5q32

MIRN145,miR-145,miRNA145

Cancer

Downregulation of miR-145 has been found in cancers of many tissue types including colon, breast, prostate, pancreas, etc. (Sachdeva et al., 2009; Bandres et al., 2006; Michael et al., 2003). For example, in situ hybridization detected accumulation of miR-145 in normal colon epithelia with no signal from adenocarcinomas cells. Loss of miR-145 in various tumors suggests its role as a tumor suppressor. In fact, miR-145 has been well documented as a tumor suppressor gene in multiple tumor types because of its anti-proliferative and pro-apoptotic effects. It is shown that miR-145 can negatively regulate multiple oncogenes such as MYC, Kras, IRS-1, ERK5, etc. involved in cell proliferation and survival (Sachdeva et al., 2009; Kent et al., 2010; Shi et al., 2007; Ibrahim et al., 2011).

Metastasis

Several reports suggest that miR-145 is a suppressor of metastasis. For example, mir-145 negatively regulates MUC1 and suppresses invasion and metastasis of the breast cancer cells (Sachdeva and Mo, 2010b). Similar findings in prostate cancer and in gliomas have further confirmed the role of miR-145 as a metastasis suppressor by targeting genes including FASCN1 and SOX2, respectively (Fang et al., 2011; Watahiki et al., 2011; Leite et al., 2011).

Stem cells and differentiation

A study has shown that miR-145 is induced during differentiation, and it directly silences the stem cell self renewal and pluripotency program by suppressing multiple pluripotent genes such as OCT4, SOX2 and KLF4 (Xu et al., 2009).

Vascular smooth muscle cells

The role of miR-145 in differentiation of vascular smooth muscle cell (VSMC) has been recently investigated. A report demonstrated that miR-145 is the most enriched microRNA in arteries and its expression is significantly downregulated in vascular walls with neointimal lesions (Chen et al., 2004). Similarly, another group, using transgenic mouse model with miR-145 promoter fused to β-galactosidase gene, found that miR-145 is cardiac-specific and smooth-muscle specific microRNA regulated by serum response factor, myocardin and Nkx2-5 (NK2 transcription factor related, locus 5) (Cordes et al., 2009). Further evidence from the miR-43/miR-145 KO rats suggests that this microRNA cluster is expressed mostly in the SMC compartment in vessels and SMC-containing organs and their loss induces an incomplete differentiation of VSMCs (Elia et al., 2009).

A comprehensive study using clinical samples combined with mouse models have found that deletion of chromosome 5q correlates with loss of two miRNAs that are abundant in hematopoietic stem/progenitor cells (HSPCs), miR-145 and miR-146a. In addition, they observed that miR-145 is highly expressed in primitive lin- (mouse) and CD34+ (human) bone marrow cells than committed cells and stable knockdown of miR-145 in these cells in mouse marrow results in 5-q syndrome (Starczynowski et al., 2010). Similar work from another group in patients with del (5q) have decreased expression of miR-145 and increased expression of Fli-1 (Kumar et al., 2011). They found that miR-145 functions through repression of Fli-1, a megakaryocyte and erythroid regulatory transcription factor and thus, cells lacking miR-145 have impaired megakaryocyte and erythroid differentiation.