VersicanV1 promotes proliferation and metastasis of hepatocellular carcinoma through the activation of EGFR-PI3K-AKT pathway
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE118820 | GEO | 2021/08/19
REPOSITORIES: GEO
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Project description:Phosphoinositide 3-kinase (PI3K) signaling, which requires spatial compartmentalization in plasma membrane micro domains, is aberrantly activated in hepatocellular carcinoma (HCC). As a synthetic enzyme of sphingomyelin, sphingomyelin synthase 2 (SMS2) regulates membrane fluidity and microdomain structure. SMS2 functions in various diseases such as atherosclerosis, and diabetes and lung injury. However, the role of SMS2 in HCC tumorigenesis is unclear. In the present study, we found that SMS2 was substantially reduced in tumor tissues and predicted poor prognosis in HCC patients. Function assays in vitro showed that SMS2 could remarkably prevent cell proliferation, cell cycle, cell migration and invasion. Experiments in vivo revealed that SMS2-deficient mice exhibited more severe carcinogenesis and metastasis induced by diethylnitrosamine/carbon tetrachloride. The result of transcriptome sequencing showed that SMS2 was involved in PI3K/Akt signaling pathway. Further study verified that SMS2 could inhibit the expression of PI3K subunit p110α by promoting the ubiquitination of p110α. SMS2 downregulation changed lipid metabolism and PTEN distribution in lipid raft, attenuated p85α-PTEN interaction, thus promoting p85α-p110α interaction. Finally, we found that loss of SMS2 could inhibiting PTEN localization in lipid rafts. The tumor suppression effect of SMS2 on HCC cells could be rescued by p110α expression. Taken together, our findings not only demonstrates that SMS2 is a prospective tumor suppressor and prognosis indicator in HCC, but also provide understanding of the molecular mechanisms by which PI3K/AKT signaling is activated.
2023-05-26 | GSE204898 | GEO
Project description:Activated HER2 and EGFR stimulate the Ras small GTPases, which in turn primarily activate the MAPK, PI3K-Akt and RalGEF-Ral pathways. While activation of the MAPK and PI3K-Akt pathways downstream of HER2 and EGFR promote mammary tumorigenesis, little is known regarding the role of the RalGEF-Ral pathway. RalGEFs convert the small GTPases RalA and RalB to an active GTP-bound state. Of the two proteins, only activated RalA is transforming, while RalB is more important for cell motility, and hence we investigated the role of RalA in HER2-overexpressing and EGFR-positive breast cancer. We now report that shRNA-mediated knockdown of RalA reduced the in vitro transformed growth and in vivo tumorigenic growth of MDA-MB-231 human breast cancer cells, while knockdown of RalB reduced migration and invasion. Lastly, we demonstrate that expression of activated HER2 increases RalA-GTP levels, and that a number of genes associated with activated RalA are elevated in tumor compared to normal mammary tissue. Taken together, these results suggest a possible role for RalA in mammary tumorigenesis. Four independent cultures of HEK-HT cells stably infected with a retrovirus confirmed to expressed RalAQ72L and four independent cultures of HEK-HT cells stably infected with a control retrovirus RalA activation expression analysis
2016-02-13 | E-GEOD-19295 | biostudies-arrayexpress
Project description:Neuroblastoma is a pediatric tumor of the peripheral sympathetic nervous system with a highly variable prognosis. Activation of the PI3K/AKT pathway in neuroblastoma is correlated with poor patient prognosis, but the precise downstream effectors mediating this effect have not been determined. Here, we identify the forkhead transcription factor FOXO3a as a key target of the PI3K/AKT pathway in neuroblastoma. FOXO3a expression was elevated in low stage neuroblastoma tumors and normal embryonal neuroblasts, but reduced in late stage neuroblastoma. Inactivation of FOXO3a by AKT was essential for neuroblastoma cell survival. Treatment of neuroblastoma cells with the dual PI3K/mTOR inhibitor PI-103 activated FOXO3a and triggered apoptosis. This effect was rescued by FOXO3a silencing. Conversely, apoptosis induced by PI-103 or the AKT inhibitor MK-2206 was potentiated by FOXO3a overexpression. Further, levels of total or phosphorylated FOXO3a correlated closely with apoptotic sensitivity to MK-2206. In clinical specimens, there was an inverse relationship between gene expression signatures regulated by PI3K signaling and FOXO3a transcriptional activity. Moreover, high PI3K activity and low FOXO3a activity were each associated with an extremely poor prognosis. Our work indicates that expression of FOXO3a and its targets offer useful prognostic markers as well as biomarkers for PI3K/AKT inhibitor efficacy in neuroblastoma. Affymetrix U133 Plus 2.0 profiling of SY5Y-TetR-FOXO3A cells treated with doxycycline and/or the PI3K/mTOR inhibitor PI-103. Each condition profiled in triplicate.
