Cancer represents one of the major public health issues and is a leading cause of worldwide mortality. Throughout the past 10 years, the cancer-related death rate was 25% of the total mortality; therefore, overcoming cancer is an urgent priority (1). After unremitting research efforts, it has been definitely proven that the initiation of cancer is the result of the deregulation of oncogenes and tumor-suppressor genes. Recently, microRNAs (miRNAs) have been identified as novel regulators of oncogenes and tumor-suppressor genes. Researchers believe that miRNAs will become a new modality for both the diagnosis and treatment of cancers (2,3).

MiRNAs are a large class of small, non-coding, single-stranded RNAs, 19–23 nucleotides in length, and constitute a novel class of gene regulators (4). These single-stranded miRNAs bind to complementary sites on the 3′ untranslated region (UTR) of target genes, and consequently regulate post-transcriptional gene expression by mRNA degradation and translational repression (5). By targeting multiple transcripts, miRNAs are involved in biological processes including cell differentiation, proliferation, apoptosis and metastasis (6).

There is increasing evidence that miRNAs widely participate in the regulation of oncogenes (7) or tumor suppressors (8) in cancer. Previous research has shown that miRNA-21 functions as an oncogene by inhibiting tumor suppressors such as phosphatase and tensin homolog (PTEN) (9) in Kazakh’s esophageal squamous cell carcinoma and programmed cell death-4 (PDCD4) in human hepatocellular carcinoma (10). Whereas, miR-15 and miR-16 induce apoptosis and act as tumor suppressors by targeting Bcl (11). It was recently suggested that the miR-29 family is involved in many diseases and pathophysiological processes. For example, miR-29 was found to play an important role in aneurysm formation (12), systemic sclerosis (13), preeclampsia (14) and irritable bowel syndrome (15), and also was found to have an impact on pathophysiological processes of liver fibrosis (16), cardiac fibrosis (17), renal fibrosis (18) and myocardial ischemia-reperfusion injury (19). More and more research indicates that miR-29 participates in the processes of apoptosis, proliferation and epithelial-mesenchymal transition (EMT) in cancer. Here, we review the relationship between miR-29 and cancer in detail.

MicroRNA is produced by shearing the arm of the stem-loop or hairpin which is a general shape of corresponding microRNA precursor or pre-miRNA. Although a mature miRNA may only come from one arm of pre-miRNA, the 3′ (3p) or the 5′ (5p) arm is predominantly processed. In terms of miR-29, the 3p arm of the miR-29 precursor is clipped as a preferential overwhelming product (miR-29 or miR-29-3p), although the 5p arm (miR-29* or miR-29-5p) also objectively exists. Thus, the human miRNA-29 family has three main members including hsa-miR-29a, hsa-miR-29b and hsa-miR-29c (Fig. 1).

These three miR-29s are distributed on two chromosomes: miR-29b2/miR-29c located on chromosome 1q32 and miR-29b1/miR-29a located on chromosome 7q32 (20). Among the members of the miR-29 family, miR-29a was firstly discovered by Lagos-Quintana et al (21). Subsequent large-scale cloning studies revealed the sequence of mature miR-29a. Mourelatos et al (22) identified miR-102 located on chromosome 7 primordially, which was known as miR-29b because of the isogeny between human miR-102 and mouse miR-29b. Researchers then found the same sequence on chromosome 1q32. Researchers distinguished them as miR-29b1 located on chromosome 7q32 and miR-29b2 located on chromosome 1q32. With the development of technology, miR-29c was found by small RNA library sequencing (23).

Transcriptional profiling studies of miRNA expression across tumor tissues or cancer cell lines have revealed that miR-29 is downregulated in the majority of cancers and upregulated in the minority. As documented in Table I, aberrant expression of miR-29 and the oncogenic or tumor-suppressive functions of miR-29 have been extensively investigated in many types of cancers.

Downregulation of miR-29 has been found in many solid tumors and hematologic neoplasms by transcript profiling or northern blot analysis. In the respiratory system, miR-29 is expressed at a lower level in lung cancer tissue when compared with that in normal lung tissue (24). Fabbri et al (25) demonstrated that expression of miR-29a, miR-29b, and miR-29c is downregulated in NSCLCs. Plaisier et al (26) found that the miR-29 family (miR-29a, miR-29b and miR-29c) inhibited specific genes associated with invasion and metastasis of lung adenocarcinoma. In the nervous system (NS), miR-29 was found to be downregulated in NS neoplasms such as glioblastomas (27) and neuroblastoma (28). In the muscular and skeletal systems, miR-29 was found to be significantly downregulated in osteoblastoma (29) and rhabdomyosarcoma (30). MiR-29a induced osteoblastic cell apoptosis by silencing Bcl-2 and Mcl-1 and inducing E2F1 and E2F3 expression (31). In the genitourinary system, all three isoforms of miR-29 (a, b and c) are highly expressed in normal tissues. However, they are downregulated in genitourinary tumors including bladder (32,33), prostate (34), ovarian (35,36), endometrial cancer (37) and renal carcinoma (38). In the hematopoietic system, miR-29 is downregulated in acute lymphoblastic leukemia (ALL) (39), acute myeloid leukemia (AML) (40), chronic lymphocytic leukemia (CLL) (41) and mantle cell lymphoma (MCL) (42) when compared with normal cases (43). In addition, miR-29 was found to be significantly downregulated in basal cell carcinoma (BCC) when compared with normal skin (44). Expression of miR-29 was also downregulated in nasopharyngeal carcinomas (45,46).

