c-Cbl mediates the degradation of tumorigenic nuclear β-catenin contributing to the heterogeneity in Wnt activity in colorectal tumors

Shashar, Moshe; Siwak, Jamaica; Tapan, Umit; Lee, Shin Yin; Meyer, Rosana D.; Parrack, Paige; Tan, Josenia; Khatami, Fatemeh; Francis, Jean; Zhao, Qing; Hartshorn, Kevan L.; Kolachalama, Vijaya B.; Chitalia, Vipul C.

doi:10.18632/oncotarget.12107

Cited by 28 publications

(41 citation statements)

References 46 publications

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“…2, A, C, and E), we posited an inverse relationship between STUB1 and TF in the uremic milieu. However, the precise demonstration of a relationship between proteins requires their quantification, which is challenging in heterogeneous human tissues using conventional methods (31). Therefore, we developed an object-level intensity estimation algorithm to quantify TF and STUB1 expressions.…”

Section: Resultsmentioning

confidence: 99%

Targeting STUB1–tissue factor axis normalizes hyperthrombotic uremic phenotype without increasing bleeding risk

et al. 2017

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Chronic kidney disease (CKD/uremia) remains vexing because it increases the risk of atherothrombosis and is also associated with bleeding complications on standard antithrombotic/antiplatelet therapies. Although the associations of indolic uremic solutes and vascular wall proteins [such as tissue factor (TF) and aryl hydrocarbon receptor (AHR)] are being defined, the specific mechanisms that drive the thrombotic and bleeding risks are not fully understood. We now present an indolic solute–specific animal model, which focuses on solute-protein interactions and shows that indolic solutes mediate the hyperthrombotic phenotype across all CKD stages in an AHR- and TF-dependent manner. We further demonstrate that AHR regulates TF through STIP1 homology and U-box–containing protein 1 (STUB1). As a ubiquitin ligase, STUB1 dynamically interacts with and degrades TF through ubiquitination in the uremic milieu. TF regulation by STUB1 is supported in humans by an inverse relationship of STUB1 and TF expression and reduced STUB1-TF interaction in uremic vessels. Genetic or pharmacological manipulation of STUB1 in vascular smooth muscle cells inhibited thrombosis in flow loops. STUB1 perturbations reverted the uremic hyperthrombotic phenotype without prolonging the bleeding time, in contrast to heparin, the standard-of-care antithrombotic in CKD patients. Our work refines the thrombosis axis (STUB1 is a mediator of indolic solute–AHR-TF axis) and expands the understanding of the interconnected relationships driving the fragile thrombotic state in CKD. It also establishes a means of minimizing the uremic hyperthrombotic phenotype without altering the hemostatic balance, a long-sought-after combination in CKD patients.

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Section: Resultsmentioning

confidence: 99%

Targeting STUB1–tissue factor axis normalizes hyperthrombotic uremic phenotype without increasing bleeding risk

et al. 2017

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“…We found that although response to first line chemotherapy was a strong and independent predictor of overall survival, Black patients still had poorer survival despite a lack of difference in the response to therapy, comorbidities, BMI or tumor burden at the time of presentation. While our study does not rule out the possibility of molecular differences (i.e., RAS mutation, BRAF mutation, and MSI status), it raises a possibility of other pathogenic factors that may contribute to racial differences [49]. More real-world studies are needed to address in depth the influence of race on CRC progression and survival.…”

