At present, the success of cancer treatment is challenging and one of the key determinants of treatment failure may be the presence of cancer stem cells (CSCs) (1). This small proportion of tumor cells plays a pivotal role in tumor growth, proliferation, invasion, distant metastasis and relapse of numerous types of cancer (2). Therefore, identifying a reliable biomarker that is associated with the treatment of human cancer and CSCs is important.

The role of oncogenic BMI-1 (also known as B-lymphoma Moloney murine leukemia virus insertion region-1), a member of the polycomb-group (PcG) family of proteins, in cancer has attracted increasing attention. Biehs et al have demonstrated that BMI-1 was important in the maintenance of stem cell properties in a mouse incisor model (3). Certain studies have also revealed that BMI-1 was involved in the self-renewal, differentiation and tumor initiation of CSCs (3–5). In addition, BMI-1 is known to be upregulated in various human cancer tissues and is important in the regulation of malignant transformation, proliferation, cell cycle, apoptosis and distant metastasis (6). The present review summarized the role of BMI-1 in human cancer and CSCs, and discussed the signaling pathways in which BMI-1 is involved. Furthermore, the potential of BMI-1 as a critical prognostic marker, as well as a future therapeutic target, was reviewed.

BMI-1 was first identified in a B-cell lymphoma as a transcriptional repressor that was a member of the PcG transcription factors (7). Overexpression of BMI-1 has been previously reported in gastric, ovarian, breast, head and neck, pancreatic and lung cancer, as well as in primary hepatocellular carcinoma (HCC) and endometrial carcinoma (8–16). In addition, BMI-1 overexpression has been identified in patients suffering from myelodysplastic syndrome, chronic myeloid leukemia, acute myeloid leukemia and lymphoma (17–20). Previous studies have indicated that the increased BMI-1 expression was associated with tumor proliferation, invasion/metastasis, chemosensitivity and patient survival (Table I).

Numerous studies have indicated that BMI-1 may promote tumor cell growth (Table I). The overexpression of BMI-1 in gastric and breast cancer has been identified to promote cell growth and proliferation, inhibit apoptosis and enhanced clone formation capability (6,21,22). By contrast, the depletion of BMI-1 in certain pancreatic cancer cell lines was found to suppress cell proliferation, sensitize apoptosis and inhibit tumor formation in nude mice (13,23–25). In addition, upregulation of BMI-1 expression enhanced the ability of colony formation in a soft agar assay in non-small cell lung cancer (NSCLC) tissues (26).

Invasion/metastasis of cancer is commonly associated with poor prognosis in patients. Strong evidence supports the involvement of BMI-1 in tumor cell invasion in gastric cancer, primary HCC, pancreatic cancer, endometrial carcinoma, and head and neck cancer (Table I). Overexpression of BMI-1 in gastric cancer resulted in increased migration and invasion abilities (21,22), while BMI-1 depletion reduced the invasiveness of HCC cells (15). Song et al also identified that upregulation of BMI-1 expression enhanced the motility and invasiveness of human nasopharyngeal epithelial cells, whereas silencing of BMI-1 expression reduced motility (27). Epithelial-mesenchymal transition (EMT) is the key process driving cancer metastasis and BMI-1 has been demonstrated to induce EMT in endometrial carcinoma cells (28). Furthermore, in vivo studies revealed that BMI-1 expression was upregulated in cancer tissues compared with matched healthy tissues and was associated with distant metastases of gastric cancer (8,29), HCC (15), lung cancer (14,30,31), endometrial carcinomas (16,28,32), and head and neck cancer (11,12,33). Several previous studies have also suggested that BMI-1 contributed to mammary carcinogenesis, axillary lymph node metastases, highly aggressive behavior and late-stage relapse in breast cancer (6,10,34–36).

Drug resistance is an important cause of cancer treatment failure and previous studies have demonstrated that the overexpression of BMI-1 was associated with cancer chemosensitivity (Table I) (9,30,31). Certain in vitro studies revealed that overexpression of BMI-1 can promote chemoresistance (23), whereas depletion of BMI-1 is able to enhance the chemosensitivity of HCC (15,37) and ovarian cancer cells (38,39). In a clinical setting, the overexpression of BMI-1 may facilitate drug resistance in hematological malignancies, including the myelodysplastic syndrome, chronic myeloid leukemia, acute myeloid leukemia and lymphoma (17–20,40). In addition, BMI-1 has been demonstrated to play an important role in chemoresistance and radiosensitivity in breast cancer (41,42).

BMI-1 has also been found to be associated with the survival of pancreatic cancer, NSCLC, ovarian carcinoma, head and neck cancer, and hematological malignancy patients (Table I), suggesting that BMI-1 is a significant prognostic factor of poor survival. For instance, Song et al investigated the survival of 72 patients with pancreatic cancer and identified that the overexpression of BMI-1 was associated with a significantly reduced overall survival (24). In addition, Yang et al studied the BMI-1 expression and survival in a cohort of 179 patients with invasive ovarian carcinoma (9). The authors demonstrated a significant association between increased BMI-1 expression and reduced patient survival (mean, 49 months), when compared with patients presenting a low BMI-1 expression (mean, 100 months; P<0.001) (9). Furthermore, Vrzalikova et al performed immunohistochemical staining for BMI-1 in 179 NSCLC samples, identifying that the five-year survival rate of BMI-1-positive patients was only 31.2%, in contrast to BMI-1-negative patients that exhibited a survival rate of 50.7% (P=0.004) (43).

