The oncogene KRAS promotes cancer cell dissemination by stabilizing spheroid formation via the MEK pathway

Ogishima, Juri; Taguchi, Ayumi; Kawata, Akihiro; Kawana, Kei; Yoshida, Midori; Yoshimatsu, Yuki; Sato, Masakazu; Nakamura, Hitomi; Kawata, Yoshimasa; Nishijima, Akira; Fujimoto, Asaha; Tomio, Kensuke; Adachi, Katsuyuki; Nagamatsu, Takeshi; Oda, Katsutoshi; Kiyono, Tohru; Osuga, Yutaka; Fujii, Tomoyuki

doi:10.1186/s12885-018-4922-4

Cited by 18 publications

(12 citation statements)

References 47 publications

(52 reference statements)

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“…Thus, other factors must explain the stemness attributes in these cells. Other candidates affecting self-renewal include MYC, EGFR, RAS, and EZH2 [ 60 , 61 , 62 , 63 ].…”

Section: Discussionmentioning

confidence: 99%

Let-7i Reduces Aggressive Phenotype and Induces BRCAness in Ovarian Cancer Cells

Chirshev

Suzuki

Wang

et al. 2021

Cancers

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High-grade serous carcinoma of the ovary is a deadly gynecological cancer with poor long-term survival. Dysregulation of microRNAs has been shown to contribute to the formation of cancer stem cells (CSCs), an important part of oncogenesis and tumor progression. The let-7 family of microRNAs has previously been shown to regulate stemness and has tumor suppressive actions in a variety of cancers, including ovarian. Here, we demonstrate tumor suppressor actions of let-7i: repression of cancer cell stemness, inhibition of migration and invasion, and promotion of apoptosis, features important for cancer progression, relapse, and metastasis. Let-7i over-expression results in increased sensitivity to the PARP inhibitor olaparib in samples without BRCA mutations, consistent with induction of BRCAness phenotype. We also show that let-7i inhibits the expression of several factors involved in the homologous recombination repair (HRR) pathway, providing potential mechanisms by which the BRCAness phenotype could be induced. These actions of let-7i add to the rationale for use of this miRNA as a treatment for ovarian cancer patients, including those without mutations in the HRR pathway.

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“…Thus, other factors must explain the stemness attributes in these cells. Other candidates affecting self-renewal include MYC, EGFR, RAS, and EZH2 [ 60 , 61 , 62 , 63 ].…”

Section: Discussionmentioning

confidence: 99%

Let-7i Reduces Aggressive Phenotype and Induces BRCAness in Ovarian Cancer Cells

Chirshev

Suzuki

Wang

et al. 2021

Cancers

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“…Jones, et al suggested that metastatic type 1 ovarian cancer with KRAS mutation has a poor prognosis (9). A recent study indicated that KRAS promoted ovarian cancer dissemination by stabilizing spheroid formation (10). Through oncomine analysis, the current study results suggested that patients with KRAS mutation status displayed higher expression levels of AURKA, BUB1, BUB1B, CDK1 and CCNA2 than those with KRAS wild type status.…”

Section: Discussionmentioning

confidence: 48%

Screening and identification of key biomarkers and related transcription factors in ovarian cancer by integrated bioinformatics analysis

