miR-708-5p: a microRNA with emerging roles in cancer

Abstract

MicroRNAs (miRNAs) are small non-coding RNAs that negatively regulate gene expression post-transcriptionally. They are crucial for normal development and maintaining homeostasis. Researchers have discovered that dysregulated miRNA expression contributes to many pathological conditions, including cancer. miRNAs can augment or suppress tumorigenesis based on their expression and transcribed targetome in various cell types. In recent years, researchers have begun to identify miRNAs commonly dysregulated in cancer. One recently identified miRNA, miR-708-5p, has been shown to have profound roles in promoting or suppressing oncogenesis in a myriad of solid and hematological tumors. This review highlights the diverse, sometimes controversial findings reported for miR-708-5p in cancer, and the importance of further exploring this exciting miRNA.

Keywords: cancer; miR-708; miR-708-5p; oncomiR; tumor suppressor.

Figure 1. MiR-708-5p gene location and transcriptional and post-transcriptional regulation

(A) MiR708 (green) is located on chromosome 11 within intron 1 of ODZ4. Transcription runs right to left in the figure. Potential enhancers are found in red. Repressors (red) and activators (green) are designated by their predicted (*) or confirmed binding sites. (?) indicates unknown activator or repressor binding. (B) Illustration of various post-transcriptional mechanisms preventing miRNA maturation and function. Mutation or altered expression of DROSHA, Exportin 5, DICER, Ago1-4, or RNA-BPs can disrupt miRNA-mediated suppression of target genes. Solid black lines indicate normal, endogenous miRNA maturation and function. Dashed red lines represent steps where miRNA biogenesis and activity may be hindered in cancer cells.

Figure 2. Model of miR-708-5p in prostate cancer

(A) Pro-oncogenic signaling of CD44, NNAT, the PI3K pathway, and KPNA4. CD44 activates MAPK and PI3K signaling pathways, potentially suppressing CHOP expression. NNAT mitigates ER stress while KPNA4 shuttles pro-oncogenic transcription factors (NF-kB, NICD) into the nucleus. Collectively, CD44, NNAT, the PI3K pathway, and KPNA4 promote invasion, proliferation, and survival in prostate cancer. (B) Proposed metformin anti-tumorigenic activities. Metformin increases miR-708-5p expression, possibly by inhibiting PI3K signaling, which in turn derepresses CHOP. Increased CHOP expression potentially promotes miR-708-5p expression in prostate cancer cells. (C) Restoration of miR-708-5p (exogenous source/long term metformin treatment) suppresses various pro-oncogenic signaling pathways. miR-708-5p directly targets KPNA4 to suppress transcription factor shuttling. miR-708-5p suppression of NNAT results in exacerbated ER stress. ER stress may further propagate CHOP and miR-708-5p expression through the UPR. PI3K signaling is mitigated through miR-708-5p targeting of CD44 and AKT2. miR-708-5p activities culminate with decreased invasion, proliferation, and survival in prostate cancer cells. Black solid lines indicate activation (arrows) or suppression (blocks) while red solid lines indicate miR-708-5p targeting. Dotted lines represent loss of signaling within a pathway.

Figure 3. MiR-708-5p research by lung cancer subtype

The oncogenic (red), tumor suppressive (green), controversial (yellow), or unknown (blue) function of miR-708-5p in various lung cancer subtypes. Circle size represents relative abundance of each subtype. [Numbers] identify citations relevant to each lung cancer subtype.

Figure 4. miR-708-5p model in lung cancer

(A) TMEM88 and p21 oncogenic and tumor suppressive mechanisms in lung cancer. Membrane bound TMEM88 suppresses pro-oncogenic WNT signaling, while cytoplasmic TMEM88 promotes tumorigenesis. Cytoplasmic p21 sequesters pro-caspase 3 to hinder pro-apoptotic signaling while nuclear p21 acts as a tumor suppressort. (B) Function of miR-708-5p on TMEM88 and p21 signaling. miR-708-5p decreases cytoplasmic p21 levels while not altering nuclear p21 levels. Deregulation of pro-caspase 3 allows for apoptotic signaling to proceed, while nuclear p21’s tumor suppressive functions remain intact. miR-708-5p may directly or indirectly suppress TMEM88. If miR-708-5p represses membrane-bound TMEM88, regulation of WNT signaling is lost, resulting in increased pro-oncogenic signaling. miR-708-5p repression of pro-tumorigenic cytoplasmic TMEM88 would result in decreased invasion, proliferation, and survival. Black solid lines indicate activation (arrows) or suppression (blocks) while red lines indicate miR-708-5p direct (solid) or unknown (dotted, ?) targeting. Dotted black lines represent signaling inhibition.