It has been demonstrated that BTG2 gene is involved in the development and differentiation of nerve cells and hematopoietic cells (18). It is overexpressed in the G0/G1 phase of the cell cycle in neuroepithelial cells (18), suggesting that it plays a role in the induction of nerve growth and differentiation. Overexpression of BTG2 is involved in the differentiation process of HL-60 cells after treatment with 12-O-tetra-decanoylphorbol-13-acetate (TPA) or retinoic acid (RA) (19). Most notably, BTG2 gene expression occurs earlier than p21 expression, indicating BTG2 plays an important role in the differentiation processes of hematopoietic cells (19).

BTG2 plays an important role in regulation of cell proliferation, through regulating the cell cycle in some solid tumors. Zhang et al (20) reported that BTG2 inhibited the proliferation and invasion of gastric cancer cells. Ma and Ni (21) demonstrated that BTG2 overexpression can suppress the cell growth and promote apoptosis in pancreatic cancer cells. Moreover, BTG2 overexpression inhibits the expression of cyclin D1, MMP-1, and MMP-2, and suppresses the proliferation of lung cancer cells (22). These findings support that BTG2 acts as an anti-proliferative gene in carcinogenesis. However, Wagener et al (23) showed that BTG2 promoted the migration of bladder cancer cells and BTG2 overexpression is associated with poor survival in patients with bladder cancer. Thus, the roles of BTG2 in oncogenesis may be cancer type-dependent.

Our previous studies demonstrated that p53, the most investigated tumor suppressor gene, can upregulate BTG2 expression, and downregulate cyclins D1 and E during hepatocarcinogenesis (1,24). When DNA is damaged, p53 is upregulated, which will induce DNA repair and cause the cell cycle arrest at G1/S-phase. If damage cannot be repaired, p53 will induce programmed cell death or apoptosis. It has been demonstrated that BTG2 exerts its antitumor effect through p53-dependent Ras signal transduction pathway (3). Thus, the BTG2 gene expression is significantly increased when DNA is damaged. Various DNA-damaging agents, such as, ionizing radiation, some chemical substances and ultraviolet may induce the BTG2 expression via p53 and cause the cell cycle arrest at G1 phase through inhibiting cyclin D1, which may promote DNA damage repair (25,26). Recently, Choi et al (27) reported that TIS21/BTG2/PC3 plays a role in the DNA damage response. In their study, TIS21/BTG2/PC3 accelerates the repair of DNA double strand breaks (DSBs) according to the increased activity of the methylation of Mre 11 and protein arginine methyltransferase 1 (PRMT1) (27). However, the detailed mechanisms for the involvement of BTG2/TIS21/ PC3 in DNA damage repair are not fully understood and need further investigation.

Several studies demonstrated that BTG2 can promote or induce cell apoptosis (21,28). Zhang et al (20) reported that BTG2 not only restrains the biological activities of gastric cancer cells, such as cell growth and proliferation, cell migration and invasion, but also promotes tumor cell apoptosis. Zhang et al (28) found that BTG2 induces cell apoptosis and suppresses cell invasion of human triple-negative breast cancer MDA-MB-231 cells. Hong et al (29) report that the treatment of U937 cells with BTG2 inhibits the expression of cell division cycle 2 kinase (cyclin B1-CDC2) and causes cell apoptosis. However, it is reported that high level of PC3 gene in PC12 cells can inhibit cell apoptosis (30). Thus, the effects of BTG2 on cell apoptosis may be cell type-dependent and the precise mechanisms need further investigation.

As aforementioned, following DNA damage, BTG2 expression is stimulated by p53 and the expression of cyclin D1 is downregulated, inhibiting G1/S transition via the pRB pathway. This pathway is a classical pathway and the activation of BTG2 is p53-dependent. BTG2 expression is also upregulated by oxidative stress via reactive oxygen species-protein kinase C-NFκB pathway, which is independent of p53 status (31). Additionally, BTG2 suppresses the expression of cyclin E and inhibits G1/S transition in 293 cells in the absence of p53, Rb and cyclin D1 (32).

