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 Table of Contents  
Year : 2018  |  Volume : 4  |  Issue : 2  |  Page : 59-63

The mechanism of BMI1 in regulating cancer stemness maintenance, metastasis, chemo- and radiation resistance

Department of Experimental Surgery, The Second Affiliated Hospital, Air Force Medical University, Xi'an 710038, Shaanxi, China

Date of Submission29-Jan-2018
Date of Acceptance13-Apr-2018
Date of Web Publication27-Apr-2018

Correspondence Address:
Dr. Yanyang Tu
Department of Experimental Surgery, The Second Affiliated Hospital, Air Force Medical University, Xi'an 710038, Shaanxi
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ctm.ctm_7_18

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BMI1 is involved in the occurrence and development of many types of cancer through a variety of signaling pathways. BMI1, which is overexpressed in cancer, is often associated with chemo- and radiation resistance and poor prognosis in cancer patients. This article reviews the current understanding of the mechanism of BMI1 in maintaining tumor stemness, promoting metastasis, and inducing chemo- and radiation resistance, aiming at providing updated information supportive of targeting BMI1 in cancer treatment.

Keywords: BMI1, chemo and radiation resistance, metastasis, tumor stemness maintenance

How to cite this article:
Xu X, Wang Z, Liu N, Zhang P, Liu H, Qi J, Tu Y. The mechanism of BMI1 in regulating cancer stemness maintenance, metastasis, chemo- and radiation resistance. Cancer Transl Med 2018;4:59-63

How to cite this URL:
Xu X, Wang Z, Liu N, Zhang P, Liu H, Qi J, Tu Y. The mechanism of BMI1 in regulating cancer stemness maintenance, metastasis, chemo- and radiation resistance. Cancer Transl Med [serial online] 2018 [cited 2019 Jan 16];4:59-63. Available from: http://www.cancertm.com/text.asp?2018/4/2/59/231378

  Introduction Top

Polycomb group (PcG) protein can inhibit the transcription of target genes through epigenetic modification of chromatin, which is involved in the regulation of tumor cell proliferation and differentiation.[1],[2],[3] PcG protein includes two core protein complexes, polycomb repressive complex 1 (PRC1) and polycomb repressive complex 2 (PRC2). B-cell-specific Moloney murine leukemia virus integration site 1 (BMI1), the first functional gene in PcG family, was identified in a mouse lymphoma caused by retrovirus in 1993.[4],[5] It has been known that BMI1 can regulate self-renewal of hematopoietic stem cells and maintain the stability of bone marrow microenvironment and promote the development of thymocytes. In addition, BMI1 can promote Th2 cell differentiation by increasing the stability of transcription factor GATA3.[5] In recent years, emerging evidences show that BMI1 plays an important role in the development of malignant tumors.[6],[7],[8],[9],[10] While, chemotherapy and radiotherapy are still two important means of cancer treatment,[11],[12] many tumor cells, especially cancer stem cells (CSCs), are resistant to these therapies, rendering the treatment ineffective and resulting in tumor recurrence.[13],[14] The CSCs with self-renewal and multidirectional differentiation potential exist in many types of tumors.[15],[16] BMI1 is functionally associated with the self-renewal of CSC and the chemo- and radiation resistance of tumor.[17] Down-regulation of BMI1 can promote apoptosis and senescence in tumor cells and increase the sensitivity of tumor cells to radiotherapy and chemotherapy,[18],[19] suggesting BMI1 as an important target for tumor therapy.[20] In this article, we review the recent advances in understanding of the functional role of BMI1 in cancer.

BMI1 expression in tumor tissue

BMI1 is the first identified member of the PcG (polycomb gene) family, which regulates cell proliferation through a variety of signaling pathways.[21] The BMI1 is located on human chromosome 10p1123 and encodes the PcG family protein with relative molecular weight of 37 kDa.[22] BMI1 does not have enzyme activity; it is a major component of PRC1 complex.[23],[24] This complex regulates transcription of many important genes, including Ink4a that encodes the expression of tumor suppressor proteins p14Arf and p16ink4a.[25],[26] BMI1 is highly expressed in a variety of human tumors, and promote rapid proliferation of CSCs leading to tumor metastasis and recurrence.[27],[28],[29] Moreover, knocking down the expression of BMI1 can induce senescence and apoptosis in some tumor cells, while rendering them sensitive to radiation and chemotherapy.[30],[31],[32] Further, it has been reported that BMI1 promotes the development of mouse lymphoma by binding to c-Myc.[33]

BMI1 is highly expressed in tumor tissues of several cancer types, such as medulloblastoma, breast cancer, chronic myeloid leukemia, head and neck cancer, colon cancer, lung cancer, prostate cancer, liver cancer and gliomas.[34],[35],[36],[37],[38],[39],[40] Moreover, increased expression of BMI1 in tumors is associated with poor prognosis of patients with lymphoma, lung cancer, gastric cancer, colon cancer, prostate cancer, cervical cancer, lymphoma, leukemia, liver cancer, gliomas, etc.[27],[41],[42],[43],[44],[45],[46] These findings suggest that down-regulating BMI1 expression could be beneficial in treating various types of cancer.

