PI3K/Akt Cooperates with Oncogenic Notch by Inducing Nitric Oxide-Dependent Inflammation

Villegas, Santiago Nahuel; Gombos, Rita; García-López, Lucia; Gutiérrez-Pérez, Irene; Garcı́a-Castillo, Jesús; Vallejo, Diana M.; Ros, Vanina Gabriela Da; Ballesta-Illán, Esther; Mihály, József; Domı́nguez, Marı́a

doi:10.1016/j.celrep.2018.02.049

“…For examples, Guo et al reported that Notch2 negatively regulates cell invasion by inhibiting the PI3K-AKT signaling pathway in gastric cancer [24], and Villegas et al found that PI3K-AKT cooperates with oncogenic Notch by inducing nitric oxide-dependent inflammation [25]. However, few studies have reported the interactions between these pathways in chondrocytes and OA pathogenesis.…”

Section: Discussionmentioning

confidence: 99%

Therapeutic effect and mechanisms of intra-articular injections of microRNA-140-5p on early-stage osteoarthritis in rats

Si¹,

Yang²,

Chen³

et al. 2020

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Background MicroRNAs (miRs) have received extensive attention in osteoarthritis (OA) pathogenesis in recent years, and our previous study have confirmed that single intra-articular injection (IAJ) of miR-140-5p alleviates early-stage OA (EOA) progression in rats. This study aims to further investigate the effects of single IAJ of miR-140-5p on different stage OA and multiple IAJs of miR-140-5p on EOA, as well as the potential mechanisms. Methods Firstly, OA model was surgically induced in rats, 9 rats were treated with IAJ of Cy5-miR-140-5p at 1 week after surgery, and fluorescence distribution was measured. Then, 72 rats were treated with single IAJ of miR-140-5p at different time after surgery or multiple IAJs of miR-140-5p at 1 week after surgery, and OA progression were evaluated macroscopically and histologically. Finally, bioinformatics analyses were performed and the potential targets and molecular mechanisms of miR-140-5p were predicted. Results Strong fluorescence was observed in the chondrocytes and joint where Cy5-miR-140-5p was injected. Behavioural scores, chondrocyte numbers and cartilage thickness in cartilage were higher, while pathological scores were lower in the miR-140-5p group than in the control group. Specifically, the earlier a single IAJ of miR-140-5p, the better the therapeutic effect, and multiple IAJs exhibited better therapeutic effect than single IAJ on EOA. Bioinformatics analyses predicted 84 potential target genes of rno-miR-140-5p and revealed that these genes enrich in various biological processes and pathways. Conclusions IAJs of miR-140-5p effectively alleviate EOA progression by modulating various biological processes and pathways, and may be a promising therapeutics for EOA.

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“…p-value ≤ 0.01) among the 24 male-specific eGenes. PI3K-AKT is known to co-operate with Notch by triggering inflammation and immunosuppression [56]. Concurrent activation of Notch and PI3K/AKT pathways can trigger tumorigenesis and is prevalent in aggressive cancers [57][58][59][60].…”