2013-05-01 | E-GEOD-42762 | biostudies-arrayexpress
Project description:To perform an integrative profile of human pancreatic cancer (PDAC) to identify prognosis-significant genes and their related pathways. A concordant survival-based whole genome in silico array analysis of DNA copy number, and mRNA & micro RNA (miRNA) expression in 25 early stage PDAC was performed. A novel composite score simultaneously integrated gene expression with regulatory mechanisms to identify the signature genes with the most levels of prognosis-significant evidence. The predominant signaling pathways were determined via a pathway-based approach. Independent patient cohorts (n= 150 and 42) were then used as in vitro validation of the array findings. We find that EGFR, SRC signaling, and PI3K/AKT pathway activation are strongly linked to clinical disease progression. Furthermore, we identify two discrete subsets of pancreatic tumors characterized by either SRC or PI3K/AKT signaling that may dictate variable responses to targeted therapy. 42 human PDAC tumors and 7 non-malignant pancreas samples snap-frozen at the time of surgery were chosen. Representative H&E sections of each were evaluated by a practicing gastrointestinal pathologist to confirm diagnosis and determine relative percentage of malignant cells. Samples with tumor cell content >30% were chosen for final multi-platform analysis (N=25). Human pancreatic samples were profiled on Affymetrix HGU133 Plus 2 arrays per manufacturer's instructions.
2011-10-07 | E-GEOD-32676 | biostudies-arrayexpress
Project description:To perform an integrative profile of human pancreatic cancer (PDAC) to identify prognosis-significant genes and their related pathways. A concordant survival-based whole genome in silico array analysis of DNA copy number, and mRNA & micro RNA (miRNA) expression in 25 early stage PDAC was performed. A novel composite score simultaneously integrated gene expression with regulatory mechanisms to identify the signature genes with the most levels of prognosis-significant evidence. The predominant signaling pathways were determined via a pathway-based approach. Independent patient cohorts (n= 150 and 42) were then used as in vitro validation of the array findings. We find that EGFR, SRC signaling, and PI3K/AKT pathway activation are strongly linked to clinical disease progression. Furthermore, we identify two discrete subsets of pancreatic tumors characterized by either SRC or PI3K/AKT signaling that may dictate variable responses to targeted therapy.
2011-10-08 | GSE32682 | GEO
Project description:To perform an integrative profile of human pancreatic cancer (PDAC) to identify prognosis-significant genes and their related pathways. A concordant survival-based whole genome in silico array analysis of DNA copy number, and mRNA & micro RNA (miRNA) expression in 25 early stage PDAC was performed. A novel composite score simultaneously integrated gene expression with regulatory mechanisms to identify the signature genes with the most levels of prognosis-significant evidence. The predominant signaling pathways were determined via a pathway-based approach. Independent patient cohorts (n= 150 and 42) were then used as in vitro validation of the array findings. We find that EGFR, SRC signaling, and PI3K/AKT pathway activation are strongly linked to clinical disease progression. Furthermore, we identify two discrete subsets of pancreatic tumors characterized by either SRC or PI3K/AKT signaling that may dictate variable responses to targeted therapy.
