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Biochemical Society Transactions Aug 2019The pancreas is a gland composed mainly by endocrine and exocrine cells, giving rise to three main tumour types. Pancreatic neuroendocrine tumour or PNET arise from the... (Review)
Review
The pancreas is a gland composed mainly by endocrine and exocrine cells, giving rise to three main tumour types. Pancreatic neuroendocrine tumour or PNET arise from the endocrine portion of the pancreas. On the contrary, pancreatic exocrine neoplasms include pancreatic ductal adenocarcinoma (PDAC) and acinar cell carcinoma. PDAC is the most common type of pancreatic cancer and one of the leading causes of cancer-related death. It has been shown that less than 3% of PDAC patients have an overall survival of up to 5 years in the U.K. This mainly arises since the majority of patients diagnosed with PDAC present with advanced unresectable disease, which is highly resistant to all forms of chemotherapy and radiotherapy. Activating mutations of an isoform of the RAS protein, KRAS, are found in almost all PDAC cases and occur during early stages of malignant transformation. KRAS mutations play a critical role as they are involved in both initiating and maintaining PDAC development. The interaction of RAS with GDP/GTP along with its recruitment to the membrane affects transduction of its activating signals to downstream effectors. In this review, we aim to summarise different mutations of RAS and their prevalence in pancreatic cancer along with other RAS-induced tumours. In addition, we briefly discuss the genetically engineered mouse models that have been developed to study KRAS-mutated adenocarcinomas in the pancreas. These provide an opportunity to also address the importance of targeting RAS for better treatment response in PDAC patients along with the challenges incurred herein.
Topics: Animals; Disease Models, Animal; Genes, ras; Humans; Mutation; Pancreatic Neoplasms; Proto-Oncogene Proteins p21(ras); Signal Transduction
PubMed: 31341034
DOI: 10.1042/BST20170521 -
Cancer Metastasis Reviews Dec 2020KRAS is one of the most commonly mutated oncogene and a negative predictive factor for a number of targeted therapies. Therefore, the development of targeting strategies... (Review)
Review
KRAS is one of the most commonly mutated oncogene and a negative predictive factor for a number of targeted therapies. Therefore, the development of targeting strategies against mutant KRAS is urgently needed. One potential strategy involves disruption of K-Ras membrane localization, which is necessary for its proper function. In this review, we summarize the current data about the importance of membrane-anchorage of K-Ras and provide a critical evaluation of this targeting paradigm focusing mainly on prenylation inhibition. Additionally, we performed a RAS mutation-specific analysis of prenylation-related drug sensitivity data from a publicly available database ( https://depmap.org/repurposing/ ) of three classes of prenylation inhibitors: statins, N-bisphosphonates, and farnesyl-transferase inhibitors. We observed significant differences in sensitivity to N-bisphosphonates and farnesyl-transferase inhibitors depending on KRAS mutational status and tissue of origin. These observations emphasize the importance of factors affecting efficacy of prenylation inhibition, like distinct features of different KRAS mutations, tissue-specific mutational patterns, K-Ras turnover, and changes in regulation of prenylation process. Finally, we enlist the factors that might be responsible for the large discrepancy between the outcomes in preclinical and clinical studies including methodological pitfalls, the incomplete understanding of K-Ras protein turnover, and the variation of KRAS dependency in KRAS mutant tumors.
Topics: Animals; Antineoplastic Agents; Genes, ras; Humans; Molecular Targeted Therapy; Neoplasms; Prenylation; Protein Processing, Post-Translational; Proto-Oncogene Proteins p21(ras)
PubMed: 32524209
DOI: 10.1007/s10555-020-09902-w -
Personalized Medicine Sep 2021
Topics: Carcinoma, Non-Small-Cell Lung; Genes, ras; Humans; Lung Neoplasms; Mutation
PubMed: 34657456
DOI: 10.2217/pme-2021-0015 -
Methods in Molecular Biology (Clifton,... 2021The MYC transcription factor coordinates a wide range of intra- and extracellular processes associated with tissue proliferation and regeneration. While these processes...
The MYC transcription factor coordinates a wide range of intra- and extracellular processes associated with tissue proliferation and regeneration. While these processes are typically tightly regulated in physiological conditions, they become deregulated in cancer, where MYC is oncogenically activated.The last decade has seen MYC progress from a renowned undruggable target to a hot topic in the cancer therapy field, as proof emerged from mouse models that its inhibition constitutes an effective and broadly applicable approach to fight cancer. However, there are several aspects of MYC biology that still appear to be elusive and maintain the interest in further studying this intriguing protein. Since MYC's discovery, more than four decades ago, multiple strategies have been developed to study it, related to the many and varied facets of its biology. This new version of The Myc gene: Methods and Protocols provides valuable tips from key "inhabitants of the MYC world," which significantly increase the reach of our investigative tools to shed light on the mysteries still surrounding MYC.
