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Knockdown of PTGS2 by CRISPR/CAS9 System Designates a New Potential Gene Target for Melanoma Treatment.

ABSTRACT: CRISPR/Cas9 has become a powerful method to engineer genomes and to activate or to repress genes expression. As such, in cancer research CRISPR/Cas9 technology represents an efficient tool to dissect mechanisms of tumorigenesis and to discover novel targets for drug development. Here, we employed the CRISPR/Cas9 technology for studying the role of prostaglandin-endoperoxide synthase 2 (PTGS2) in melanoma development and progression. Melanoma is the most aggressive form of skin cancer with a median survival of less than 1 year. Although oncogene-targeted drugs and immune checkpoint inhibitors have demonstrated a significant success in improving overall survival in patients, related toxicity and emerging resistance are ongoing challenges. Gene therapy appears to be an appealing option to enhance the efficacy of currently available melanoma therapeutics leading to better patient prognosis. Several gene therapy targets have been identified and have proven to be effective against melanoma cells. Particularly, PTGS2 is frequently expressed in malignant melanomas and its expression significantly correlates with poor survival in patients. In this study we investigated on the effect of ptgs2 knockdown in B16F10 murine melanoma cells. Our results show that reduced expression of ptgs2 in melanoma cells: i) inhibits cell proliferation, migration, and invasiveness; ii) modulates immune response by impairing myeloid derived suppressor cell differentiation; iii) reduces tumor development and metastasis in vivo. Collectively, these findings indicate that ptgs2 could represent an ideal gene to be targeted to improve success rates in the development of new and highly selective drugs for melanoma treatment.

SUBMITTER: Ercolano G

PROVIDER: S-EPMC6915044 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Knockdown of PTGS2 by CRISPR/CAS9 System Designates a New Potential Gene Target for Melanoma Treatment.

Ercolano Giuseppe G De Cicco Paola P Rubino Valentina V Terrazzano Giuseppe G Ruggiero Giuseppina G Carriero Roberta R Kunderfranco Paolo P Ianaro Angela A

Frontiers in pharmacology 20191205

CRISPR/Cas9 has become a powerful method to engineer genomes and to activate or to repress genes expression. As such, in cancer research CRISPR/Cas9 technology represents an efficient tool to dissect mechanisms of tumorigenesis and to discover novel targets for drug development. Here, we employed the CRISPR/Cas9 technology for studying the role of prostaglandin-endoperoxide synthase 2 (PTGS2) in melanoma development and progression. Melanoma is the most aggressive form of skin cancer with a medi ...[more]

PMID: 31920649

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Project description:BackgroundPrimary hyperoxaluria type 1 (PH1) is a rare genetic disorder caused by endogenous overproduction of hepatic oxalate, leading to hyperoxaluria, recurrent calcium oxalate kidney stones, and end-stage renal disease. Lactate dehydrogenase (LDH) is an ideal target for diminishing oxalate production as it is responsible for glyoxylate to oxalate conversion in the liver, the last step of oxalate metabolism. Here, we investigated the therapeutic efficacy and potential side effects of clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 technology to ameliorate PH1 via specifically disrupting the hepatic LDH.MethodsPheochromocytoma (PC12) cells were used to assess the efficacy of cleavage of single-guide RNAs in vitro. PH1 neonatal rats were injected with a single administration of adeno-associated virus to deliver the CRISPR/Cas9 system that targeted LDH. Three weeks after injection, a liver biopsy was performed to detect LDH expression, liver injury, and liver metabolomics. Urinary oxalate was regularly monitored, and renal calcium oxalate deposition was evaluated after 4 weeks of 0.5% ethylene glycol challenge. After 6 months of treatment, animals were euthanized, and ex-liver organs were harvested for toxicity analysis.ResultsThe Ldha gene was specifically knocked out in 20% of the liver cells of PH1 rats in the treatment group, leading to a 50% lower LDH expression than that in the control group. Compared to the control groups, urinary oxalate levels were significantly decreased, and renal calcium oxalate precipitation was largely mitigated in the treatment group throughout the entire 6-month study period. While no CRISPR/Cas9-associated off-target edits or hepatotoxicity were detected, we observed mild metabolic changes in the liver tricarboxylic acid (TCA) and glycolysis pathways.ConclusionsCRISPR/Cas9-mediated LDH disruption may represent an applicable new strategy for alleviating PH1 for its long-lasting effect and low editorial efficiency requirements.

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Knockdown of PTGS2 by CRISPR/CAS9 System Designates a New Potential Gene Target for Melanoma Treatment.

Publications

Knockdown of PTGS2 by CRISPR/CAS9 System Designates a New Potential Gene Target for Melanoma Treatment.

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