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MiR-17 inhibition enhances the formation of kidney cancer spheres with stem cell/ tumor initiating cell properties.

ABSTRACT: Renal cell carcinoma (RCC) is an aggressive disease, with 35% chance of metastasis. The 'cancer stem cell' hypothesis suggests that a subset of cancer cells possess stem cell properties and is crucial in tumor initiation, metastasis and treatment resistance. We isolated RCC spheres and showed that they exhibit cancer stem cell/ tumor initiating cell-like properties including the formation of self-renewing spheres, high tumorigenicity and the ability to differentiate to cell types of the original tumor. Spheres showed increased expression of stem cell-related transcription factors and mesenchymal markers. miRNAs were differentially expressed between RCC spheres and their parental cells. Inhibition of miR-17 accelerated the formation of RCC spheres which shared molecular characteristics with the spontaneous RCC spheres. Target prediction pointed out TGF? pathway activation as a possible mechanism to drive RCC sphere formation. We demonstrate that miR-17 overexpression interferes with the TGF?-EMT axis and hinders RCC sphere formation; and validated TGFBR2 as a direct and biologically relevant target during this process. Thus, a single miRNA may have an impact on the formation of highly tumorigenic cancer spheres of kidney cancer.

SUBMITTER: Lichner Z

PROVIDER: S-EPMC4467387 | biostudies-literature | 2015 Mar

REPOSITORIES: biostudies-literature

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miR-17 inhibition enhances the formation of kidney cancer spheres with stem cell/ tumor initiating cell properties.

Lichner Zsuzsanna Z Saleh Carol C Subramaniam Venkateswaran V Seivwright Annetta A Prud'homme Gerald Joseph GJ Yousef George Makram GM

Oncotarget 20150301 8

Renal cell carcinoma (RCC) is an aggressive disease, with 35% chance of metastasis. The 'cancer stem cell' hypothesis suggests that a subset of cancer cells possess stem cell properties and is crucial in tumor initiation, metastasis and treatment resistance. We isolated RCC spheres and showed that they exhibit cancer stem cell/ tumor initiating cell-like properties including the formation of self-renewing spheres, high tumorigenicity and the ability to differentiate to cell types of the original ...[more]

PMID: 25011053

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Project description:BackgroundIn older adults (aged 70-74 years), African-Americans have 4-fold higher risk of developing hypertension-attributed end-stage renal disease (ESRD) than European-Americans. A hypothesized mechanism linking hypertension and progressive chronic kidney disease (CKD) is the innate immune response and inflammation. Persons with CKD are also more susceptible to infection. Gene expression in peripheral blood can provide a view of the innate immune activation profile. We aimed to identify differentially expressed genes, microRNAs, and pathways in peripheral blood between cases with CKD and high blood pressure under hypertension treatment versus controls without CKD and with controlled blood pressure in African Americans.MethodsCase and control pairs (N = 15x2) were selected from those without diabetes and were matched for age, sex, body mass index, APOL1 risk allele count, and hypertension medication use. High blood pressure under hypertension treatment was defined as hypertension medication use and systolic blood pressure (SBP) ≥ 145 mmHg. CKD was defined as estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73m2. Cases were selected from those with CKD and high blood pressure under hypertension treatment, and controls were selected from those without CKD (eGFR: 75-120 mL/min/1.73m2 and urine albumin-to-creatinine ratio < 30mg/g) and with blood pressure controlled by hypertension medication use (SBP < 135 mmHg and D(diastolic)BP < 90 mm Hg). We perform RNA sequencing of mRNA and microRNA and conducted differential expression and co-expression network analysis.ResultsOf 347 miRNAs included in the analysis, 14 were significantly associated with case status (Benjamini-Hochberg adjusted p-value [BH p] < 0.05). Of these, ten were downregulated in cases: three of each belong to the miR-17 and miR-15 families. In co-expression network analysis of miRNA, one module, which included 13 of the 14 significant miRNAs, had significant association with case status. Of the 14,488 genes and 41,739 transcripts included in the analysis, none had significant association with case status. Gene co-expression network analyses did not yield any significant associations for mRNA.ConclusionWe have identified 14 differentially expressed miRNAs in the peripheral blood of CKD cases with high blood pressure under hypertension treatment as compared to appropriate controls. Most of the significant miRNAs were downregulated and have critical roles in immune cell functions. Future studies are needed to replicate our findings and determine whether the downregulation of these miRNAs in immune cells may influence CKD progression or complications.

Dataset Information

MiR-17 inhibition enhances the formation of kidney cancer spheres with stem cell/ tumor initiating cell properties.

Publications

miR-17 inhibition enhances the formation of kidney cancer spheres with stem cell/ tumor initiating cell properties.

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