Expression Patterns of Growth and Survival Genes with Prognostic Implications in Advanced Pancreatic Cancer

Pectasides, Dimitrios; Kotoula, V.; Papaxoinis, George; Alexopoulou, Zoi; Dervenis, Christos; Samantas, Epaminontas; Papaparaskeva, Kleo; Charalambous, Elpida; Gkakou, Chrysoula; Agalianos, Christos; Kalogeras, Konstantine T.; Pentheroudakis, George; Fountzilas, George

doi:10.21873/anticanres.11232

Cited by 4 publications

(4 citation statements)

References 27 publications

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“…Notably, our study did not find significant association of RAS overexpression with RAS mutations. Similarly, a recent report also showed KRAS mutation did not correlate with mRNA expression [ 13 ]. These results suggested that RAS overexpression and mutations were independent events contributing to the pathogenesis of AML.…”

Section: Discussionmentioning

confidence: 90%

KRAS overexpression independent of RAS mutations confers an adverse prognosis in cytogenetically normal acute myeloid leukemia

Zhou

Yao

et al. 2017

Oncotarget

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The prognostic value of RAS mutations has been systematically investigated in acute myeloid leukemia (AML). However, clinical significance of RAS expressions in AML remains poorly determined. To explore the clinical significance, we analyzed KRAS and NRAS expressions in 143 de novo AML patients by real-time quantitative PCR. KRAS and NRAS expressions were significantly up-regulated in AML patients. KRAS and NRAS mutations were identified in 4% (6/143) and 8% (12/143) of these patients, respectively. However, no significant association was observed between RAS mutations and expressions. High KRAS expression was associated with older age, higher white blood cells, and a tendency of higher platelets, whereas high NRAS expression was only correlated with older age. Complete remission (CR) rate and overall survival of AML patients were adversely affected by KRAS overexpression, but not NRAS overexpression. Multivariate analysis revealed that KRAS acted as an independent prognostic predictor in cytogenetically normal AML (CN-AML). Moreover, the prognostic value of KRAS expression was validated using the published data from Gene Expression Omnibus datasets. In the follow-up patients, KRAS expression rather than NRAS expression in CR time tended to decrease compared to newly diagnosis time, and both KRAS and NRAS expressions were significantly increased when in relapse time. Our findings revealed that RAS overexpression and mutations were common events in AML with potential therapeutic target value. KRAS overexpression independent of RAS mutations conferred an adverse prognosis in CN-AML.

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Section: Discussionmentioning

confidence: 90%

KRAS overexpression independent of RAS mutations confers an adverse prognosis in cytogenetically normal acute myeloid leukemia

Zhou

Yao

et al. 2017

Oncotarget

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“…NFKB1 and IKBKG are part of the NF- κ B signaling pathway. As a transcription factor, NFKB1 is closely related to the risk of PDAC occurrence and prognosis [ 37 ]. Low expression of MUC4 inhibited the expression of NFKB1 , thereby downregulating the NF- κ B signaling pathway to inhibit the migration and invasion of PDAC cells along the nerve [ 38 ].…”

Section: Discussionmentioning

confidence: 99%

Gene Differential Expression and Interaction Networks Illustrate the Biomarkers and Molecular Biological Mechanisms of Unsaponifiable Matter in Kanglaite Injection for Pancreatic Ductal Adenocarcinoma

