Oncogenic KRAS: Signaling and Drug Resistance

Kim, Hyeon Jin; Lee, Han Na; Jeong, Mi Suk; Jang, Se Bok

doi:10.3390/cancers13225599

Cited by 42 publications

(36 citation statements)

References 82 publications

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“…K‐ras signaling is a well established pathway for oncogenic transformation. 52 Our data suggested that K‐ras signaling pathway upregulation was related to the acquisition of tumorigenic potential in high‐CIN cells. It was also suggested that inhibition of the K‐ras signaling pathway can be a strategy to eradicate CIN cancer cells.…”

Section: Discussionmentioning

confidence: 59%

“…We also found that high‐CIN cells were specifically sensitive to the inhibitors of the K‐ras signaling pathway in 3D culture. K‐ras signaling is a well established pathway for oncogenic transformation 52 . Our data suggested that K‐ras signaling pathway upregulation was related to the acquisition of tumorigenic potential in high‐CIN cells.…”

Section: Discussionmentioning

confidence: 61%

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High levels of chromosomal instability facilitate the tumor growth and sphere formation

et al. 2022

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Most cancer cells show chromosomal instability (CIN), a condition in which chromosome missegregation occurs at high rates. Growing evidence suggests that CIN is not just a consequence of, but a driving force for, oncogenic transformation, although the relationship between CIN and tumorigenesis has not been fully elucidated. Here we found that conventional two‐dimensional (2D) culture of HeLa cells, a cervical cancer‐derived cell line, was a heterogenous population containing cells with different CIN levels. Although cells with high‐CIN levels (high‐CIN cells) grew more slowly compared with cells with low‐CIN levels (low‐CIN cells) in 2D monolayer culture, they formed tumors in nude mice and larger spheres in three‐dimensional (3D) culture, which was more representative of the in vivo environment. The duration of mitosis was longer in high‐CIN cells, reflecting their higher mitotic defects. Single‐cell genome sequencing revealed that high‐CIN cells exhibited a higher karyotype heterogeneity compared with low‐CIN cells. Intriguingly, the karyotype heterogeneity was reduced in the spheres formed by high‐CIN cells, suggesting that cells with growth advantages were selected, although genomic copy number changes specific for spheres were not identified. When we examined gene expression profiles, genes related to the K‐ras signaling were upregulated, while those related to the unfolded protein response were downregulated in high‐CIN cells in 3D culture compared with 2D culture, suggesting the relevance of these genes for their survival. Our data suggested that, although CIN is disadvantageous in monolayer culture, it promotes the selection of cells with growth advantages under in vivo environments, which may lead to tumorigenesis.

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Section: Discussionmentioning

confidence: 59%

Section: Discussionmentioning

confidence: 61%

High levels of chromosomal instability facilitate the tumor growth and sphere formation

et al. 2022

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“…Our results showed that the high-risk group was mainly involved in unfolded protein response, DNA repair signaling, and epithelial-mesenchymal transition signaling pathway and glycolysis pathway (Figures 7(a) – 7(d) ), which are related to the initiation of metastasis in cancer progression [ 18 – 20 ]. The low-risk group was mainly involved in estrogen response early and KRAS signaling pathway (Figures 7(e) and 7(f) ), which are important for oncogene of osteosarcoma [ 21 , 22 ]. These results indicated that there were differences in biological characteristics between high-risk and low-risk groups, which affected tumorigenesis and progression of osteosarcoma and survival of osteosarcoma patients.…”

Section: Resultsmentioning

confidence: 99%

m6A-Related lncRNAs Predict Overall Survival of Patients and Regulate the Tumor Immune Microenvironment in Osteosarcoma

