J. C. Sporn1, E. Katsuta1, L. Yan2, K. Takabe1 1Roswell Park Cancer Institute,Surgical Oncology,Buffalo, NY, USA 2Roswell Park Cancer Institute,Biostatistics & Bioinformatics,Buffalo, NY, USA
Introduction:
miRNAs are a diverse family of RNA molecules. They are typically about 18 to 24 nucleotides in length and regulate translation and stability of partially complementary target mRNAs. It has been shown that miRNA expression is severely dysregulated in cancer cells and that altered expression of certain miRNAs can promote tumorigenesis. Some miRNAs were found to be overexpressed in cancer cells and shown to promote proliferation in vitro and tumorigenesis in vivo, other miRNAs may be downregulated in cancer cells subsequently failing to inhibit the expression of oncogenic protein and thus promoting tumorigenesis. miR-9 was shown to increase breast cancer cell motility and invasiveness in vitro and to promote metastasis formation in mice by inhibition of E-cadherin expression. Interestingly, miR-9 was also linked to downregulation of two sirtuins, SIRT1 and SIRT3. Sirtuins (of which there are seven in humans) are NAD+-dependent enzymes involved in a variety of cellular pathways including stress-response and chromatin-silencing. SIRT1 is downregulated in BRCA1-associated breast cancer compared with normal controls and inhibition of BRCA1-mutant tumor growth by the anticancer agent resveratrol upregulated SIRT1 activity.
Methods:
We utilized the TCGA dataset to analyze the expression of miR-9-5p in human breast cancer patients. To link the expression levels with the provided TCGA survival data, we used the OncoLnc platform. 988 patients were divided at the 50th percentile into two equal groups of 494 according to their expression levels (low expression versus high expression). Cox regression was performed and a Kaplan plot was calculated. We further compared the expression levels of SIRT1 to SIRT7 between the groups with low and high expression of miR-9-5p.
Results:
The miR-9-5p expression ranged from 22.98 to 562.5 in the ‘low’ and from 567.51 to 164644.95 in the ‘high’ expression group. Survival analysis showed that high expression of miR-9-5p was associated with worse prognosis (p-value= 0.00801). This is in line with previous in vitro findings linking increased miR-9 expression with invasiveness and metastatic potential in breast cancer. While there was a trend towards lower expression of SIRT1 in the group with high expression of miR-9-5p, it did not reach statistical significance. However, there was a statistically significant decrease in SIRT3 levels in the group with high expression of miR-9-5p (p<0.001).
Conclusion:
Our analysis supports an important link between miR-9 and sirtuins and identifies miR9-5p as a novel biomarker to predict survival in breast cancer patient.