Although miR-29 is downregulated in the vast majority of cancers, it is also upregulated in a minority of cancers. MiR-29 is also expressed at a high level in tumor tissues or serum from breast cancer patients when compared to its expression in normal cells or serum from healthy individuals (47). The upregulated expression of miR-29 was also detected in several rare diseases such as malignant pleural mesothelioma (48) and diffuse large B lymphoma (49). Notably, although miR-29 is downregulated in ALL, Garzon et al (39) found that miR-29 was highly expressed in acute myeloid leukemia bearing cytoplasmic nucleophosmin (NPMc⁺ AML). This phenomenon indicates that there are wide differences in the expression profile of miR-29 in subtypes of the same cancer.

The differential expression of miR-29 has also been noted in the digestive system. The expression of miR-29 is downregulated in gastric carcinoma (50). A low level of miR-29 caused loss of inhibition of cyclin E expression, resulting in esophageal carcinoma cell cycle activation (51). Several studies have demonstrated that high expression of miR-29 induces hepatocellular carcinoma cell apoptosis, while downregulation of miR-29 increases HCC tumorigenicity and metastasis (52,53). Mott et al (54) found a high level of miR-29 in normal cholangiocytes by northern blot analysis. It is notable that downregulation of miR-29 was associated with upregulated Mcl-1 protein in cholangiocarcinoma. In contrast, upregulation of miR-29a was observed in the plasma of colorectal cancer (CRC) patients. This, it may be a potential biomarker to differentiate CRC from controls (55). Wang and Gu (56) found that serum miR-29a was also significantly higher in patients with colorectal liver metastasis when compared with the serum level in CRC patients. It appears that miR-29 is associated with the degree of malignancy in colorectal cancer.

miR-29 is generated by non-coding mRNA splicing and is regulated by many signaling molecules such as Myc, EZH2, YY1, HDAC and GATA3. These regulatory proteins control expression of miR-29 mainly in the early stages (Fig. 2).

In this regard, in CLL, histone deacetylases (HDACs) can downregulate the level of miR-29 (57). Intensive research has demonstrated that HDAC3 (one member of the HDACs) is a component part of the HDAC3-EZH2 complex, and MYC suppresses miR-29 expression through the HDAC3-EZH complex (58). There are two other miRNAs (miR-26a and miR-494) indirectly involved in the MYC-EZH2-miR-29 axis. MYC upregulates EZH2 by repressing miR-26a which is an inhibitor of EZH2, and EZH2 suppresses miR-494 which could inhibit MYC. Through miR-26a and miR-494, MYC and EZH2 form a positive feedback loop. Next, EZH2 combined with HDAC3 results in a low level of miR-29 expression (58–60).

Wang et al (61) described the regulation and function of miR-29 in myogenesis and rhabdomyosarcoma (RMS) and found that miR-29 participates in the regulatory circuit involving NF-κB and YY1. In RMS cells and primary tumors, the NF-κB-YY1 pathway is activated while miR-29 is epigenetically silenced. miR-29 is repressed by YY1 which can be activated by NF-κB. On the other hand, miR-29 can also target its repressor YY1 in turn. Wang et al (61) also found that miR-29 and YY1 suppress each other; miR-29 blocks YY1 translation and YY1 inhibits miR-29 transcription, and constructs a negative feedback loop. NF-κB further regulates this loop which directly activates YY1 and indirectly controls miR-29.

In addition to MYC and YY1, there are other regulators of miR-29. The hematopoietic key transcription factor CEBPA can induce miR-29 expression. Notable, since CEBPA is located on chromosome 7q, CEBPA selectively upregulates miR-29a/b1 expression on chromosome 7q32.3, while it cannot affect miR-29b2/c on chromosome 1q32.2 (62).

As previously confirmed, IFN is an agonist of signal transducer and activator of transcription 1 (STAT1) and CDK6, two targets of miR-29. Schmitt et al (63) found that STAT1 upregulated the tumor suppressing miR-29 in melanoma cells. They also observed that increased expression of interferon-γ (IFN-γ) resulted in G1-arrest of melanoma cells involving CDK6 repression.

Recently, researchers have demonstrated that, in breast cancer, GATA3, a transcription factor, suppresses metastasis and alters the tumor microenvironment by inducing miR-29b expression. As a tumor-suppressor gene, GATA3 is lost in breast cancer, and is correlated with a worse patient prognosis (64,65).

As a newly discovered tumor suppressor in most cancers, miR-29 can downregulate oncogenes and/or upregulate tumor suppressors; thus, miR-29 can induce apoptosis in cancer cells and inhibit proliferation and invasiveness of human cancer cells (66). Notably, in some tumors such as breast cancer and colon cancer, miR-29 can induce epithelial-to-mesenchymal transition. In the present review, we present a mechanism by which miR-29 functions (Figs. 3 and 4).

With the rapid development of biotechnology, the mysteries of microRNAs are gradually being solved. MicroRNAs have an extremely close relationship with tumors and play an important role in the process of tumor initiation and development. In most cancers, miR-29s act as tumor suppressors by influencing apoptosis, methylation, invasion, proliferation and chemotherapeutic sensitivity. However, it nust be noted that miR-29 acts as a promoter of metastasis. This phenomenon is noted in different types of cancers. We highlight that miR-29 also plays diverse roles in the digestive system. The mechanism of this phenomenon has not been fully explained. Therefore, the relationship between miR-29 and cancer (particularly digestive system neoplasms) require further research.