Qin¹,

Yuan²,

Liu³

et al. 2020

Preprint

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Background Ovarian tumors are the most malignant tumors of all gynecological tumors, and although multiple efforts have been made to elucidate the pathogenesis, the molecular mechanisms of ovarian cancer remain unclear. Methods In this study, we used bioinformatics to identify genes involved in the carcinogenesis and progression of ovarian cancer. Three microarray datasets (GSE14407, GSE29450, and GSE54388) were downloaded from Gene Expression Omnibus (GEO) database, and differentially expressed genes (DEGs) were identified. For a more in-depth understanding of the DEGs, functional and pathway enrichment analyses were performed and a protein-protein interaction (PPI) network was constructed. The associated transcriptional factor (TFs) regulation network of the DEGs was also constructed. Kaplan Meier-plotter, Gene Expression Profiling Interactive Analysis (GEPIA), the Human Protein Atlas (HPA) database and the Oncomine database were implemented to validated hub genes. Results A total of 514 DEGs were detected after the analysis of the three gene expression profiles, including 171 upregulated and 343 downregulated genes. Nine hub genes ( CCNB1, CDK1, BUB1, CDC20, CCNA2, BUB1B, AURKA, RRM2, TTK) were obtained from the PPI network. Survival analysis showed that high expression levels of seven hub genes ( CCNB1, BUB1, BUB1B, CCNA2, AURKA, CDK1, and RRM2) were associated with worse overall survival (OS). All of seven hub genes were discovered highly expressed in ovarian cancer samples compared to normal ovary samples in GEPIA. Immunostaining results from the HPA database suggested that the expressions of CCNB1, CCNA2, AURKA, and CDK1 proteins were increased in ovarian cancer tissues, and Oncomine analysis indicated that the expression patterns of BUB1B, CCNA2, AURKA, CCNB1, CDK1, and BUB1 have associated with patient clinicopathological information. From the gene-transcriptional factor network, key transcriptional factors, such as POLR2A, ZBTB11, KLF9, and ELF1, were identified with close interactions with these hub genes. Conclusion We identified six significant DEGs with poor prognosis in ovarian cancer, which could be of potential biomarkers for ovarian cancer patients.

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“…The KRAS gene, a crucial molecule in the major intracellular signaling pathways (such as the EGFR and the mitogen activated protein kinase/ extracellular signal-regulated kinase (MAPK/ERK) signaling pathways), exerts substantial regulatory effects on multiple tumors. For example, its proteins can promote the growth (11) and metastasis (12,13) of most tumors and serve as the evaluation indexes for chemotherapy in pancreatic cancer (14). The KRAS gene has an elevated mutation rate in some tumors, which may regulate important signaling pathways and protein networks (15).…”

Section: Discussionmentioning

confidence: 99%

The relationship between KRAS gene mutation and intestinal flora in tumor tissues of colorectal cancer patients

Sui¹,

Chen²,

Liu³

et al. 2020

Ann Transl Med

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Background: Colorectal cancer is among the most prominent malignant tumors endangering human health, with affected populations exhibiting an increasingly younger trend. The Kirsten ras (KRAS) gene acts as a crucial regulator in this disease and influences multiple signaling pathways. In the present study, the KRAS gene mutation-induced alteration of intestinal flora in colorectal cancer patients was explored, and the intestinal microbes that may be affected by the KRAS gene were examined to provide new insights into the diagnosis and treatment of colorectal cancer.Methods: Deoxyribonucleic acid (DNA) was extracted from 177 colorectal cancer patients in our hospital.The mutation of the KRAS gene was subsequently detected using real-time fluorescence quantitative polymerase chain reaction (qPCR), and survival analysis was performed. Moreover, genomic DNA was extracted from the fecal microbes in 30 of these patients, and the differences in the intestinal flora between mutation and non-mutation groups were evaluated using linear discriminant analysis (LDA) Effect size (LEfSe) analysis.Results: KRAS gene mutation substantially affected the distant metastasis of colorectal cancer, and the survival prognosis in the non-mutation group was significantly superior compared to the mutation group.The mutation group had a notably higher prevalence of microbes including Roseburia, Parabacteroides, Metascardovia, Staphylococcus, Staphylococcaceae, and Bacillales than the non-mutation group. The presence of microbes in the non-mutation group, such as Clostridiales, Bacteroidetes, Lachnospiraceae, Coprococcus, and Ruminococcaceae was markedly higher than in the mutation group. Firmicutes were negatively correlated with the presence of Actinomyces and Bacteroidetes, while Bacteroidetes were positively associated with the level of Actinomyces. Conclusions: In colorectal cancer, KRAS gene mutation can remarkably affect the survival prognosis and change the composition and abundance of intestinal flora, such as Roseburia, Parabacteroides, Metascardovia, Staphylococcus, and Bacillales, thereby influencing tumor development.

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The oncogene KRAS promotes cancer cell dissemination by stabilizing spheroid formation via the MEK pathway

Cited by 18 publications

References 47 publications

Let-7i Reduces Aggressive Phenotype and Induces BRCAness in Ovarian Cancer Cells

Let-7i Reduces Aggressive Phenotype and Induces BRCAness in Ovarian Cancer Cells

Screening and identification of key biomarkers and related transcription factors in ovarian cancer by integrated bioinformatics analysis

The relationship between KRAS gene mutation and intestinal flora in tumor tissues of colorectal cancer patients

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