SIX2 Effects on Wilms Tumor Biology

Pierce, Janene; Murphy, Andrew J.; Panzer, Alexis; Caestecker, Christian de; Ayers, Gregory D.; Neblett, David; Saito-Diaz, Kenyi; Caestecker, Mark de; Lovvorn, Harold N.

doi:10.1016/j.tranon.2014.09.005

Cited by 28 publications

(33 citation statements)

References 36 publications

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“…However, SIX2 levels were not associated with gender, age at diagnosis, and outcome (all P>0.05). Consistent with earlier reports [28], the correlation between tumor tissue and preoperative venous blood with respect to SIX2 methylation was 0.131 (P = 0.228) and 0.451 for SIX2 expression (P=0.004). Correlation between SIX2 hypomethylation and overexpression in WT As shown in Table 3, we observed a significant correlation between SIX2 hypomethylation and overexpression in WT tissue.…”

Section: Msp and Qrt-pcr Analysis Of The Six2 Gene In Wtsupporting

confidence: 91%

“…An earlier study on a specific Wilms' tumor cell line, based on flow cytometry and scratch tests, revealed that overexpression of SIX2 leads to a significant increase in the percentage of cells in the S-phase and enhances cell proliferation and migration [27]. Using a validated model of SIX2 overexpression in a WT cell line, Pierce's research team have observed significantly enhanced cell survival in soft agar and an early effect to increase cell proliferation, shifting the balance in WNT/β-catenin signaling away from a differentiation path and toward a stem cell survival path [28]. Survival and ROC curve analyses disclosed that SIX2 expression is markedly associated with poor outcome, and sensitivity and specificity are significantly increased in diagnosis of short vs. long overall survival in WT children using the SIX2 expression level in preoperative venous blood as a biomarker.…”

Section: Discussionmentioning

confidence: 99%

“…Upregulation of SIX2 expression has been shown to facilitate transformation from human multipotent stem cells to renal progenitor cells [25]. Moreover, high protein and gene levels of SIX2 have been detected in human WT tissues and cell line [26][27][28]. Earlier studies suggest that persistence or reactivation of embryonal transcriptional programs is fundamental for tumorigenesis [26].…”

Section: Introductionmentioning

confidence: 99%

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Assessment of promoter methylation and expression of SIX2 as a diagnostic and prognostic biomarker in Wilms’ tumor

Song

Yue

et al. 2015

Tumor Biol.

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This study was designed to evaluate the utility of expression and DNA methylation patterns of the sine oculis homeobox homolog 2 (SIX2) gene in early diagnosis and prognosis of Wilms' tumor (WT). Methylation-specific polymerase chain reaction (MSP), real-time quantitative polymerase chain reaction (qRT-PCR), receiver operating characteristic (ROC), and survival curve analyses were utilized to measure the expression and DNA methylation patterns of SIX2 in a cohort of WT tissues, with a view to assessing their diagnostic and prognostic value. Relative expression of SIX2 mRNA was higher, while the promoter methylation level was lower in the WT than control group (P < 0.05) and closely associated with poor survival prognosis of WT children (P < 0.05). Increased expression and decreased methylation of SIX2 were correlated with increasing tumor size, clinical stage, vascular invasion, and unfavorable histological differentiation (P < 0.05). ROC curve analysis showed areas under the curve (AUCs) of 0.579 for methylation and 0.917 for expression in WT venous blood, indicating higher diagnostic yield of preoperative SIX2 expression. The preoperative venous blood SIX2 expression level serves as an underlying biomarker for early diagnosis of WT. SIX2 overexpression and concomitantly decreased promoter methylation are significantly associated with poor survival of WT children.

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Section: Msp and Qrt-pcr Analysis Of The Six2 Gene In Wtsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Assessment of promoter methylation and expression of SIX2 as a diagnostic and prognostic biomarker in Wilms’ tumor

Song

Yue

et al. 2015

Tumor Biol.

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“…Results from StarBase prediction confirmed that SIX2 was a potential candidate gene of miR‐335‐5p. As a potent oncogene, SIX2 has previously been demonstrated to accelerate tumorigenesis through regulating the proliferation of tumor cells . Similarly, the higher expression of SIX2 was validated in BC tissues and cells relative to the corresponding controls.…”

Section: Discussionmentioning

confidence: 79%

Circular RNA 0007255 regulates the progression of breast cancer through miR‐335‐5p/SIX2 axis

