RABIF promotes hepatocellular carcinoma progression through regulation of mitophagy and glycolysis
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1165735 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR30807641_1.fastq.gz | Fastqsanger.gz | |||
| SRR30807641_2.fastq.gz | Fastqsanger.gz | |||
| SRR30807642_1.fastq.gz | Fastqsanger.gz | |||
| SRR30807642_2.fastq.gz | Fastqsanger.gz | |||
| SRR30807643_1.fastq.gz | Fastqsanger.gz |
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Project description:The RAB interacting factor (RABIF) is a putative guanine nucleotide exchange factor that also functions as a RAB-stabilizing holdase chaperone. It has been implicated in pathogenesis of several cancers. However, the functional role and molecular mechanism of RABIF in hepatocellular carcinoma (HCC) are not entirely known. Here, we demonstrate an upregulation of RABIF in patients with HCC, correlating with a poor prognosis. RABIF inhibition results in decreased HCC cell growth both in vitro and in vivo. Our study reveals that depleting RABIF attenuates the STOML2-PARL-PGAM5 axis-mediated mitophagy. Consequently, this reduction in mitophagy results in diminished mitochondrial reactive oxygen species (mitoROS) production, thereby alleviating the HIF1α-mediated downregulation of glycolytic genes HK1, HKDC1, and LDHB. Additionally, we illustrate that RABIF regulates glucose uptake by controlling RAB10 expression. Importantly, the knockout of RABIF or blockade of mitophagy sensitizes HCC cells to sorafenib. This study uncovers a novel role of RABIF crucial for HCC growth and identifies it as a potential therapeutic target.
2024-09-28 | GSE278116 | GEO
Project description:Accumulating evidence suggests that DEAD-box proteins are essential in RNA metabolism and play pivotal roles in cancer progression. However, the mechanisms underlying how DDX24 drives hepatocellular carcinoma (HCC) remain largely unknown. In this study, we demonstrated that DDX24 was an oncogene and identified DDX24 promoted HCC development via interacting with NCL.
2021-01-29 | PXD023321 | Pride
Project description:Understanding the mechanisms underlying evasive resistance in cancer is an unmet medical need to improve the efficacy of current therapies. In hepatocellular carcinoma (HCC), aberrant expression of hypoxia inducible factor 1 a (HIF1a) and increased aerobic glycolysis metabolism represent drivers of the development of resistance to therapy with the multi-kinase inhibitor Sorafenib. However, it has remained unknown how HIF1a is activated and how its activity and the subsequent induction of aerobic glycolysis promotes Sorafenib resistance in HCC. Here, we report the ubiquitin-specific peptidase USP29 as a new regulator of HIF1a and of aerobic glycolysis during the development of Sorafenib resistance in HCC. In particular, we have identified USP29 as a critical deubiquitylase (DUB) of HIF1a, which directly deubiquitinates and stabilizes HIF1a and, thus, promotes its transcriptional activity. Among the transcriptional targets of HIF1a is the gene encoding for hexokinase 2 (HK2), a key enzyme of the glycolytic pathway. The absence of USP29, and thus of HIF1a transcriptional activity, reduces the levels of aerobic glycolysis and reinstalls the sensitivity to Sorafenib treatment in Sorafenib-resistant HCC cells in vitro and in xenograft transplantation mouse models in vivo. Notably, the absence of USP29 and high HK2 expression levels correlate with the response of HCC patients to Sorafenib therapy. Together, the data demonstrate that, as a DUB of HIF1a, USP29 promotes Sorafenib resistance in HCC cells by upregulating glycolysis, thereby opening new avenues for therapeutically targeting Sorafenib-resistant HCC in patients.
2021-07-27 | GSE158458 | GEO
Project description:Hepatocellular carcinoma (HCC) is characteristically one of the most rapidly proliferating tumors which outgrows functional blood supply and results in regional oxygen deprivation. Overexpression of PIM1, a serine/threonine kinase, has been identified recently in human cancers. Knowledge on PIM1 in HCC is however, scarce. By immunohistochemical analysis on 56 human primary HCC samples, we observed overexpression of PIM1 in 39% of the cases. In two independent cohorts of paired primary and extra-hepatic metastatic HCC tissues, PIM1 expression was higher (p=0.002) in the extra-hepatic metastatic HCC tissues as compared with the corresponding primary HCCs. PIM1 was markedly up-regulated in multiple HCC cell lines in hypoxic condition (1% O2) versus normoxia (20% O2). Silencing of PIM1 suppressed HCC cell invasion in vitro as compared to non-target control, and decreased HCC cell proliferation in vitro and tumor growth and metastatic potential in vivo. Knockdown of PIM1 significantly reduced glucose uptake by HCC cells and was associated with decreased levels of p-AKT and key molecules in the glycolytic pathway. Taken together, PIM1 is up-regulated by hypoxia in HCC and promotes tumor growth and metastasis through facilitating cancer cell glycolysis. Targeting PIM1 may have potential role in the management of HCC.