The low expression of BTG2 is found in many human cancer tissues and its loss is related to cell migration and invasion. Lim et al (33) reported that BTG2 has a negative effect on cancer cell metastasis by inhibiting Src-FAK (focal adhesion kinase) signaling through downregulation of reactive oxygen species (ROS) generation. Wagener et al (23) also reported that endogenous BTG2 expression contributes to the migratory potential of bladder cancer cells and the high levels of BTG2 in bladder cancers are correlated with poor clinical prognosis in patients with bladder cancer.

A recent study demonstrated that cisplatin attenuates prostate cancer cell proliferation in part by upregulation of BTG2 through the p53-dependent pathway or p53-independent NF-κB pathway (34). BTG2 negatively regulates JAK2/STAT3 signaling through the regulation of ROS generation indirectly (35). Therefore, it is likely that BTG2 exerts its antitumor activity via the downregulation of cytokine secretion.

PC3/Tis21 knockout mice display impaired terminal differentiation of hippocampal granule neurons and defective contextual memory (36). Moreover, BTG2 regulates the differentiation of HL-60 cells mainly through activation of Erk1/2 and inhibition of Akt, resulting in the downregulation of c-Myc (37).

BTG2 negatively regulates cyclin D1 and decreases the expression of FoxM1 cell cycle regulatory factor through inhibiting the binding of cyclin B1/Cdks (38). Ryu et al (39) found that BTG2 is upregulated by PKC-δ in U937 cells, and induces G2/M arrest and cell death through inhibiting cyclin B1-Cdc2 binding. BTG2 stimulates PRMT1 (protein arginine methyltransferase 1), promoting DNA repair of DSBs and Mre 11 methylation (27,40). In addition, BTG2 upregulates Bax gene to promote apoptosis (41).

It has been demonstrated that BTG2 is one of the important radiation response genes (25). A recent study showed that BTG2 improves the radiosensitivity of breast cancer cells by affecting cell cycle distribution, enhancing radiation-induced apoptosis, and inhibiting DNA repair-related protein expression (42). Moreover, Chu et al (26) reported that cancer-associated fibroblasts (CAFs) can reduce the levels of GADD45 and BTG2, both are major radiation-induced genes. These data suggest that BTG2 may be one of the most important response genes during radiotherapy.

In summary, BTG2 plays an important role in cancer development and progression (Fig. 2). However, like other genes, the regulatory mechanisms of BTG2 in cancer are complex and need further investigation.

miRNA-21 (miR-21) is one of the important miRNAs and is widely distributed in human tissues and cells. The overexpression of miRNA-21 has been observed in a variety of carcinomas, such as prostate, gastric, colon breast and lung cancers; miRNA-21 promotes cell growth and proliferation and inhibits cell apoptosis (47–53). Recent studies demonstrated that BTG2 is a new target gene of miR-21 in prostate cancer cells (49), laryngeal cancer cells (52) and melanoma cells (53). Liu et al (52) uncovered that miR-21 promotes the proliferation of laryngeal cancer cells through downregulation of BTG2. Sun et al (54) reported that miR-21 is overexpressed and negatively regulates BTG2 expression in lung cancer cells, promoting lung cancer cells growth, progression and invasion. Coppola et al (49) demonstrated that the loss of BTG2 and upregulation of miR-21 contribute to the epithelial-mesenchymal transition in prostate cancer cells. Thus, miR-21 plays an important role in regulating BTG2 gene during carcinogenesis.

Several studies have shown that BTG2 is regulated by other miRNAs in different cancers. A recent study demonstrated that miR-21, miR-23A and miR-27A cooperatively regulate the expression of tumor suppressor genes, including PDCD4, BTG2 and NEDD4L (55). Jalava et al (56) reported that androgen-mediated miR-32 is overexpressed in castration-resistant prostate cancer (CRPC), resulting in a reduced expression of BTG2. Alvarez-Saavedra et al (57) report that BTG2 and Paip2a are direct targets of miR-132 in the mouse suprachiasmatic nucleus. Interestingly, our previous study also observed that overexpression of miR-18 in hepatocellular cancer cells negatively regulates the BTG2 expression (58).