BMI‑1 promotes invasion and metastasis in endometrial adenocarcinoma and is a poor prognostic factor

Abstract

Endometrial adenocarcinoma is one of the most common types of gynecological malignancies and its incidence and mortality rates are increasing. Due to tumor recurrence and metastasis, the overall five-year survival rate of patients with endometrial adenocarcinoma is shortened. The aim of the present was to investigate the role of the polycomb group protein B-lymphoma Mo-MLV insertion region 1 (BMI-1) in the invasion, metastasis and the epithelial-mesenchymal transition (EMT) of endometrial adenocarcinoma cells, as well its effects on the prognosis of patients with endometrial adenocarcinoma. Immunohistochemistry was used to examine the expression profile of BMI-1 in normal and endometrial adenocarcinoma tissues. Western blotting was used to examine the expression levels of BMI-1 and EMT markers. Kaplan-Meier plots and a Cox proportional hazards model were used to assess the overall survival. MTT cell viability assays were used to detect the proliferation of endometrial cancer cells. Transwell assays were used to examine cell migration and invasion. Small interfering RNA was used to downregulate BMI-1 expression levels, to study its effect on EMT. Immunohistochemical and clinicopathological analyses showed that BMI-1 expression was increased in endometrial adenocarcinoma tissue compared with the normal endometrial tissue (P<0.05). The increased expression levels of BMI-1 were closely associated with stage, myometrial invasion and lymph node metastasis (P<0.05). Kaplan-Meier plots and a Cox proportional hazards model showed that increased BMI-1 expression was associated with a less favorable prognosis [P=0.040, hazards ratio (HR)=1.596] and was associated with late-stage adenocarcinoma (P=0.006, HR=1.670). Myometrial invasion (P=0.006, HR=1.509) and lymph node metastasis (P=0.004, HR=1.703) were determined to predict a less favorable prognosis. Downregulation of BMI-1 reduced migration and invasion in endometrial cancer cells in vivo. It was also found that downregulation of BMI-1 increased the expression levels of the epithelial markers E-cadherin and keratin, and decreased the expression levels of the mesenchymal markers N-cadherin, vimentin and the downstream transcription factor, Slug. In conclusion, BMI-1 expression was correlated with tumor invasion and metastasis, contributing to deep myometrial invasion and lymph node metastasis, and was a poor prognostic factor for endometrial adenocarcinoma.

Inhibition of BMI-1 Induces Apoptosis through Downregulation of DUB3-Mediated Mcl-1 Stabilization

“…BMI-1 is involved in the plasticity, proliferation, and growth of CSCs through the regulation of the Ink4a/Arf, Notch, and Wnt/β-catenin signaling pathways [ 9 , 10 ]. Moreover, BMI-1 is upregulated in many cancers and is associated with proliferation, invasion, metastasis, apoptosis, and malignant transformation in cancer cells [ 11 , 12 , 13 , 14 ]. Therefore, BMI-1 as a significant prognostic marker may be an effective target for cancer therapy.…”

High BMI1 Expression with Low CD8+ and CD4+ T Cell Activity Could Promote Breast Cancer Cell Survival: A Machine Learning Approach

“…In a study of prostate cancer, high BMI1 expression was found to be correlated with unfavorable factors, such as a high Gleason score and extraprostatic extension with prostate-specific antigen recurrence [ 17 ]. A study by Yu et al demonstrated that BMI1 expression was higher in endometrial adenocarcinoma tissues than in normal tissues and that high BMI1 expression was correlated with a poor survival rate [ 18 ]. A study of hematologic malignancies reported that BMI1 was highly expressed in patients with acute myelogenous leukemia or chronic myelogenous leukemia compared to the normal control group [ 19 ].…”

“…B-lymphoma Moloney murine leukemia virus insertion region-1 (BMI1), a polycomb group family member, is an essential transcriptional repressor and plays an important role in the regulation of stem cell self-renewal in both endogenous and cancer stem cells [12]. Many studies have reported that high BMI1 expression is associated with poor prognosis in different types of malignancies, such as pancreatic adenocarcinoma, hepatocellular carcinoma, prostate cancer, nasopharyngeal cancer, endometrial adenocarcinoma, acute myeloid leukemia, and chronic myeloid leukemia [13][14][15][16][17][18][19][20].…”

The Crucial Roles of Bmi-1 in Cancer: Implications in Pathogenesis, Metastasis, Drug Resistance, and Targeted Therapies

“…Cancer cells have the characteristics of invasion into surrounding tissues and metastasis to distant tissues, and they continue to grow in these organs, destroying the function of the organs, and finally causing the death of the patient. The expression of Bmi-1 is closely related to tumor migration and invasion [ 93 , 95 , 106 , 107 , 108 , 109 ]. It has been reported that down-regulation of Bmi-1 reduces the migration and invasion of endometrial cancer cells in vivo and in vitro, by increasing the expression levels of E-cadherin and keratin, and down-regulating N-Cadherin, vimentin, and SLUG [ 106 ].…”

“…The expression of Bmi-1 is closely related to tumor migration and invasion [ 93 , 95 , 106 , 107 , 108 , 109 ]. It has been reported that down-regulation of Bmi-1 reduces the migration and invasion of endometrial cancer cells in vivo and in vitro, by increasing the expression levels of E-cadherin and keratin, and down-regulating N-Cadherin, vimentin, and SLUG [ 106 ]. Likewise, Bmi-1 induces miR-27a and miR-155 to negatively regulate the expression of raf kinase inhibitory protein (RKIP), which promotes the migration and invasion of gastric cancer cells [ 107 ].…”