miR‐221/222 cluster expression improves clinical stratification of non‐muscle invasive bladder cancer (TaT1) patients' risk for short‐term relapse and progression

Abstract

Clinical heterogeneity of bladder cancer prognosis requires the identification of bladder tumors' molecular profile to improve the prediction value of the established and clinically used markers. In this study, we have analyzed miR-221/222 cluster expression in bladder tumors and its clinical significance for patients' prognosis and disease outcome. The study included 387 tissue specimens. Following extraction, total RNA was polyadenylated at 3'-end and reversed transcribed. SYBR-Green based qPCR assays were performed for the quantification of miR-221/222 expression. Extensive statistical analysis was completed for the evaluation of miR-221/222 cluster's clinical significance. The expression of miR-221/222 is significantly downregulated in tumors compared to normal urothelium, while ROC curve and logistic regression analysis highlighted cluster's discriminatory ability. However, miR-222 levels were increased in muscle-invasive (T2-T4) compared to superficial tumors (TaT1), and in high compared to low-grade tumors. Kaplan-Meier survival curves and Cox regression analysis revealed the stronger risk of TaT1 patients overexpressing miR-222 for disease short-term relapse and progression following treatment. Moreover, multivariate Cox models highlighted the independent prognostic value of miR-222 overexpression for TaT1 patients' poor prognosis. Finally, the analysis of miR-222 expression improved significantly the positive prediction strength of the clinically used prognostic markers of tumor stage, grade, EORTC risk-stratification and recurrence at the first follow-up cystoscopy for TaT1 patients' outcome, and resulted to higher clinical net benefit following decision curve analysis. In conclusion, the expression of miR-221/222 cluster is deregulated in bladder tumors and miR-222 overexpression results to a superior positive prediction of TaT1 patients' short-term relapse and progression.

RETRACTED: The Effect of MCM3AP-AS1/miR-211/KLF5/AGGF1 Axis Regulating Glioblastoma Angiogenesis

“…miRNAs are highly conserved small non-coding RNAs containing about 20 nucleotides. It is well-established that miRNAs directly target and bind to mRNAs, which in turn negatively regulate the expression of target genes ( Tsikrika et al, 2017 ). miR-211 is located in intron 6 of the TRPM1 gene on chromosome 15 ( Margue et al, 2013 ).…”

Prognostic Role of miR-221 and miR-222 Expression in Cancer Patients: A Systematic Review and Meta-Analysis

“…Then, the entire text of the remaining 362 studies was assessed, determining the removal of 312 further studies. Finally, 50 articles, published between 2009 and 2018, were included in the systematic review [35,36,37,38,39,40,41,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66,67,68,69,70,71,72,73,74,75,76,77,78,79,80,81,82,83,84,85,86,87,88,89,90,91,92,93]. A detailed flow-chart illustrating the literature selection process is presented in Figure 1.…”

“…In particular, this cluster might promote the overcoming of the status of cell quiescence and increase proliferation, survival, and metastatic potential, acting as an oncogene [31,33,34]. In addition, it is well documented that miR-221 and miR-222 play a key role in modulating the clinical outcome in cancer patients in both solid and hematological malignancies [30,35]. In this regard, the prognostic value of miR-221 and miR-222 expression in cancer has been extensively investigated in the last decade, with controversial results.…”

Non-coding RNAs: the riddle of the transcriptome and their perspectives in cancer

“…Altered expression levels of miRNAs between malignant tumors and healthy tissues facilitate cancer diagnosis, ameliorate tumor staging and inform clinicians about relapse risk and/or disease progression as well as therapeutic efficacy, reducing the unwanted under-or overtreatment. The prognostic and predictive value improves by the synergy of more than two miRNAs, encouraging the development of multipurpose miRNA signatures as diagnostic or prognostic tools (46)(47)(48). For instance, combination of miR-15a-5p, miR-16, miR-24-3p, miR-28-5p, miR-34a, miR-96, miR-182, and miR-224, which have been proposed as molecular biomarkers with significant prognostic value in colorectal cancer (CRC); has already been proposed as a prognostic signature in this malignancy (49)(50)(51)(52)(53)(54)(55)(56)(57); another very important miRNA that could be added in this molecular signature is miR-21, a predictor of metastatic tumor potential in this cancer (58).…”