BMI1 and the stemness maintenance of tumor cells

Tumor tissue is composed of heterogeneous cells, including cancer stem cells that are capable of promoting the growth of existing tumor.[47] The expression of BMI1 had been closely associated with the ability of stemness maintenance and self-renewal in both normal and tumor cells.[48],[49],[50],[51] The co-expression of BMI1 and deubiquitinase USP22 is favorable to maintain stem-like properties in cancer cells.[52] The deficiency of BMI1 has been shown to affect the self-renewal of normal hematopoietic stem cells in BMI1 gene knockout mice.[53] Moreover, the expression of BMI1 is not only required for the stemness maintenance of normal stem cells, but also for the leukemic stem cells and progenitor cells.[54] It has been validated that BMI1 can promote the self-renewal and proliferation of many types of cancer cells, particularly those derived from liver cancer, glioblastoma, and breast cancer.[55],[56],[57] In addition, BMI1 can also induce epithelial-mesenchymal transition (EMT) mediated by TWIST-1,[58] which provides a mechanistic explanation of the relationship between EMT and cancer stemness.[59] Moreover, knocking out BMI1 prevents the stemness maintenance through derepression of p16INK4a/p14ARF.[60] Taken together, these findings suggest that BMI1 plays an important role in the maintenance of both normal stem cells and cancer stem cells, and thus in tumorigenesis.

BMI1 and tumor metastasis

BMI1 also plays an important role in tumor metastasis. It has been shown that shRNA-specific knockdown of BMI1 in lung adenocarcinoma cell line can significantly inhibit their migration and metastasis underin vitro andin vivo condition, respectively.[61] Interestingly, in cooperation with H-Ras, BMI1 has been shown to induce breast cancer cell transfer to the brain. The study used MCF10A cells to examine tumorigenicity in nude mice, comparing cells that overexpressed H-Ras with those that overexpressed both BMI1 and H-Ras. The results showed that, although both cells were able to form tumors, the metastasis ability of BMI1 and H-Ras group was much stronger than the H-Ras alone group. Moreover, cells that overexpress H-Ras alone did not exhibit spontaneous brain metastases, suggesting that BMI1 may plays a primary role in the brain metastasis of MCF10A tumor cells.[62] Similarly, knocking down BMI1 can reverse the TWIST1 induced EMT in FaDu cells, while also impairing their ability to invade and metastasize in vitro. In addition, overexpression of BMI1 alone can induce EMT in these tumor cells, which is mainly manifested by reduced expression of epidermal markers and increased expression of mesenchymal markers.[63] Guo et al.[64] also confirmed that BMI1 plays a very important role in the metastasis and invasion of breast cancer cells. Overexpression of BMI1 can enhance the migration and invasion ability of human mammary epithelial cells (HMECs). When the expression of BMI1 was inhibited, the migration and invasion abilities of these cells were weakened, and tumor formation was also suppressed. Further, decreased BMI1 expression in these cells had an inhibitory effect on tumor metastasis to the lung in nude mice.[64] Li et al.[65] found that miRNA-194 targets the 3'-UTR of BMI1 to down-regulate BMI1 expression in gastric cancer cells. In response to BMI1 down-regulation, the expression of p16 increased, thereby inhibiting the proliferation and cloning ability of the cells, reducing the expression of stem cell markers and suppressed the expression of chemoresistance-related genes. The results also show that the upregulation of BMI1 can increase the invasion and metastasis of gastric cancer cells.[65] Thus, BMI1 not only plays an important regulatory role in tumorigenesis, but also mediates tumor invasion and metastasis. This shows that BMI1 cannot be ignored of its position in a variety of tumor occurrence, invasion and metastasis.