Dan

Zhang

et al. 2022

BioMed Research International

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Background. Kanglaite injection (KLTi) has shown good clinical efficacy in the treatment of pancreatic ductal adenocarcinoma (PDAC). While previous studies have demonstrated the antitumor effects of the oil compounds in KLTi, it is unclear whether the unsaponifiable matter (USM) also has antitumor effects. This study used network pharmacology, molecular docking, and database verification methods to investigate the molecular biological mechanisms of USM. Methods. Compounds of USM were obtained from GC-MS, and targets from DrugBank. Next, the GEO database was searched for differentially expressed genes in cancerous tissues and healthy tissues of PDAC to identify targets. Subsequently, the protein-protein interaction of USM and PDAC targets was constructed by BisoGenet to extract candidate genes. The candidate genes were enriched using GO and KEGG by Metascape, and the gene-pathway network was constructed to screen the key genes. Molecular docking and molecular dynamic simulations of core compound targets were finally performed and to explore the diagnostic, survival, and prognosis value of targets. Results. A total of 10 active compounds and 36 drug targets were screened for USM, 919 genes associated with PDAC, and 139 USM candidate genes against PDAC were excavated. The enrichment predicted USM by acting on RELA, NFKB1, IKBKG, JUN, MAPK1, TP53, and AKT1. Molecular docking and dynamic simulations confirmed the screened core targets had good affinity and stability with the corresponding compounds. In diagnostic ROC validation, the above targets have certain accuracy for diagnosing PDAC, and the combined diagnosis is more advantageous. As the most diagnostic value of RELA, it is equally significant in predicting disease-specific survival and progression-free interval. Conclusions. USM in KLTi plays an anti-PDAC role by intervening in the cell cycle, inducing apoptosis, and downregulating the NF-κB, MAPK, and PI3K-Akt pathways. It might participate in the pancreatic cancer pathway, and core target groups have diagnostic, survival, and prognosis value biomarker significance.

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“…AKT3 had been reported to be expressed in various cancers, including breast cancers, ovarian cancers and gliomas [21][22][23][24][25][26][27]. AKT3 mRNA expression had been reported previously in pancreatic cancer cells [28][29][30]. To our knowledge, this is the first report of AKT3 protein expression in a pancreatic cancer cell line confirmed by gene editing.…”

Section: Generation Of Kpc Cell Lines Deficient In Akt Isoforms By Cr...mentioning

confidence: 69%

Down-regulation of AKT proteins slows the growth of mutant-KRAS pancreatic tumors

Chen,

Jiang,

You

et al. 2024

Preprint

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Serine/threonine kinase AKT isoforms play a well-established role in cell metabolism and growth. Most pancreatic adenocarcinoma (PDAC) harbors activation mutations of KRAS, which activates the PI3K/AKT signaling pathway. However, AKT inhibitors are not effective in the treatment of pancreatic cancer. To better understand the role of AKT signaling in mutant-KRAS pancreatic tumors, this study utilizes proteolysis-targeting chimeras (PROTACs) and CRISPR-Cas9-genome editing to investigate AKT proteins. PROTAC down-regulation of AKT proteins markedly slowed the growth of three pancreatic tumor cell lines harboring mutant KRAS. In contrast, inhibition of AKT kinase activity alone had very little effect on the growth of these cell lines. Concurrent genetic deletion of all AKT isoforms (AKT1, AKT2, and AKT3) in the KPC (KrasG12D; Trp53R172H; Pdx1-Cre) pancreatic cancer cell line also dramatically slowed its growth in vitro and when orthotopically implanted in syngeneic mice. Surprisingly, insulin-like growth factor-1 (IGF-1), but not epidermal growth factor (EGF), restored KPC cell growth in serum-deprived conditions and the IGF-1 growth stimulation effect was AKT dependent. RNA-seq analysis of AKT1/2/3-deficient KPC cells suggested that reduced cholesterol synthesis may be responsible for the decreased response to IGF-1 stimulation. These results indicate that the presence of all three AKT isoforms supports pancreatic tumor cell growth and pharmacological degradation of AKT proteins may be more effective than AKT catalytic inhibitors for treating pancreatic cancer.

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Expression Patterns of Growth and Survival Genes with Prognostic Implications in Advanced Pancreatic Cancer

Cited by 4 publications

References 27 publications

KRAS overexpression independent of RAS mutations confers an adverse prognosis in cytogenetically normal acute myeloid leukemia

KRAS overexpression independent of RAS mutations confers an adverse prognosis in cytogenetically normal acute myeloid leukemia

Gene Differential Expression and Interaction Networks Illustrate the Biomarkers and Molecular Biological Mechanisms of Unsaponifiable Matter in Kanglaite Injection for Pancreatic Ductal Adenocarcinoma

Down-regulation of AKT proteins slows the growth of mutant-KRAS pancreatic tumors

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