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Integrated functional ceRNA network analysis reveals that circLIPH promotes pancreatic cancer progression via the miR-769-3p/GOLM1/mTOR pathway

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) is the most common malignancy of the pancreas with a high mortality rate because of metastasis of advanced tumors and recurrence after treatment. To identify more informative detection, diagnostic, and prognostic markers for improving the clinical therapeutic outcome of PDAC patients, we employed an SBC ceRNA array to screen differentially expressed ceRNAs in PDAC tumors, and circRNA/lncRNA-miRNA-mRNA regulatory networks were constructed. Gain- and loss-of-function experiments were also conducted to verify the biological function of circLIPH in vitro and in vivo. We found that 145 mRNAs and 358 circRNAs were differentially expressed in PDAC tumors. High circLIPH expression was correlated with tumor size and stage, and the inhibition of circLIPH repressed pancreatic cancer progression. We identified that circLIPH promoted pancreatic cancer progression via the miR-769-3p/GOLM1/mTOR pathway and might be a key regulator of tumorigenesis in PDAC.

ORGANISM(S): Homo sapiens

PROVIDER: GSE247209 | GEO | 2024/12/31

REPOSITORIES: GEO

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Project description:Cyclooxygenase-2 (COX-2) is upregulated in pancreatic ductal adenocarcinomas (PDAC). However, how COX-2 promotes PDAC development is unclear. While previous studies have evaluated the efficacy of COX-2 inhibition via the use of non steroidal anti-inflammatory drugs (NSAIDs) or the COX-2 inhibitor celecoxib in PDAC models, none have addressed the cell intrinsic vs. microenvironment roles of COX-2 in modulating PDAC initiation and progression. We tested the cell intrinsic role of COX-2 in PDAC progression, using both loss-of-function and gain-of-function approaches. Cox-2 deletion in Pdx1+ pancreatic progenitor cells significantly delays the development of PDAC in mice with K-ras activation and Pten haploinsufficiency. Conversely, COX-2 over-expression promotes early onset and progression of PDAC in the K-ras mouse model. Loss of PTEN function is a critical factor in determining lethal PDAC onset and overall survival. Mechanistically, COX-2 over-expression increases P-AKT levels in the precursor lesions of Pdx1+;K-rasG12D/+;Ptenlox/+ mice in the absence of Pten LOH. In contrast, Cox-2 deletion in the same setting diminishes P-AKT levels and delays cancer progression. These data suggest an important cell intrinsic role for COX-2 in tumor initiation and progression through activation of the PI3K/AKT pathway. PDAC that is independent of intrinsic COX-2 expression eventually develops with decreased FKBP5 and increased GRP78 expression, two alternate pathways leading to AKT activation. Together, these results support a cell intrinsic role for COX-2 in PDAC development and suggest that, while anti-COX-2 therapy may delay the development and progression of PDAC, mechanisms known to increase chemoresistance through AKT activation must also be overcome. Murine mutants with pancreatic specific loss of Pten (Pten +/-) and K-ras activation (K-rasG12D) and either COX-2 over-expression (Cox-2 COE) or knockout (Cox-2 KO) under regulation of the Pdx-1 promoter developed pancreatic ductal adenocarcinoma. RNA was extracted from pancreatic tumors from individual mutants with pathology thought to closely mimic the human disease. Pancreatic tissue was subject to RNA extraction and hybridization on Affymetrix cDNA microarrays.

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Integrated functional ceRNA network analysis reveals that circLIPH promotes pancreatic cancer progression via the miR-769-3p/GOLM1/mTOR pathway

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