An EGFR/PI3K/AKT axis promotes accumulation of the Rac1-GEF Tiam1 that is critical in EGFR-driven tumorigenesis

Zhu, Guixin; Fan, Zhimeng; Ding, Mei; Zhang, Han-bin; Mu, Libing; Ding, Yuchuan; Zhang, Y; Jia, Baoqing; Chen, Liang; Chang, Zhijie; Wu, Wei

doi:10.1038/onc.2015.45

Cited by 78 publications

(61 citation statements)

References 62 publications

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“…Encompassed within the validations were the novel reciprocal miRNA-mRNA pairings miR-133a/ MCL1 (down-up; target mRNA significant in ERBB pathway by Global test), miR-96/ FOXO3A (up-down; non-small cell lung cancer signaling), miR-513c/ STAT1 (down-up; JAK/STAT pathway), miR-34a/ PPP2R2A (down-up; tight junction signaling), miR-145/ ITPR2 (down-up; phosphatidylinositol signaling) and miR-145/ MKK4 (down-up; ERBB pathway) ( Figures 2A and 3 ). Interestingly, four of the target mRNAs ( FOXO3A, STAT1, PPP2R2A and ITPR2 ) in these pairings are also known to participate downstream of ERBB signaling and hence included in Figure 2A for illustration (25-29). …”

Section: Resultsmentioning

confidence: 99%

Identification and Functional Validation of Reciprocal microRNA–mRNA Pairings in African American Prostate Cancer Disparities

Wang

Ceniccola

Yang

et al. 2015

Clinical Cancer Research

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Purpose African Americans (AA) exhibit higher rates of prostate cancer (PCa) incidence and mortality compared to European American (EA) men. In addition to socioeconomic influences, biological factors are believed to play a critical role in PCa disparities. We investigated whether population-specific and -enriched miRNA-mRNA interactions might contribute to PCa disparities. Experimental Design Integrative genomics was employed, combining miRNA and mRNA profiling, miRNA target prediction, pathway analysis and functional validation, to map miRNA-mRNA interactions associated with PCa disparities. Results We identified 22 AA-specific and 18 EA-specific miRNAs in PCa versus patient-matched normal prostate, and 10 ‘AA-enriched/-depleted’ miRNAs in AA PCa versus EA PCa comparisons. Many of these population-specific/-enriched miRNAs could be paired with target mRNAs that exhibited an inverse pattern of differential expression. Pathway analysis revealed epidermal growth factor receptor (EGFR or ERBB) signaling as a critical pathway significantly regulated by AA-specific/-enriched mRNAs and miRNA-mRNA pairings. Novel miRNA-mRNA pairings were validated by qRT-PCR, western blot and/or IHC analyses in PCa specimens. Loss/gain of function assays performed in population-specific PCa cell lines confirmed miR-133a/MCL1, miR-513c/STAT1, miR-96/FOXO3A, miR-145/ITPR2 and miR-34a/PPP2R2A as critical miRNA-mRNA pairings driving oncogenesis. Manipulating the balance of these pairings resulted in decreased proliferation and invasion, and enhanced sensitization to docetaxel-induced cytotoxicity in AA PCa cells. Conclusion Our data suggest that AA-specific/-enriched miRNA-mRNA pairings may play a critical role in the activation of oncogenic pathways in AA PCa. Our findings also suggest that miR-133a/MCL1, miR-513c/STAT1 and miR-96/FOXO3A may have clinical significance in the development of novel strategies for treating aggressive PCa.