Section: 5 Conclusionmentioning

confidence: 99%

Racial differences in colorectal cancer survival at a safety net hospital

Tapan

Lee

Weinberg

et al. 2017

Cancer Epidemiology

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Background While racial disparity in colorectal cancer survival have previously been studied, whether this disparity exists in patients with metastatic colorectal cancer receiving care at safety net hospitals (and therefore of similar socioeconomic status) is poorly understood. Methods We examined racial differences in survival in a cohort of patients with stage IV colorectal cancer treated at the largest safety net hospital in the New England region, which serves a population with a majority (65%) of non-Caucasian patients. Data was extracted from the hospital's electronic medical record and the survival differences among different racial and ethnic groups were examined graphically using Kaplan-Meier analysis. A univariate cox proportional hazards model and a multivariable adjusted model were generated. Results Black patients had significantly lower overall survival compared to White patients, with median overall survival of 1.9 years and 2.5 years respectively. In a multivariate analysis, Black race posed a significant hazard (HR 1.7, CI 1.01-2.9, p = 0.0467) for death. Though the response to therapy emerged as a strong predictor of survival (HR = 0.4, CI = 0.2-0.7, p = 0.0021), it was comparable between Blacks and Whites. Conclusions Despite presumed equal access to healthcare and socioeconomic status within a safety-net hospital system, our results reinforce the findings from previous studies regarding lower colorectal cancer survival in Black patients, and point to the importance of investigating other risk factors including genetic and pathogenic differences.

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“…[26][27][28] To further uncover the underlying mechanisms of the suppression of RCC cell growth and migration mediated by miR-200a-3p, we searched for miRNA targets and identified CBL as a novel target of miR-200a-3p. 30 High CBL expression has actually been recognized as linked with the development of several types of cancer, including gliomas, gastric carcinoma, colorectal cancer, prostate cancer, breast cancer and non-small-cell lung cancer. 29 For example, CBL generally targets receptor tyrosine kinases and other nonreceptor tyrosine kinases, such as Src family kinases, and mutations in the components of this pathway may result in tumorigenesis.…”

Section: Discussionmentioning

confidence: 99%

Decreased miR‐200a‐3p is a key regulator of renal carcinoma growth and migration by directly targeting CBL

Ding

Sun

Zhong

et al. 2018

J of Cellular Biochemistry

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Although emerging evidence has revealed that microRNAs (miRNAs) dysregulation contribute to carcinogenesis, the mechanism underlying their roles in renal cell carcinoma (RCC) is unclear. The purpose of the current study was to analyze the association of miR-200a-3p expression with RCC and to understand potential novel target genes, functions and mechanisms of miR-200a-3p in RCC. MiR-200a-3p expression levels were first measured by quantitative real-time polymerase chain reaction and in situ hybridization in pairs of RCC tissue samples. Next, the potential miR-200a-3p target gene was analyzed using a combination of computer-aided algorithms, luciferase reporter assays and Western blot analysis. Finally, the biological roles of miR-200a-3p in RCC tumorigenesis were investigated both in vitro by 5-ethynyl-20-deoxyuridine, apoptosis assay and transwell assay, as well as in vivo using a xenograft mouse model. Our results demonstrated that miR-200a-3p was remarkably downregulated in RCC tissues compared with normal adjacent tissue, and CBL is a direct target of miR-200a-3p. An inverse correlation between miR-200a-3p and CBL was observed in RCC tissue samples. Mechanistic investigations revealed that ectopic expression of miR-200a-3p in RCC cell lines suppressed cell proliferation and migration and enforced cell apoptosis by directly inhibiting CBL in vitro and in vivo, whereas silencing miR-200a-3p resulted in the opposite effects. Additionally, overexpressing CBL abolished the effects induced by miR-200a-3p overexpression. Taken together, our results show that the miR-200a-3p/CBL regulation axis is a novel mechanism underlying RCC pathogenesis and may serve as a candidate biomarker and therapeutic target in RCC.

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c-Cbl mediates the degradation of tumorigenic nuclear β-catenin contributing to the heterogeneity in Wnt activity in colorectal tumors

Cited by 28 publications

References 46 publications

Targeting STUB1–tissue factor axis normalizes hyperthrombotic uremic phenotype without increasing bleeding risk

Targeting STUB1–tissue factor axis normalizes hyperthrombotic uremic phenotype without increasing bleeding risk

Racial differences in colorectal cancer survival at a safety net hospital

Decreased miR‐200a‐3p is a key regulator of renal carcinoma growth and migration by directly targeting CBL

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