay and the wound healing assay were conducted to determine the invasive ability of the cells. RT-qPCR and Western blot analyses were performed to evaluate the mRNA and protein expression levels of specific genes, respectively.ResultsTYMS was found to be upregulated in both HCC cells and patient samples. High expression of TYMS was associated with an unfavorable prognosis in HCC patients based on the TCGA-LIHC dataset. Cell proliferation, apoptosis, and invasion assays revealed that TYMS promoted the proliferation and invasion of HCC cells as well as inhibited apoptosis. In addition, TYMS is a downstream target of FOXM1. TYMS knockdown reversed the 5-FU resistance caused by FOXM1 overexpression and re-sensitized HCC cells to 5-FU treatment.ConclusionThis study suggested that TYMS serves as an oncogene in HCC, and targeting the FOXM1-TYMS axis may help improve the survival of HCC patients as well as provide new insights for treating advanced HCC patients.
| S-EPMC8801073 | biostudies-literature
Project description:Nuclear protein 1 (NUPR1) is a transcriptional coregulator that has been implicated in the development of various cancer types. In addition, de novo fatty acid synthesis plays a pivotal role in hepatocellular carcinoma (HCC) development. However, little is currently known on the role of NUPR1 in hepatocellular carcinoma. In this study, bioinformatics analysis was conducted to analyze the expression level, prognosis value and enriched pathways of NUPR1 in Liver Hepatocellular Carcinoma (LIHC). We found that NUPR1 was significantly upregulated in human hepatocellular carcinoma cells compared with normal hepatocytes from LIHC patients in TCGA cohorts and our patients. Kaplan-Meier analysis and COX proportional hazard progression model showed that high expression of NUPR1 was correlated with a poor prognosis of LIHC patients. CCK-8, EdU and colony formation assays were performed to explore the effect of NUPR1 on the proliferation of HCC cells, then wound healing and transwell migration assays were performed to evaluate the effects of NUPR1 on cell migration. Furthermore, subcutaneous xenograft models were established to study tumor growth. Results showed that NUPR1 overexpression correlated with a highly proliferative and aggressive phenotype. In addition, NUPR1 knockdown significantly inhibited hepatocellular carcinoma cell proliferation and migration in vitro and hindered tumorigenesis in vivo. Mechanistically, endogenous NUPR1 could interact with sterol regulatory element binding protein 1 (SREBP1) and upregulated lipogenic gene expression of fatty acid synthase (FASN), resulting in the accumulation of lipid content. Moreover, pharmacological or genetic blockade of the NUPR1-SREBP1/FASN pathway enhanced anticancer activity in vitro and in vivo. Overall, we identified a novel function of NUPR1 in regulating hepatocellular carcinoma progression via modulation of SREBP1-mediated de novo lipogenesis. Targeting NUPR1-SREBP1/FASN pathway may be a therapeutic alternative for hepatocellular carcinoma.
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Project description:BackgroundThe upregulation of ADAM17 has been reported to be associated with invasion and metastasis in various tumors, however the molecular mechanism of ADAM17 in the progression of hepatocellular carcinoma (HCC) remain to be clarified. Human matrix metalloproteinase 21 (MMP21), the newest member of the MMP gene family, has been suggested to play an important role in embryogenesis and tumor progression. So far, nothing is known about the relationship between ADAM17 and MMP21.MethodsIn this study, the expression level of ADAM17 and MMP21 in HCC tissues was measured by immunohistochemistry. The Scratch wounding assay and Transwell were used to identify the invasion and metastasis ability. ELISA was used to evaluate the production of MMP21. Coimmunoprecipitation experiments demonstrated a direct association between ADAM17 and MMP21. HPLC was used to confirmed that ADAM17 participated in the maturation of MMP21.ResultsOur present data indicated that ADAM17 and MMP21 was significantly upregulated in human HCC tissues. Knockdown of ADAM17 in HCC inhibited cell invasion and metastasis. Moreover, ADAM17 regulates the secretion and expression of MMP21. Furthermore we discovered a direct association between ADAM17 and MMP21, and we also found MMP21 prodomain could be cleaved by ADAM17.ConclusionOur data suggest that ADAM17 plays an important role in the development of HCC invasion and metastasis and this function may be implement by MMP21.