Meng

Wei

et al. 2022

Computational Intelligence and Neuroscience

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Background. m6A-related lncRNAs have demonstrated great potential tumor diagnostic and therapeutic targets. The goal of this work was to find m6A-regulated lncRNAs in osteosarcoma patients. Method. The Cancer Genome Atlas (TCGA) database was used to retrieve RNA sequencing and medical information from osteosarcoma sufferers. The Pearson’s correlation test was used to identify the m6A-related lncRNAs. A risk model was built using univariate and multivariable Cox regression analysis. Kaplan–Meier survival analysis and receiver functional requirements were used to assess the risk model's performance (ROC). By using the CIBERSORT method, the associations between the relative risks and different immune cell infiltration were investigated. Lastly, the bioactivities of high-risk and low-risk subgroups were investigated using Gene Set Enrichment Analysis (GSEA). Result. A total of 531 m6A-related lncRNAs were obtained from TCGA. Seven lncRNAs have demonstrated prognostic values. A total of 88 OS patients were separated into cluster 1, cluster 2, and cluster 3. The overall survival rate of OS patients in cluster 3 was more favorable than that of those in cluster 1 and cluster 2. The average Stromal score was much higher in cluster 1 than in cluster 2 and cluster 3 ( P < 0.05 ). The expression levels of lncRNAs used in the construction of the risk prediction model in the high-risk group were generally lower than those in the low-risk group. Analysis of patient survival indicated that the survival of the low-risk group was higher than that of the high-risk group ( P < 0.0001 ) and the area under the curve (AUC) of the ROC curve was 0.719. Using the CIBERSORT algorithm, the results revealed that Macrophages M0, Macrophages M2, and T cells CD4 memory resting accounted for a large proportion of immune cell infiltration. By GSEA analysis, our results implied that the high-risk group was mainly involved in unfolded protein response, DNA repair signaling, and epithelial-mesenchymal transition signaling pathway and glycolysis pathway; meanwhile, the low-risk group was mainly involved in estrogen response early and KRAS signaling pathway. Conclusion. Our investigation showed that m6A-related lncRNAs remained tightly connected to the immunological microenvironment of osteosarcoma tumors, potentially influencing carcinogenesis and development. The immune microenvironment and immune-related biochemical pathways can be changed by regulating the transcription of M6A modulators or lncRNAs. In addition, we looked for risk-related signaling of m6A-related lncRNAs in osteosarcomas and built and validated the risk prediction system. The findings of our current analysis will facilitate the assessment of outcomes and the development of immunotherapies for sufferers of osteosarcomas.

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“…Thus, the results reported in Figure 4 let us conclude that exposing GO to the plasma of NOP, PDAC, and breast cancer patients lead to personalized coronas of significantly different protein composition. According to the literature, we can speculate that these differences may be the consequence of alterations in the human proteome, resulting from mutations of genes that are known to be involved in the processes of carcinogenesis for both pancreatic and breast cancer (e.g., K-RAS and BRCA) [32]. Nonetheless, it has been recently reported that altered protein profiles in pancreatic and breast cancer occur and most of these proteins are involved in amino-acid, lipids, monosaccharides, and sulfur compound synthesis and metabolism [33].…”

Section: Discussionmentioning

confidence: 99%

Magnetic Levitation of Personalized Nanoparticle–Protein Corona as an Effective Tool for Cancer Detection

et al. 2022

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Unprecedented opportunities for early stage cancer detection have recently emerged from the characterization of the personalized protein corona (PC), i.e., the protein cloud that surrounds nanoparticles (NPs) upon exposure to a patients’ bodily fluids. Most of these methods require “direct characterization” of the PC., i.e., they necessitate protein isolation, identification, and quantification. Each of these steps can introduce bias and affect reproducibility and inter-laboratory consistency of experimental data. To fulfill this gap, here we develop a nanoparticle-enabled blood (NEB) test based on the indirect characterization of the personalized PC by magnetic levitation (MagLev). The MagLev NEB test works by analyzing the levitation profiles of PC-coated graphene oxide (GO) NPs that migrate along a magnetic field gradient in a paramagnetic medium. For the test validation, we employed human plasma samples from 15 healthy individuals and 30 oncological patients affected by four cancer types, namely breast cancer, prostate cancer, colorectal cancer, and pancreatic ductal adenocarcinoma (PDAC). Over the last 15 years prostate cancer, colorectal cancer, and PDAC have continuously been the second, third, and fourth leading sites of cancer-related deaths in men, while breast cancer, colorectal cancer, and PDAC are the second, third and fourth leading sites for women. This proof-of-concept investigation shows that the sensitivity and specificity of the MagLev NEB test depend on the cancer type, with the global classification accuracy ranging from 70% for prostate cancer to an impressive 93.3% for PDAC. We also discuss how this tool could benefit from several tunable parameters (e.g., the intensity of magnetic field gradient, NP type, exposure conditions, etc.) that can be modulated to optimize the detection of different cancer types with high sensitivity and specificity.

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Oncogenic KRAS: Signaling and Drug Resistance

Cited by 42 publications

References 82 publications

High levels of chromosomal instability facilitate the tumor growth and sphere formation

High levels of chromosomal instability facilitate the tumor growth and sphere formation

m6A-Related lncRNAs Predict Overall Survival of Patients and Regulate the Tumor Immune Microenvironment in Osteosarcoma

Magnetic Levitation of Personalized Nanoparticle–Protein Corona as an Effective Tool for Cancer Detection

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