Topics: Animals; Genes, myc; Humans; Neoplasms; Proto-Oncogene Proteins c-myc
PubMed: 34019283
DOI: 10.1007/978-1-0716-1476-1_1 -
Journal of B.U.ON. : Official Journal... 2020During laryngeal carcinogenesis, a variety of genomic imbalances are involved in hyperplastic and dysplastic laryngeal epithelia as early or progressive genetic events,... (Review)
Review
During laryngeal carcinogenesis, a variety of genomic imbalances are involved in hyperplastic and dysplastic laryngeal epithelia as early or progressive genetic events, respectively. Oncogenes' overactivation is a crucial genetic event in malignant and pre-malignant neoplastic epithelia. Especially, deregulation of crucial pathways including transcription factors - such as c-Fos and c-Jun - leads to an aberrant expression of other crucial genes responsible for cell homeostasis. Upregulation of c-Fos and c-Jun proto-oncogenes -due to increased copy numbers (amplification) or intra-genic point mutations- seems to be correlated with aggressive biological behaviour in laryngeal squamous cell carcinomas (LSCCs). In the current special molecular article we explored the role of c-Fos/c-Jun complex deregulation in LSCC.
Topics: Animals; Genes, fos; Genes, jun; Humans; Laryngeal Neoplasms; Proto-Oncogene Proteins c-fos; Proto-Oncogene Proteins c-jun; Signal Transduction; Squamous Cell Carcinoma of Head and Neck
PubMed: 32521843
DOI: No ID Found -
International Journal of Molecular... Sep 2023Important advances in diabetic retinopathy (DR) research and management have occurred in the last few years. Neurodegenerative changes before the onset of microvascular... (Review)
Review
Important advances in diabetic retinopathy (DR) research and management have occurred in the last few years. Neurodegenerative changes before the onset of microvascular alterations have been well established. So, new strategies are required for earlier and more effective treatment of DR, which still is the first cause of blindness in working age. We describe herein gene regulation through Lnc-RNAs as an interesting subject related to DR. Long non-coding RNAs (Lnc-RNAs) are non-protein-coding transcripts larger than 200 nucleotides. Lnc-RNAs regulate gene expression and protein formation at the epigenetic, transcriptional, and translational levels and can impact cell proliferation, apoptosis, immune response, and oxidative stress. These changes are known to take part in the mechanism of DR. Recent investigations pointed out that Lnc-RNAs might play a role in retinopathy development as Metastasis-Associated Lung Adenocarcinoma Transcript (Lnc-MALAT1), Maternally expressed gene 3 (Lnc-MEG3), myocardial-infarction-associated transcript (Lnc-MIAT), Lnc-RNA H19, Lnc-RNA HOTAIR, Lnc-RNA ANRIL B-Raf proto-oncogene (Lnc-RNA BANCR), small nucleolar RNA host gene 16 (Lnc-RNA SNHG16) and others. Several molecular pathways are impacted. Some of them play a role in DR pathophysiology, including the PI3K-Akt signaling axis, NAD-dependent deacetylase sirtuin-1 (Sirti1), p38 mitogen-activated protein kinase (P38/mapk), transforming growth factor beta signaling (TGF-β) and nuclear factor erythroid 2-related factor 2 (Nrf2). The way Lnc-RNAs affect diabetic retinopathy is a question of great relevance. Performing a more in-depth analysis seems to be crucial for researchers if they want to target Lnc-RNAs. New knowledge on gene regulation and biomarkers will enable investigators to develop more specialized therapies for diabetic retinopathy, particularly in the current growing context of precision medicine.
Topics: Humans; Diabetic Retinopathy; RNA, Long Noncoding; Phosphatidylinositol 3-Kinases; Retinal Diseases; Proto-Oncogenes; Diabetes Mellitus
PubMed: 37762249
DOI: 10.3390/ijms241813947 -
International Journal of Molecular... Sep 2021In principle, an oncogene is a cellular gene (proto-oncogene) that is dysfunctional, due to mutation and fusion with another gene or overexpression. Generally, oncogenes... (Review)
Review
In principle, an oncogene is a cellular gene (proto-oncogene) that is dysfunctional, due to mutation and fusion with another gene or overexpression. Generally, oncogenes are viewed as deregulating cell proliferation or suppressing apoptosis in driving cancer. The cancer stem cell theory states that most, if not all, cancers are a hierarchy of cells that arises from a transformed tissue-specific stem cell. These normal counterparts generate various cell types of a tissue, which adds a new dimension to how oncogenes might lead to the anarchic behavior of cancer cells. It is that stem cells, such as hematopoietic stem cells, replenish mature cell types to meet the demands of an organism. Some oncogenes appear to deregulate this homeostatic process by restricting leukemia stem cells to a single cell lineage. This review examines whether cancer is a legacy of stem cells that lose their inherent versatility, the extent that proto-oncogenes play a role in cell lineage determination, and the role that epigenetic events play in regulating cell fate and tumorigenesis.