| S-EPMC4484426 | biostudies-literature
Project description:BackgroundThe shortening of 3' untranslated regions (3'UTRs) of messenger RNAs(mRNAs) by alternative polyadenylation (APA) is an important mechanism for oncogene activation. Cleavage stimulation factor 2 (CSTF2), an important regulator of APA, has been reported to have a tumorigenic function in urothelial carcinoma of the bladder and lung cancers. However, the tumor-promoting role of CSTF2 in hepatocellular carcinoma (HCC) and its underlying molecular mechanism remains unclear.MethodsMultiple databases were used to analyze the expression level and prognostic value of CSTF2 in HCC. Function enrichment analysis was used to investigate the molecular mechanism of CSTF2 for the occurrence and development of HCC. The biological function in HCC cell lines in vitro was determined by CCK8, colony formation, Transwell migration, and invasion assay. Moreover, the tumorigenic function of CSTF2 in vivo was measured by a subcutaneous tumor formation or injecting four plasmids into a mouse tail vein within 5-7 s in an immunocompetent HCC mouse model. In addition, aerobic glycolysis in HCC cells was determined by measuring the extracellular acid rate (ECAR) and extracellular glucose and lactate levels.ResultsBioinformatics analysis revealed that CSTF2 was overexpressed in HCC tissues. The high expression of CSTF2 was correlated with a poor prognosis and high histological grades. CSTF2 knockout inhibited the proliferation, migration, and invasion of HCC cells. In addition, CSTF2 knockout HCC cells failed to form tumors by a subcutaneous graft experiment. Furthermore, endogenous CSTF2 knockout attenuated hepatocarcinogenesis in an immunocompetent HCC mouse model. Function enrichment analysis suggested that the high expression of CSTF2 was associated with enhanced glycolysis. Moreover, we found that CSTF2 knockout reduced the level of the short 3' UTR isoform of hexokinase 2 and increased its level of long 3'UTR. Furthermore, CSTF2 knockout inhibited ECAR levels, glucose uptake, and lactate production.ConclusionOur results indicated that CSTF2 is highly expressed in HCC and is correlated with a poor prognosis and high histological grade. The knockout of CSTF2 inhibits the tumorigenesis and procession of HCC both in vitro and in vivo. Moreover, CSTF2 is associated with enhanced glycolysis. Therefore, this study suggests that CSTF2 might be a new prognostic biomarker and therapeutic target for HCC.
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Project description:USP29-mediated HIF1a stabilization promotes Sorafenib resistance of hepatocellular carcinoma cells by upregulating glycolysis
| PRJNA665259 | ENA
Project description:Hepatitis B virus (HBV) is one of predisposing factors for hepatocellular carcinoma (HCC). The role of HBV x protein (HBx) in mediating the induction and maintenance of cancer stemness during HBV-related HCC attracts considerable attention, but the exact mechanism has not been clearly elucidated. Here, ABCG2-dependent stem-like side population cells, which are thought to be liver cancer stem cells (LCSCs), were present in HCC cells, and the fraction of this subset was increased in HBx-expressing HCC cells. In addition, glycolysis was upregulated in LCSCs and HBx-expressing HCC cells, and intervention of glycolysis attenuated cancer stem-like phenotypes. Mitochondria play an important role in the maintenance of energy homeostasis, BNIP3L-dependent mitophagy was also activated in LCSCs and HBx-expressing HCC cells, which triggered a metabolic shift toward glycolysis. In summary, we proposed a positive feedback loop, in which HBx induced BNIP3L-dependent mitophagy which upregulated glycolytic metabolism, increasing cancer stemness of HCC cells in vivo and in vitro. BNIP3L might be a potential therapeutic target for intervention of LCSCs-associated HCC. Anti-HBx, a monoclonal antibody targeting intracellular HBx, had the potential to delay the progression of HBV infection related-HCC.
| S-EPMC7139741 | biostudies-literature
Project description:Sharpin (Shank-associated RH domain-interacting protein, also known as SIPL1) is a multifunctional molecule that participates in various biological settings, including nuclear factor-κB signaling activation and tumor suppressor gene inhibition. Sharpin is upregulated in various types of cancers, including hepatocellular carcinoma (HCC), and is implicated in tumor progression. However, the exact roles of Sharpin in tumorigenesis and tumor progression remain largely unknown. Here, we report novel mechanisms of HCC progression through Sharpin overexpression. Sharpin was upregulated in human HCC tissues. Increased Sharpin expression enhanced hepatoma cell invasion, whereas decrease in Sharpin expression by RNA interference inhibited invasion. Microarray analysis identified that versican, a chondroitin sulfate proteoglycan that plays crucial roles in tumor progression and invasion, was also upregulated in stably Sharpin-expressing cells. Versican expression increased in the majority of HCC tissues and knocking down of versican greatly attenuated hepatoma cell invasion. Sharpin expression resulted in a significant induction of versican transcription synergistically with Wnt/-catenin pathway activation. Furthermore, Sharpin overexpressing cells had high tumorigenic properties in vivo. These results demonstrate that Sharpin promotes versican expression synergistically with the Wnt/-catenin pathway, potentially contributing to HCC development. A Sharpin/versican axis could be an attractive therapeutic target for this currently untreatable cancer.
2017-01-23 | GSE87149 | GEO
Project description:DIS3L2 promotes progression of hepatocellular carcinoma via hnRNP U-mediated alternative splicing
| PRJNA552471 | ENA
Project description:USP1 modulates hepatocellular carcinoma progression via Hippo/TAZ axis
| PRJNA903373 | ENA