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Section: Resultsmentioning

confidence: 99%

Identification and Functional Validation of Reciprocal microRNA–mRNA Pairings in African American Prostate Cancer Disparities

Wang

Ceniccola

Yang

et al. 2015

Clinical Cancer Research

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“…6 The final scores were defined by multiplying the intensity scores with the scores of the extent of stained cells. After cooling to room temperature, each section was blocked for endogenous peroxidase activity by incubation with 0.3% H 2 O 2 for 10 minutes.…”

Section: Immunohistochemistrymentioning

confidence: 99%

The clinical and prognostic significance of YWHAZ in non‐small–cell lung cancer patients: Immunohistochemical analysis

Deng¹,

Zheng

2018

J of Cellular Biochemistry

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YWHAZ has been suggested to as an oncogene in various human malignancies, including non‐small–cell lung cancer (NSCLC). Our study presents more evidence to confirm the clinical significance and biological function of YWHAZ in NSCLC. In our results, YWHAZ was upregulated in lung squamous cell carcinoma tissues and lung adenocarcinoma tissues through analyzing The Cancer Genome Atlas (TCGA) database, and confirmed high levels of YWHAZ messenger RNA and protein in lung squamous cell carcinoma tissues and lung adenocarcinoma tissues through quantitative real‐time polymerase chain reaction and immunohistochemistry. Moreover, YWHAZ overexpression was correlated with advanced clinical stage, more lymph node metastasis and present distant metastasis in NSCLC patients. Survival analysis indicated that high level of YWHAZ protein expression was associated with short overall survival time in NSCLC patients, and YWHAZ expression was independent prognostic factors for overall survival in NSCLC patients. Moreover, Silencing of YWHAZ expression represses NSCLC cell migration and invasion. In conclusion, YWHAZ is a credible prognostic biomarker, and may be a therapeutic target in NSCLC.

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“…3 H and I); therefore PLEKHG3 is not the only RhoGEF that is activated by PI3K to induce cell polarity. In addition to PLEKHG3, PI3K might regulate other GEFs that can also activate Rac1, such as guanine nucleotide exchange factor VAV2 (32) or T-lymphoma invasion and metastasis 1 (TIAM1) (3,33,34), to induce cell polarity and migration. Based on the findings described above, we propose a tentative model for how PLEKHG3 pathways enhance cell polarity and cell migration.…”

Section: Plekhg3 Enhances Polarized Cell Migration Via a Positive Feementioning

confidence: 99%

PLEKHG3 enhances polarized cell migration by activating actin filaments at the cell front

Nguyen

Park

et al. 2016

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

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Cells migrate by directing Ras-related C3 botulinum toxin substrate 1 (Rac1) and cell division control protein 42 (Cdc42) activities and by polymerizing actin toward the leading edge of the cell. Previous studies have proposed that this polarization process requires a local positive feedback in the leading edge involving Rac small GTPase and actin polymerization with PI3K likely playing a coordinating role. Here, we show that the pleckstrin homology and RhoGEF domain containing G3 (PLEKHG3) is a PI3K-regulated Rho guanine nucleotide exchange factor (RhoGEF) for Rac1 and Cdc42 that selectively binds to newly polymerized actin at the leading edge of migrating fibroblasts. Optogenetic inactivation of PLEKHG3 showed that PLEKHG3 is indispensable both for inducing and for maintaining cell polarity. By selectively binding to newly polymerized actin, PLEKHG3 promotes local Rac1/Cdc42 activation to induce more local actin polymerization, which in turn promotes the recruitment of more PLEKHG3 to induce and maintain cell front. Thus, autocatalytic reinforcement of PLEKHG3 localization to the leading edge of the cell provides a molecular basis for the proposed positive feedback loop that is required for cell polarization and directed migration.PLEKHG3 | cell polarity | F-actin binding | positive feedback | PI3K

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An EGFR/PI3K/AKT axis promotes accumulation of the Rac1-GEF Tiam1 that is critical in EGFR-driven tumorigenesis

Cited by 78 publications

References 62 publications

Identification and Functional Validation of Reciprocal microRNA–mRNA Pairings in African American Prostate Cancer Disparities

Identification and Functional Validation of Reciprocal microRNA–mRNA Pairings in African American Prostate Cancer Disparities

The clinical and prognostic significance of YWHAZ in non‐small–cell lung cancer patients: Immunohistochemical analysis

PLEKHG3 enhances polarized cell migration by activating actin filaments at the cell front

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