Jia

et al. 2020

Thoracic Cancer

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Background Breast cancer (BC) is a common cancer in women worldwide. Emerging evidence has indicated that circular RNA hsa‐circ_0007255 (circ_0007255) is a prognostic mediator in BC progression. However, the functional role of circ_0007255 needs to be determined. Methods The expression of circ_0007255, microRNA (miR)‐335‐5p, and SIX Homeobox 2 (SIX2) was evaluated using quantitative real‐time polymerase chain reaction (qRT‐PCR) or western blot assay. Actinomycin D and RNase R treatment was performed to analyze the stability of circ_0007255. Additionally, Seahorse extracellular flux, colony formation and transwell analyses were carried out to detect oxygen consumption ratio (OCR), colony formation and cell mobility, respectively. The interaction between miR‐335‐5p and circ_0007255 or SIX2 was confirmed via dual‐luciferase reporter assay. A xenograft tumor model was established to explore the role of circ_0007255 in vivo. Results Circ_0007255 and SIX2 were overexpressed, but miR‐335‐5p was diminished in BC tissues and cells. Circ_0007255 absence inhibited oxygen consumption, colony formation, cell migration and invasion, and these effects were particularly abrogated via miR‐335‐5p upregulation in BC cells. Moreover, SIX2 deficiency eliminated the promotion effects of miR‐335‐5p inhibitor on oxygen consumption, colony formation, and cell mobility in BC cells. Importantly, circ_0007255 inhibited tumor growth in vivo. Mechanically, circ_0007255 was a sponge of miR‐335‐5p to regulate SIX2 expression in BC progression. Conclusion Circ_0007255 functioned as a novel oncogene in the progression of BC by regulating miR‐335‐5p/SIX2 axis, and might be a promising biomarker for BC treatment. Key points Significant findings of the study: Levels of circ_0007255 and SIX2 were upregulated, but miR‐335‐5p was diminished in BC tissues and cells. Circ_0007255 was an oncogene in BC development and exerted its function via miR‐335‐5p/SIX2 axis in BC. Tumor growth was reduced by circ_0007255 absence. What this study adds: Circ_0007255 functioned as a novel oncogene in the progression of BC by regulating miR‐335‐5p/SIX2 axis, and might be a promising biomarker for BC treatment.

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“…Briefly, using formalin fixed paraffin embedded renal tumor and adjacent kidney specimens collected prospectively and archived in our IRB-approved laboratory embryonal tumor repository, we created two tissue microarrays (TMA) comprised of 148 total punches (~1 mm in diameter each) derived from 32 consecutive childhood WT’s 15 . Serial 5 µm sections of these two TMAs were included for the IHC analysis, which was concentrated on the 32 WT specimens.…”

Section: Methodsmentioning

confidence: 99%

A Murine Model of K-RAS and β-Catenin Induced Renal Tumors Expresses High Levels of E2F1 and Resembles Human Wilms Tumor

Polosukhina

Love

et al. 2015

Journal of Urology

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Background Wilms tumor (WT) is the most common renal neoplasm of childhood. We previously showed that restricted activation of the WNT/β-catenin pathway in renal epithelium late in kidney development is sufficient to induce small primitive neoplasms with features of epithelial WT. Metastatic disease progression required simultaneous addition of an activating mutation of the oncogene K-RAS. Here, we sought to define the molecular pathways activated in this process and their relationship to human renal malignancies. Methods Affymetrix expression microarray data from murine kidneys with activation of K-ras, Ctnnb1 (β-catenin), or both restricted to renal epithelium were analyzed and compared to publically available expression data from normal and neoplastic human renal tissue. Target genes were verified by immunoblot and immunohistochemistry. Results Mouse kidney tumors with activation of K-ras and Ctnnb1 and human renal malignancies have similar mRNA expression signatures and are associated with activation of networks centered on β-catenin and TP53. Up-regulation of WNT/β-catenin targets (MYC, Survivin, FOXA2, Axin2, Cyclin D1) was confirmed by immunoblotting. K-RAS/β-catenin murine kidney tumors were more similar to human WT than other renal malignancies and demonstrated activation of a TP53 dependent network of genes including the transcription factor E2F1. Up-regulation of E2F1 was confirmed in both murine and human WT samples. Conclusions Simultaneous activation of K-RAS and β-catenin in embryonic renal epithelium leads to neoplasms similar to human WT associated with activation of TP53 and up-regulation of E2F1. Further studies to evaluate the role of TP53 and E2F1 in human WT are warranted.

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SIX2 Effects on Wilms Tumor Biology

Cited by 28 publications

References 36 publications

Assessment of promoter methylation and expression of SIX2 as a diagnostic and prognostic biomarker in Wilms’ tumor

Assessment of promoter methylation and expression of SIX2 as a diagnostic and prognostic biomarker in Wilms’ tumor

Circular RNA 0007255 regulates the progression of breast cancer through miR‐335‐5p/SIX2 axis

A Murine Model of K-RAS and β-Catenin Induced Renal Tumors Expresses High Levels of E2F1 and Resembles Human Wilms Tumor

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