Overexpression of BMI-1 has also been revealed to correlate with pediatric brain tumors, skin cancer, melanoma, prostate cancer and bladder cancer (44–47). Cancer cell proliferation, invasion/metastasis and chemosensitivity are associated with cancer treatment failure and may induce poor prognosis in patients. However, numerous studies have demonstrated that the treatment failure of various human cancer types is associated with CSCs (3,48). BMI-1 has received increasing attention, since it has been demonstrated to be important in maintaining the properties of CSCs. Therefore, studies further addressing the effect of BMI-1 on CSCs are essential to understand the role of CSCs in human cancer, and may lead to improved treatment strategies.

The CSC hypothesis was first described by Park et al (49) in 1971. Advances in CSC isolation were initially achieved in hematological malignancies, with CSCs first detected in acute myeloid leukemia. Subsequently, using similar strategies and technologies, and taking advantage of available surface markers, CSCs have been identified in a range of epithelial and other solid organ malignancies, indicating that these cells are involved in the majority of malignancies (50). CSCs are defined by their extensive self-renewal, differentiation and tumor initiation properties (3–5). Thus, the signaling pathways required for the maintenance of CSCs are candidate targets for a successful molecular therapy of various tumors. Recent studies have demonstrated that BMI-1 is involved in the regulation of CSCs.

BMI-1 is indispensable for the regulation of self-renewal by normal stem cells, leukemic stem cells (LSCs) and hematopoietic stem cells (HSCs) (51–54). For instance, Park et al (54) revealed that the number of HSCs in the fetal liver of BMI-1-null mice was normal, whereas it was markedly reduced in postnatal BMI-1-null mice. In addition, transplanted fetal liver and bone marrow cells obtained from the mice were able to contribute only transiently to hematopoiesis. No self-renewal was detected in adult HSCs, indicating a cell autonomous defect in BMI-1-null mice (54) and the importance of BMI-1 in the self-renewal of normal stem cells.

BMI-1 is also indispensable for the regulation of self-renewal in human solid tumors, including oral, esophageal, prostate, pancreatic, neuronal, non-small cell lung and breast cancer (2,26,48,55–58). In order to examine the function of BMI-1 in stem cells, Lukacs et al identified that decreased expression of BMI-1 in prostate cells reduced the number and size of spheres formed by these cells, while increased BMI-1 expression enhanced the sphere formation and size (4). Furthermore, Biehs et al reported that BMI-1 was expressed by incisor stem cells and that deletion of BMI-1 resulted in a reduced number of stem cells and perturbed gene expression (3). BMI-1 is known to be highly enriched in CD133-positive cells of human glioblastoma multiforme (GBM). A previous cell biology study revealed that BMI-1 prevents CD133-positive cell apoptosis and differentiation into neurons and astrocytes (5). In addition, the study demonstrated that BMI-1 is involved in GBM tumor growth and required to sustain CSC renewal and differentiation (5).

CSCs are associated with tumor initiation and malignant transformation. Previous studies demonstrated that BMI-1 plays an important role in these processes. For instance, in breast cancer, CSCs were no longer able to initiate tumors following the knocking down of BMI-1 expression by short hairpin RNA (59). However, tumor initiation was rescued with the introduction of a BMI-1 overexpression vector in the BMI-1 knockdown cells (59). In a clinical setting, a high expression of BMI-1 is associated with precancerous lesions of esophageal adenocarcinoma (60) and oral cancer (61), which implies that BMI-1 is involved in malignant transformation.

Considering the aforementioned findings, BMI-1 is required for the maintenance of self-renewal, tumor initiation and prevention of inappropriate differentiation of CSCs. However, the molecular mechanisms underlying these biological processes remain unclear.

A number of previous studies have demonstrated that BMI-1, a member of the PcG family, is associated with various types of human cancer and overexpression of BMI-1 plays a vital role in cancer cell proliferation, invasion/metastasis, chemosensitivity and patient survival. Furthermore, BMI-1 is involved in the maintenance of self-renewal, tumor initiation and prevention of inappropriate differentiation of CSCs by participating in multiple signaling pathways, suggesting that BMI-1 is important in maintaining the CSC properties. The presence of CSCs induces treatment failure of human tumors. Certain studies have indicated that silencing BMI-1 can reduce the malignant biological behavior of cancer, as well as the self-renewal and differentiation of CSCs. Therefore, BMI-1 is hypothesized to affect the malignant biological behavior of human tumors by regulating the self-renewal and differentiation of CSCs. In conclusion, BMI-1 may represent a promising target for the prevention and therapy of various human cancer types. Further understanding the molecular mechanism underlying the regulation of BMI-1 in human cancer and CSCs is of great clinical value.