2011-10-08 | GSE32678 | GEO
Project description:To perform an integrative profile of human pancreatic cancer (PDAC) to identify prognosis-significant genes and their related pathways. A concordant survival-based whole genome in silico array analysis of DNA copy number, and mRNA & micro RNA (miRNA) expression in 25 early stage PDAC was performed. A novel composite score simultaneously integrated gene expression with regulatory mechanisms to identify the signature genes with the most levels of prognosis-significant evidence. The predominant signaling pathways were determined via a pathway-based approach. Independent patient cohorts (n= 150 and 42) were then used as in vitro validation of the array findings. We find that EGFR, SRC signaling, and PI3K/AKT pathway activation are strongly linked to clinical disease progression. Furthermore, we identify two discrete subsets of pancreatic tumors characterized by either SRC or PI3K/AKT signaling that may dictate variable responses to targeted therapy.
2011-10-08 | GSE32676 | GEO
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:To perform an integrative profile of human pancreatic cancer (PDAC) to identify prognosis-significant genes and their related pathways. A concordant survival-based whole genome in silico array analysis of DNA copy number, and mRNA & micro RNA (miRNA) expression in 25 early stage PDAC was performed. A novel composite score simultaneously integrated gene expression with regulatory mechanisms to identify the signature genes with the most levels of prognosis-significant evidence. The predominant signaling pathways were determined via a pathway-based approach. Independent patient cohorts (n= 150 and 42) were then used as in vitro validation of the array findings. We find that EGFR, SRC signaling, and PI3K/AKT pathway activation are strongly linked to clinical disease progression. Furthermore, we identify two discrete subsets of pancreatic tumors characterized by either SRC or PI3K/AKT signaling that may dictate variable responses to targeted therapy. 42 human PDAC tumors and 7 non-malignant pancreas samples snap-frozen at the time of surgery were chosen. Representative H&E sections of each were evaluated by a practicing gastrointestinal pathologist to confirm diagnosis and determine relative percentage of malignant cells. Samples with tumor cell content >30% were chosen for final multi-platform analysis (N=25). Copy number analysis of Affymetrix SNP 6.0 arrays was performed for 25 PDAC samples. The HapMap270 file supplied by Affymetrix was used as the reference model for copy number inference.
2011-10-07 | E-GEOD-32682 | biostudies-arrayexpress
Project description:To perform an integrative profile of human pancreatic cancer (PDAC) to identify prognosis-significant genes and their related pathways. A concordant survival-based whole genome in silico array analysis of DNA copy number, and mRNA & micro RNA (miRNA) expression in 25 early stage PDAC was performed. A novel composite score simultaneously integrated gene expression with regulatory mechanisms to identify the signature genes with the most levels of prognosis-significant evidence. The predominant signaling pathways were determined via a pathway-based approach. Independent patient cohorts (n= 150 and 42) were then used as in vitro validation of the array findings. We find that EGFR, SRC signaling, and PI3K/AKT pathway activation are strongly linked to clinical disease progression. Furthermore, we identify two discrete subsets of pancreatic tumors characterized by either SRC or PI3K/AKT signaling that may dictate variable responses to targeted therapy. 42 human PDAC tumors and 7 non-malignant pancreas samples snap-frozen at the time of surgery were chosen. Representative H&E sections of each were evaluated by a practicing gastrointestinal pathologist to confirm diagnosis and determine relative percentage of malignant cells. Samples with tumor cell content >30% were chosen for final multi-platform analysis (N=25). Genomic miRNAa of human pancreatic samples were profiled on miRCURY LNA™ microRNA Array kit v.11.0 - human, mouse & rat arrays per manufacturer's instructions.
2011-10-07 | E-GEOD-32678 | biostudies-arrayexpress