Role of the ERas gene in gastric cancer cells

Liu, Yang; Wang, Zhaoqian; Li, Huiming; Wu, Zhaoping; Fang, Wei; Wang, Huiping

doi:10.3892/or.2013.2417

Cited by 16 publications

(12 citation statements)

References 20 publications

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“…Previous work has shown that ERas activates the PI3K pathway, but not the MAPK pathway, when expressed in mouse ES cells or human cell lines (39,40). Thus, we examined AKT, ERK, and MEK phosphorylation in 451Lu cells overexpressing ERAS and found robust AKT phosphorylation, whereas MAPK activity was unaffected (Fig.…”

Section: −08mentioning

confidence: 88%

“…It was first identified as a potent oncogene in murine ES cells because of its ability to promote constitutive activation of the PI3K pathway (39). More recently, human ERAS has been proposed to play a role in cancers of the gastrointestinal tract (40,56), and in vitro studies have suggested a role in the resistance of cell lines to chemotherapeutics (57,58).…”

Section: Discussionmentioning

confidence: 99%

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BRAF inhibitor resistance mediated by the AKT pathway in an oncogenic BRAF mouse melanoma model

Perna

Karreth

Rust

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

129

127

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BRAF (v-raf murine sarcoma viral oncogene homolog B) inhibitors elicit a transient anti-tumor response in ∼80% of BRAF V600 -mutant melanoma patients that almost uniformly precedes the emergence of resistance. Here we used a mouse model of melanoma in which melanocyte-specific expression of Braf V618E (analogous to the human BRAF V600E mutation) led to the development of skin hyperpigmentation and nevi, as well as melanoma formation with incomplete penetrance. Sleeping Beauty insertional mutagenesis in this model led to accelerated and fully penetrant melanomagenesis and synchronous tumor formation. Treatment of Braf V618E transposon mice with the BRAF inhibitor PLX4720 resulted in tumor regression followed by relapse. Analysis of transposon insertions identified eight genes including Braf, Mitf, and ERas (ES-cell expressed Ras) as candidate resistance genes. Expression of ERAS in human melanoma cell lines conferred resistance to PLX4720 and induced hyperphosphorylation of AKT (v-akt murine thymoma viral oncogene homolog 1), a phenotype reverted by combinatorial treatment with PLX4720 and the AKT inhibitor MK2206. We show that ERAS expression elicits a prosurvival signal associated with phosphorylation/inactivation of BAD, and that the resistance of hepatocyte growth factor-treated human melanoma cells to PLX4720 can be reverted by treatment with the BAD-like BH3 mimetic ABT-737. Thus, we define a role for the AKT/BAD pathway in resistance to BRAF inhibition and illustrate an in vivo approach for finding drug resistance genes. melanoma | drug resistance | BRAF inhibitors | mouse models T he discovery that ∼50-60% of melanomas carry BRAF V600E point mutations (1) prompted the generation of compounds specifically targeting this hyperactive mutated kinase. One such compound, PLX4032, has shown unprecedented therapeutic efficacy in clinical trials and was therefore FDA-approved for clinical therapy under the name vemurafenib. Despite its remarkable efficacy, almost all patients receiving BRAF inhibitor treatment relapsed after weeks to months of therapy (2-5). Acquired resistance to BRAF inhibitors has since been a major focus of research and two major paths to resistance have emerged: MAPK-dependent and MAPK-independent mechanisms. MAPK-dependent mechanisms primarily involve reactivation of the MAPK pathway to substitute for the inhibition of BRAF V600E. This may be achieved through mechanisms including expression of alternative splicing forms of BRAF V600E

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Section: −08mentioning

confidence: 88%

Section: Discussionmentioning

confidence: 99%

BRAF inhibitor resistance mediated by the AKT pathway in an oncogenic BRAF mouse melanoma model

Perna

Karreth

Rust

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

129

127

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“…WNT9A is a member of WNT gene family and correlated with oncogenesis [21]. ERAS may be involved in the pathogenesis and chemotherapy resistance of some types of cancers [22, 23]. Our study indicated their role in SCLC oncogenesis where TP53 and RB1 inactivation are absent.…”

Section: Discussionmentioning

confidence: 64%

Tumor Mutational Burden and Genomic Alterations in Chinese Small Cell Lung Cancer Measured by Whole-Exome Sequencing