Section: Sex-specific Germline Genetic Effects On Tumor Gene Expressimentioning

confidence: 99%

Distinct molecular etiologies of male and female hepatocellular carcinoma

Natri

¹

,

Wilson

²

,

Buetow

³

2019

Preprint

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Background: Sex-differences in cancer occurrence and mortality are evident across tumor types; men exhibit higher rates of incidence and often poorer responses to treatment. Targeted approaches to the treatment of tumors that account for these sex-differences require the characterization and understanding of the fundamental biological mechanisms that differentiate them. Hepatocellular Carcinoma (HCC) is the second leading cause of cancer death worldwide, with the incidence rapidly rising. HCC exhibits a male-bias in occurrence and mortality, but previous studies have failed to explore the sex-specific dysregulation of gene expression in HCC. Methods: Here, we characterize the sex-shared and sex-specific regulatory changes in HCC tumors in the TCGA LIHC cohort using combined and sex-stratified differential expression and eQTL analyses. Results: By using a sex-specific differential expression analysis of tumor and tumor-adjacent samples, we uncovered etiologically relevant genes and pathways differentiating male and female HCC. While both sexes exhibited activation of pathways related to apoptosis and cell cycle, males and females differed in the activation of several signaling pathways, with females showing PPAR pathway enrichment while males showed PI3K, 305 PI3K/AKT, FGFR, EGFR, NGF, GF1R, Rap1, DAP12, and IL-2 signaling pathway enrichment. Using eQTL analyses, we discovered germline variants with differential effects on tumor gene expression between the sexes. 24.3% of the discovered eQTLs exhibit differential effects between the sexes, illustrating the substantial role of sex in modifying the effects of eQTLs in HCC. The genes that showed sex-specific dysregulation in tumors and those that harbored a sex-specific eQTL converge in clinically relevant pathways, suggesting that the molecular etiologies of male and female HCC are partially driven by differential genetic effects on gene expression. Conclusions: Sex-stratified analyses detect sex-specific molecular etiologies of HCC. Overall, our results provide new insight into the role of inherited genetic regulation of transcription in modulating sex-differences in HCC etiology and provide a framework for future studies on sex-biased cancers.

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“…p-value ≤ 0.01) among the 24 male-specific eGenes. PI3K-AKT is known to co-operate with Notch by triggering inflammation and immunosuppression [56]. Concurrent activation of Notch and PI3K/AKT pathways can trigger tumorigenesis and is prevalent in aggressive cancers [57][58][59][60].…”

Section: Sex-specific Germline Genetic Effects On Tumor Gene Expressimentioning

confidence: 99%

Distinct molecular etiologies of male and female hepatocellular carcinoma

Natri

¹

,

Wilson

²

,

Buetow

³

2019

Preprint

0

View full text Add to dashboard Cite

Background: Sex-differences in cancer occurrence and mortality are evident across tumor types; men exhibit higher rates of incidence and often poorer responses to treatment. Targeted approaches to the treatment of tumors that account for these sex-differences require the characterization and understanding of the fundamental biological mechanisms that differentiate them. Hepatocellular Carcinoma (HCC) is the second leading cause of cancer death worldwide, with the incidence rapidly rising. HCC exhibits a male-bias in occurrence and mortality, but previous studies have failed to explore the sex-specific dysregulation of gene expression in HCC. Methods: Here, we characterize the sex-shared and sex-specific regulatory changes in HCC tumors in the TCGA LIHC cohort using combined and sex-stratified differential expression and eQTL analyses. Results: By using a sex-specific differential expression analysis of tumor and tumor-adjacent samples, we uncovered etiologically relevant genes and pathways differentiating male and female HCC. While both sexes exhibited activation of pathways related to apoptosis and cell cycle, males and females differed in the activation of several signaling pathways, with females showing PPAR pathway enrichment while males showed PI3K, 305 PI3K/AKT, FGFR, EGFR, NGF, GF1R, Rap1, DAP12, and IL-2 signaling pathway enrichment. Using eQTL analyses, we discovered germline variants with differential effects on tumor gene expression between the sexes. 24.3% of the discovered eQTLs exhibit differential effects between the sexes, illustrating the substantial role of sex in modifying the effects of eQTLs in HCC. The genes that showed sex-specific dysregulation in tumors and those that harbored a sex-specific eQTL converge in clinically relevant pathways, suggesting that the molecular etiologies of male and female HCC are partially driven by differential genetic effects on gene expression. Conclusions: Sex-stratified analyses detect sex-specific molecular etiologies of HCC. Overall, our results provide new insight into the role of inherited genetic regulation of transcription in modulating sex-differences in HCC etiology and provide a framework for future studies on sex-biased cancers.

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PI3K/Akt Cooperates with Oncogenic Notch by Inducing Nitric Oxide-Dependent Inflammation

Cited by 78 publications

References 63 publications

Therapeutic effect and mechanisms of intra-articular injections of microRNA-140-5p on early-stage osteoarthritis in rats

Therapeutic effect and mechanisms of intra-articular injections of microRNA-140-5p on early-stage osteoarthritis in rats

Distinct molecular etiologies of male and female hepatocellular carcinoma

Distinct molecular etiologies of male and female hepatocellular carcinoma

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