Topics: Animals; Biomarkers, Tumor; Cell Lineage; Cell Transformation, Neoplastic; Epigenesis, Genetic; Gene Expression Regulation, Neoplastic; Humans; Neoplastic Stem Cells; Oncogene Proteins, Fusion; Oncogenes; Proto-Oncogene Mas; Proto-Oncogenes
PubMed: 34575830
DOI: 10.3390/ijms22189667 -
Current Opinion in Pediatrics Feb 2020The current review aims to highlight the frequency of RAS mutations in pediatric leukemias and solid tumors and to propose strategies for targeting oncogenic RAS in... (Review)
Review
PURPOSE OF REVIEW
The current review aims to highlight the frequency of RAS mutations in pediatric leukemias and solid tumors and to propose strategies for targeting oncogenic RAS in pediatric cancers.
RECENT FINDINGS
The three RAS genes (HRAS, NRAS, and KRAS) comprise the most frequently mutated oncogene family in human cancer. RAS mutations are commonly observed in three of the leading causes of cancer death in the United States, namely lung cancer, pancreatic cancer, and colorectal cancer. The association of RAS mutations with these aggressive malignancies inspired the creation of the National Cancer Institute RAS initiative and spurred intense efforts to develop strategies to inhibit oncogenic RAS, with much recent success. RAS mutations are frequently observed in pediatric cancers; however, recent advances in anti-RAS drug development have yet to translate into pediatric clinical trials.
SUMMARY
We find that RAS is mutated in common and rare pediatric malignancies and that oncogenic RAS confers a functional dependency in these cancers. Many strategies for targeting RAS are being pursued for malignancies that primarily affect adults and there is a clear need for inclusion of pediatric patients in clinical trials of these agents.
Topics: Antineoplastic Agents; Child; GTP Phosphohydrolases; Genes, ras; Humans; Membrane Proteins; Molecular Targeted Therapy; Mutation; Neoplasms; Proto-Oncogene Proteins p21(ras)
PubMed: 31815779
DOI: 10.1097/MOP.0000000000000856 -
Blood Aug 2022
Topics: DNA-Binding Proteins; Humans; Leukemia; Phosphoproteins; Proto-Oncogenes; RNA Splicing Factors
PubMed: 36006671
DOI: 10.1182/blood.2022017380 -
Current Cancer Drug Targets 2018PRDM14 belongs to the PR domain-containing (PRDM) family. Although a precise understanding focused on the function of PRDM14 to maintain stemness and pluripotency in... (Review)
Review
PRDM14 belongs to the PR domain-containing (PRDM) family. Although a precise understanding focused on the function of PRDM14 to maintain stemness and pluripotency in embryonic stem cells via epigenetic mechanisms, growing experimental evidence has been linked PRDM14 to human cancers. In adults, PRDM14 has low expression in human tissues. Aberrant PRDM14 expression is connected with various malignant histological types and solid cancers, where PRDM14 can act as a driver of oncogenic processes. Overexpression of RPDM14 enhanced cancer cells growth and reduced cancer cells sensitive to chemotherapeutic agents. Reducing the expression of PRDM14 in cancer cells can enhance the therapeutic sensitivity of drugs to cancer cells, suggesting that aberrant PRDM14 may have a carcinogenic characteristic in tumor therapy and as a new molecular target. This review summarizes the structure and oncogenic properties of PRDM14 in different malignancies and suggests that PRDM14 may be a potential therapeutic molecular target for tumor treatment.
Topics: Adult; Animals; Biomarkers, Tumor; Cell Proliferation; Cell Transformation, Neoplastic; DNA-Binding Proteins; Drug Resistance, Neoplasm; Gene Expression Regulation; Humans; Mice; Molecular Targeted Therapy; Neoplasms; Proto-Oncogenes; RNA-Binding Proteins; Repressor Proteins; Transcription Factors
PubMed: 29714146
DOI: 10.2174/1568009618666180430143055