Zou

Zeng

et al. 2019

BioMed Research International

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Purpose Studies on genetic alterations of the heterogenous small cell lung cancer (SCLC) are rare. We carried out the present study to clarify the genomic alterations and TMB levels of Chinese SCLC patients by whole-exome sequencing. Materials and Methods Whole-exome sequencing by next-generation sequencing technique was implemented on twenty SCLC samples. Significant somatic mutations and copy number variations were screened, followed by comparison with the data extracted from COSMIC. Besides, altered signaling pathways were examined in order to figure out actionable targets. Results A total of 8,062 nonsynonymous mutations were defined. The number of mutations for each case ranged from 98 to 864. As for base substitutions, a total of 15,817 substitutions were detected with C > A conversion which was correlated to smoking occupying 25.57%. The TMB values ranged from 2.51/Mb to 22.1/Mb with a median value of 9.95/Mb. RB1 was the most frequently mutated gene altered in 18 (90%) cases, followed by TP53 altered in 17 (85%) cases. Other commonly changed genes were PTEN, and RBL1, with frequencies of 55% and 50%, respectively. SOX2 significantly amplified in 6 (30%) cases and MYCN amplified in 1 (5%) patient. Notch signaling pathway and PI3K/AKT/mTOR signaling pathway were universally and significantly changed. Major genomic alterations were in consistency with data from COSMIC, but frequencies of less common mutations were different. Conclusion TP53 and RB1 inactivations were universally detected in SCLC. The Notch and PI3K/AKT/mTOR signaling pathways were both significantly altered, implying potential actionable targets.

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“…Pseudogenes, which are highly homologous with their parental genes, are ideal candidates to sustain the expression of their parental genes by serving as competing endogenous RNAs ( ceRNAs ) which compete for the binding site of the same mRNAs [16, 28]. In addition, some could regulate the expression of functional genes by producing endogenous small interference RNAs ( siRNAs ) [29, 30] and antisense RNAs ( asRNAs ) [31, 32], and some even could encode functional proteins [33, 34]. It is speculated that pseudogenes can be the supplement to their parental genes via gene mutation in a particular position.…”

Section: Discussionmentioning

confidence: 99%

Pseudogene BMI1P1 expression as a novel predictor for acute myeloid leukemia development and prognosis

et al. 2016

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The BMI1P1 levels of 144 de novo AML patients and 36 healthy donors were detected by real-time quantitative PCR (RQ-PCR). BMI1P1 was significantly down-regulated in AML compared with control (P < 0.001). A receiver operating characteristic (ROC) curve revealed that BMI1P1 expression could differentiate patients with AML from control subjects (AUC = 0.895, 95% CI: 0.835–0.954, P < 0.001). The percentage of blasts in bone marrow (BM) was significantly lower in BMI1P1 high-expressed group versus low-expressed group (P = 0.008). BMI1P1 high-expressed cases had significantly higher complete remission (CR) than BMI1P1 low-expressed cases (P = 0.023). Furthermore, Kaplan–Meier demonstrated that both whole AML cohort and non-M3-AML patients with low BMI1P1 expression showed shorter leukemia free survival (LFS, P = 0.002 and P = 0.01, respectively) and overall survival (OS, P < 0.001 and P = 0.011, respectively) than those with high BMI1P1 expression. Multivariate analysis also showed that BMI1P1 over-expression was an independent favorable prognostic factor for OS in both whole and non-M3 cohort of AML patients (HR = 0.462, 95% CI = 0.243–0.879, P = 0.019 and HR = 0.483, 95% CI = 0.254–0.919, P = 0.027). To further investigate the significance of BMI1P1 expression in the follow-up of AML patients, we monitored the BMI1P1 level in 26 de novo AML patients and found that the BMI1P1 level increased significantly from the initial diagnosis to post-CR (P < 0.001). These results indicated that BMI1P1 might contribute to the diagnosis of AML and the assessment of therapeutic effect.

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Role of the ERas gene in gastric cancer cells

Cited by 16 publications

References 20 publications

BRAF inhibitor resistance mediated by the AKT pathway in an oncogenic BRAF mouse melanoma model

BRAF inhibitor resistance mediated by the AKT pathway in an oncogenic BRAF mouse melanoma model

Tumor Mutational Burden and Genomic Alterations in Chinese Small Cell Lung Cancer Measured by Whole-Exome Sequencing

Pseudogene BMI1P1 expression as a novel predictor for acute myeloid leukemia development and prognosis

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