Exploring The Role of microRNAs in Renal Cell Carcinoma Metastasis: Moving into a New Era of Personalized Medicine
Year: 2015
Type: dissertation
Abstract: Renal Cell Carcinoma (RCC) is the most common adult kidney neoplasm with clear cell renal cell carcinoma (ccRCC) representing the most common subtype. Metastatic renal cell carcinoma (mRCC) is an aggressive treatment-resistant tumor. Patients diagnosed at the metastatic stage have poor prognosis with only (~9%) 5-year survival rate. MicroRNAs (miRNAs) are small non-coding RNAs that regulate different cellular functions and play crucial role in tumor development and progression. In this thesis we examined the role of miRNAs in RCC tumor progression and provided a preliminary evidence that miRNAs are promising RCC prognostic and predictive biomarkers. miRNA metastatic signature was identified by comparing primary and metastatic RCC tumors. We validated this signature on matched primary and metastatic RCC pairs. miR-192, miR-194 and miR-215 were significantly downregulated in metastatic RCC tumors. Gain of function study showed that restoration of the expression levels of these miRNAs decreased cellular invasion and migration in RCC cell line model. Through our experimental and bioinformatics analyses, we uncovered a miRNA network that participates in tumor progression and aggressive behavior. This network has divergent and convergent properties. Also, we examined the clinical utility of miR-215 and miR-126 as prognostic markers in ccRCC. Lower expression of either miR-215 or miR-126 was associated with significantly shorter survival. Furthermore, we tested the clinical utility of miRNAs as RCC predictive markers and we identified the differentially expressed miRNAs between mRCC patients with short and long survival under sunitinib treatment. We constructed statistical models that can accurately distinguish between the two groups. miR-221 and miR-222 overexpression was associated with poor survival under sunitinib treatment. Overexpression of these two miRNAs decreased angiogenesis and interestingly, they reduced endothelial cellular proliferation while increasing tumor cellular proliferation. Collectively, our analysis shows that miRNAs play an important role in ccRCC progression and represent promising prognostic and predictive biomarkers. Our findings can pave the way towards development of novel targeted therapies.
Source: TSpace (University of Toronto)
Author: Heba Wahba Zekri Khella
Language: English
Subfield: Cancer Research
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W2560127071