A Clinical Evaluation of Circulating MiR-106a and Raf-1 as Breast Cancer Diagnostic and Prognostic Markers

Abstract

Objective: MicroRNAs (MiRNAs) regulate mammalian cell growth, differentiation, and apoptosis by altering the expression of other genes and serve multiple roles in tumorigenesis and progression. Proto-oncogene serine/threonineprotein kinase (RAF-1) functions as a part of the MAPK/ERK signal transduction pathway. The present study aim was to prospectively evaluate MicroRNA 106a (MiR-106a) and RAF-1 as a diagnostic and prognostic factor in early prediction of breast cancer (BC), recurrence and early detection of distant metastasis as well as to analyses the statistical correlation between MiR-106a and RAF-1 levels and clinical-pathological parameters including tumor size, lymph node, histological type and grading. Methods: Sera and plasma of 30 normal women and 50 women with breast carcinoma were assayed for MiR-106a by RT-qPCR as well as levels of Hb, WBCs and platelets count and RAF-1 by solid phase enzyme-linked immunosorbent assay (ELISA). Results: The patients' characteristics, they were classified according to grade into 8% grade I, 66% grade II, 22% grade III and 4% grade IV. The stages were classified according to the TNM system as stage II was the highest percentage 66%, while the lowest percentage was 10% for stage I and 24% for stage III. Also, Hb% and RAF-1 levels were significantly decreased in breast cancer patients as compared with healthy control. On the other hand, MiRNA-106a gene expression was non-significantly increased in positive lymph node metastasis patients (FC=3.66) when compared to patients with negative lymph node metastasis (FC=3.51). In addition, MiR-106a was significantly up-regulated in breast cancer patients with a fold of change 3.63 when compared to control samples. Conclusion: Expression of MiR-106a gene can be used as a diagnostic and prognostic noninvasive biomarker which can stimulates breast cancer cell invasion and proliferation through downregulation of Raf-1 levels.

miRNA Expression Profiling in Human Breast Cancer Diagnostics and Therapy

“…Altogether, it was reported that miR-106a could contribute to enhanced cell proliferation due to lowered sensitivity to chemotherapeutic agents [69,102]. Another study revealed a possible correlation between miR-106a levels and breast cancer cell proliferation mediated by RAF-1, activating the MAPK/ERK signaling pathway [68].…”

“…The candidates were selected based on the latest reports indicating the role of miRNA in breast cancer. Consequently, a broad analysis of selected miRNA targets suggested some good candidate markers based on the global data at TargetScanHuman Induction of EMT and gemcitabine resistance [63] PI3K/Akt, MEK/ERK [58] Activation PI3K/Akt and MEK/ERK signaling pathways [58] Development of MDR [58] TPM1, TGF-β [64] Repression of expression TPM1 [65,66] Increased BC cells proliferation, migration, invasion, survival, and EMT [64] Mesenchymal cell markers (N-cadherin, Vimentin, α-SMA) [67] Activation of mesenchymal cell markers [67] Re-expression of miR-21 is responsible for migration and invasion by activating the EMT process in MCF7 cells [67] Epithelial cell marker (E-cadherin) [67] Inhibition of epithelial cell marker [67] miR-106a Upregulated Serum, qRT-PCR [68] Bcl-2,ABCG2, BAX, P53, RUNX3 [69] Upregulation of Bcl-2 protein and multidrug transporter ABCG2. Downregulation of BAX protein and genes products: P53, RUNX3 [69] Promotes BC cells proliferation and invasion [69] * Inhibition of miR-106a downregulates the expression of Bcl-2, ABCG2 and upregulates the BAX, P53, RUNX3 expression [69] RAF-1 [68] Decreases RAF-1 levels and RAF-1 is a part of MAPK/ERK signaling pathway [68] Possibly induces proliferation and decreases apoptosis in BC cells through regulation of the MAPK/ERK signaling pathway, which controls gene expression [68] ZBTB4 [70][71][72] Negative regulation of ZBTB4 gene, which functions as a tumor suppressor gene [70][71][72] * Restoration of ZBTB4 suppress Sp1, Sp3, Sp4 expression resulting in inhibition of BC cells proliferation, invasion [70][71][72] miR-155 Upregulated Serum, qRT-PCR [73] TERF1 [74] Reduction in the...…”

miR-125 in Breast Cancer Etiopathogenesis: An Emerging Role as a Biomarker in Differential Diagnosis, Regenerative Medicine, and the Challenges of Personalized Medicine

“…Another player in BC etiopathogenesis is miR-106a, which promotes cancer progression through the downregulation of RAF-1 [ 69 ], P53 , BAX , and RUNX3 and the upregulation of Bcl-2 and ABCG2 ; it also confers cisplatin resistance upon its upregulation [ 70 , 71 ].…”

Addressing the Clinical Feasibility of Adopting Circulating miRNA for Breast Cancer Detection, Monitoring and Management with Artificial Intelligence and Machine Learning Platforms

“…On the contrary, the level of circulating miRNAs is helpful to classify BC based on the clinical and histopathological grading [ 47 , 48 ]. For instance, the increased levels of exosomal miR-363-5p [ 25 ] and circulating miR-106a levels [ 49 ] were useful to differentiate BC with and without lymph node involvement. A clinical study reported that the elevation of four serum miRNAs, including miR-16-5p, miR-17-3p, miR-451a and miR-940, was observed in metastatic BC as compared to local, non-metastatic BC [ 50 ] and downregulation of plasma miR-195 level was also observed in metastatic BC [ 51 ].…”