| S-EPMC7579888 | biostudies-literature
Project description:As a member of damage-associated molecular patterns (DAMPs), extracellular high-mobility group box 1 (HMGB1) plays a critical role in hepatocellular carcinoma (HCC) progression. Cluster differentiation 44 (CD44) has been demonstrated to participate in HCC progression. However, the relationship between extracellular HMGB1 and CD44 remains unclear. In this study, our results indicated that extracellular HMGB1 promoted the invasion, sphere formation and EMT process of HCC by increasing CD44 expression, which was dependent on miR-21. Moreover, miR-21 upregulated CD44 expression via activating OCT4/TGF-β1 signaling. Finally, we demonstrated the activation of Rage/JNK signaling caused by extracellular HMGB1 was responsible for miR-21 overexpression. Together, these findings reveal an important role of extracellular HMGB1 in HCC progression through upregulating miR-21/CD44.
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| S-EPMC11341911 | biostudies-literature
Project description:BackgroundCircular RNA (circRNA), a new class of non-coding RNA, has obvious correlations with the occurrence and development of many diseases, including tumors. This study aimed to investigate the potential roles of circPAK1 in hepatocellular carcinoma (HCC).MethodsHigh-throughput sequencing was performed on 3 pairs of HCC and matched normal tissues to determine the upregulated circRNAs. The expression level of circPAK1 was detected by qRT-PCR in HCC and paired with normal liver tissue samples. The effects of circPAK1 on proliferation, invasion, metastasis and apoptosis of HCC cells were evaluated by in vitro and in vivo experiments. We also constructed Chitosan/si-circPAK1 (CS/si-circPAK1) nanocomplexes using Chitosan material to evaluate its in vivo therapeutic effect on HCC. High-throughput sequencing, RNA-sequencing, RNA probe pull-down, RNA immunoprecipitation and Co-Immunoprecipitation assays were performed to explore the relationship between circPAK1, 14-3-3ζ, p-LATS1 and YAP. Exosomes isolated from lenvatinib-resistant HCC cell lines were used to evaluate the relationship between exosomal circPAK1 and lenvatinib resistance.ResultsCircPAK1, a novel circRNA, is highly expressed in HCC tumor tissues and cell lines as well as correlated with poor outcomes in HCC patients. Functionally, circPAK1 knockdown inhibited HCC cell proliferation, migration, invasion and angiogenesis while circPAK1 overexpression promoted HCC progression. The tumor-promoting phenotypes of circPAK1 on HCC were also confirmed by animal experiments. Importantly, the application of CS/si-circPAK1 nanocomplexes showed a better therapeutic effect on tumor growth and metastasis. Mechanistically, circPAK1 enhanced HCC progression by inactivating the Hippo signaling pathway, and this kind of inactivation is based on its competitively binding of 14-3-3 ζ with YAP, which weakens the recruitment and cytoplasmic fixation of 14-3-3 ζ to YAP, thus promoting YAP nucleus localization. Additionally, circPAK1 could be transported by exosomes from lenvatinib-resistant cells to sensitive cells and induce lenvatinib resistance of receipt cells.ConclusionCircPAK1 exerts its oncogenic function by competitively binding 14-3-3 ζ with YAP, thus promoting YAP nucleus localization, leading to the inactivation of a Hippo signaling pathway. Exosomal circPAK1 may drive resistance to lenvatinib, providing a potential therapeutic target for HCC patients.
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Project description:Cystatin SN, a specific cysteine protease inhibitor, is thought to be involved in various malignant tumors. Therefore, we evaluated the role of cystatin SN in hepatocellular carcinoma (HCC). Notably, cystatin SN was elevated in tumorous samples and cells. Moreover, overexpression of cystatin SN was correlated with tumor diameter and TNM stage. Cox multivariate analysis displayed that cystatin SN was an independent prognosis indicator and that high cystatin SN level was associated with a dismal prognosis. Moreover, cystatin SN enhancement facilitated the proliferation, migratory, and invasive potential of Huh7 and HCCLM3 cells, whereas cystatin SN knockdown caused the opposite effect. Cystatin SN also modulated the epithelial-mesenchymal transition progression through the PI3K/AKT pathway. In vivo cystatin SN promoted HCCLM3 cell growth and metastasis in xenograft mice model. Thus, cystatin SN was involved in HCC progression and could be a latent target for HCC treatment.
| S-EPMC6767558 | biostudies-literature