Abstract
MicroRNAs (miRNAs) are key regulators of tumor progression. Based on microarray data, we identified miR-99a as a potential tumor suppressor in breast cancer. Expression of miR-99a is frequently down-regulated in breast cancer tissues relative to normal breast tissues. Reduced miR-99a expression was highly associated with lymph node metastasis and shorter overall survival of patients with breast cancer. Gain- and loss-of-function studies revealed that, miR-99a significantly inhibits breast cancer cell proliferation, migration, and invasion. An integrated bioinformatics analysis identified HOXA1 mRNA as the direct functional target of miR-99a, and this regulation was confirmed by luciferase reporter assay. Furthermore, we showed for the first time that HOXA1 expression is elevated in breast cancer tissues. Knockdown of HOXA1 significantly inhibited breast cancer cell proliferation, migration and invasion, and restoration of HOXA1 partially rescued the inhibitory effect of miR-99a in breast cancer cells. Collectively, our data indicate that miR-99a plays a tumor-suppressor role in the development of breast cancer, and could serve as a potential therapeutic target for breast cancer treatment.
Highlights
Breast cancer is the most commonly diagnosed cancer and the leading cause of cancer death in women worldwide, accounting for 23% of total new cancer cases and 14% of total cancer death [1]
We found that expression of miR-99a was significantly reduced in breast cancer tissues relative to normal breast tissues, and miR-99a down-regulation was associated with breast cancer progression
One of the down-regulated miRNAs was miR-99a, whose role in breast cancer was largely unknown; we focused on this miRNA in our subsequent investigations
Summary
Breast cancer is the most commonly diagnosed cancer and the leading cause of cancer death in women worldwide, accounting for 23% of total new cancer cases and 14% of total cancer death [1]. MicroRNAs (miRNAs) are a class of endogenous, non-protein-coding RNA about 22 nucleotides in length. These small RNAs post-transcriptionally regulate the translation and degradation of mRNAs by base-pairing to the 3′ untranslated regions (UTRs) of target mRNAs [5]. We demonstrated that in primary breast cancer tissues, expression of miR-30a was significantly lower than in paired normal tissues, and overexpression of miR-30a suppressed breast tumor growth and metastasis by targeting metadherin [12]. We demonstrated that miR-339–5p can strongly suppress the expression of MDM2 and increase the levels and function of p53 protein; consistent with these observations, forced expression of miR-339–5p inhibits the progression of colorectal cancers in vitro and in vivo [13]. The functional significance of miRNA dysregulation in breast cancer remains unclear
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