BMI1 and resistance to chemo- and radio-therapy

Studies have shown that overexpression of TWIST, HIF-1 and BMI1 can attenuate the radiosensitivity of tumor cells.[63] In a breast cancer study, overexpression of BMI1 could effectively delay doxorubicin-induced DNA double-strand break in the tumor cells, suggesting that BMI1 might contribute to chemoresistance in breast cancer.[66] Moreover, Down-regulation of BMI1 expression by RNA interference can inhibit the proliferation of MCF7 breast cancer cells, and increase the proapoptotic activity of doxorubicin on these cells, indicating that BMI1 is able to regulate the sensitivity of MCF7 cells to chemotherapeutic drugs.[67] Interestingly, Crea et al.[68] also found that down-regulation of BMI1 expression effectively enhances the therapeutic efficacy of docetaxel in prostate cancer. They found that BMI1 could enhance the cellular antioxidant response, which increases the tumor cells' tolerance to chemotherapeutic drugs.[68] The overexpression of BMI1 is associated with poor prognosis of myelodysplastic syndrome, thus serving as the prognostic indicator of the condition. This is correlated with BMI1 mediated downregulation of apoptosis-inducing pathways, such as TRAIL, TNF-α, DAC, and AZA, that can be reversed by BMI1 gene silencing.[69] Wang et al.[70] found that BMI1 gene silencing can reduce intracellular GSH level in ovarian cancer cells, thus decreasing their resistance to the chemotherapeutic drug, cisplatin. Combining BMI1 gene silencing with cisplatin treatment can effectively inhibit the proliferation of ovarian cancer cells.[70] Moreover, knockdown of BMI1 by shRNA can reduce the pancreatic cancer cells' resistance to gemcitabine. Decreased BMI1 expression impairs the invasion ability of pancreatic cancer cells, underin vitro condition. Such a reduction in resistance and invasion ability of pancreatic cancer cells is associated with transformation of stromal cells into epidermal cells. It was also confirmed that the tumorigenicity of pancreatic cancer cells was weakened after knocking out BMI1 in nude mice.[71]

BMI1 can not only mediate the chemotherapeutic drug resistance in many kinds of tumors, but also can regulate the sensitivity of some tumors to radiotherapy. It has been reported that BMI1 knockout enhances the sensitivity of C666-1, the nasopharyngeal carcinoma cell line, to radiotherapy. The data showed that C666-1 cells treated with radiotherapy alone can still form tumors, whereas the C666-1 cells receiving both BMI1 gene silencing and radiation-treatment completely failed to form tumors (follow-up = 6 months) in vivo, which has been correlated to activation of the P53-mediated apoptotic pathway.[72] Facchino et al.[73] found that BMI1 recruits DNA damage repair factors in both normal cells and glioblastoma cells, rendering them resistant to radiotherapy. BMI1 knockout blocks DNA damage recognition, resulting in decreased repair capacity in glioblastoma cells. Exposure to the radiation dose of 3 Gy, the cell cycle was arrested initially and reestablished after 16 h of irradiation in control group, whereas in the BMI1 knockout group, the cell cycle remained arrested even after 16 h, and most of the cells were apoptotic.[73]

BMI1 potential in the treatment of cancer

As a protooncogene, BMI1 has been proved to be closely related to the occurrence and development of various tumors. BMI1 can participate in tumor progression through a variety of pathways. Therefore, understanding the molecular mechanism of BMI1 is of high clinical importance, which could lead to development of novel strategies for the treatment of tumors. It is known that some small molecule inhibitors such as broad-spectrum HDAC inhibitors[74] and artemisinin extract[75] can reduce the expression of BMI1 and are hoped to become new drugs in oncology. PTC-209, a small-molecule inhibitor of BMI1, could induce cell cycle arrest and reduce the population of biliary tract cancer stem cell; a promising function that can be used for clinical treatment of various other tumors.[76] Chen et al.[77] found that targeting BMI1+ cancer stem cells improves cellular sensitivity to chemotherapy in squamous cell carcinoma of the head and neck.

However, the toxicity is also an important factor to consider. It remains unknown whether down-regulating the expression of BMI1 in the human body is safe or not. The BMI1 knockout mice can be used to do such studies on pharmacology and toxicology. Moreover, studies have shown that tumor cells show poorer tolerance than normal human progenitor cells in response to reduced expression of BMI1 by siRNAs.[78]

  Conclusion Top

In summary, the oncogene BMI1 plays a very important role in the development and progression of tumors, involving tumor proliferation, metastasis, invasion, chemo- and radiotherapy resistance, and many others [Figure 1]. Moreover, BMI1 is also important for the cancer stem maintenance and self-renewal of tumor cells. Therefore BMI1 has recently attracted prime attention in cancer research. However, the molecular mechanism of BMI1 in cancer has not yet been completely elucidated. A therapeutic strategy targeting BMI1 could be promising in treatment of cancer patients by effectively improving the chemo- and radio- therapy sensitivity of tumor cells and thus overcoming poor prognosis.
Figure 1: Mechanism of BMI1 mediated tumor progression

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Financial support and sponsorship

The study was financially supported by the National Natural Science Foundation of China (81572983, 81702458).

Conflicts of interest

There are no conflicts of interest.

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