Bmi-1 Promotes the Chemoresistance, Invasion and Tumorigenesis of Pancreatic Cancer Cells

Abstract

Background/Aims: The polycomb protein Bmi-1 plays oncogenic roles in various cancers. Here we aimed to investigate the contribution of Bmi-1 on the malignant behaviors of pancreatic cancer such as chemoresistance, invasion and tumorigenesis. Methods and Results: The MTT cell proliferation assay showed that shRNA mediated Bmi-1 knockdown and enhanced the chemosensitivity of pancreatic cancer cells to gemcitabine. The transwell invasion assay showed that Bmi-1 knockdown inhibited the invasion of pancreatic cancer cells in vitro. Notably, the reduced abilities of chemoresistance and invasion were associated with the transition from the mesenchymal phenotype to the epithelial phenotype of pancreatic cancer cells. Moreover, Bmi-1 knockdown led to the inhibition of the PI3K-Akt pathway and disrupted the sphere-forming abilities of pancreatic cancer cells. A nude mouse xenograft experiment demonstrated that pancreatic cancer cells depleted of Bmi-1 showed weak tumorigenicity in vivo. Conclusion: Our data suggest that Bmi-1 plays an important role in the progression of pancreatic cancer and represents a novel target for antitumor therapy of pancreatic cancer.

The Clinicopathological Significance of Bmi-1 Expression in Pathogenesis and Progression of Gastric Carcinomas

“…In the present study, Bmi-1 protein is observed to exist in the cytoplasm of gastric lesions, opposite to its nuclear expression pattern in breast (Yin et al, 2011; Wang et al, 2012), pancreatic (Yin et al, 2011), cervical , esophageal squamous , tongue squamous (Häyry et al, 2010), colon , bladder (Qin et al, 2009) and endometric (Engelsen et al, 2008) cancer cells. Another group also found cytoplasmic Bmi-1 expression in oropharyngeal squamous cell carcinoma (Huber et al, 2011).…”

“…These findings suggested that Bmi-1 overexpression was involved in the growth, invasion and metastasis of gastric carcinoma and might be employed to indicate the biological behaviors of gastric carcinoma in clinicopathological practice. It was reported that Bmi-1 knockdown can enhance the chemosensitivity, cell cycle arrest and apoptosis, and inhibit invasive ability possibly via the inhibition of the PI3K-Akt pathway (Xiao and Deng, 2009;Song et al, 2010;Wang et al, 2010;Guo et al, 2011;Xu et al, 2011;Yin et al, 2011). Overexpression of Bmi-1 increases the motility and invasive properties of immortalized human mammary epithelial cells.…”

MicroRNA-452 suppresses pancreatic cancer migration and invasion by directly targeting B-cell-specific Moloney murine leukemia virus insertion site 1

“…In pancreatic cancer, BMI1 is upregulated and expression levels of BMI1 are associated with proliferation, survival and poor prognosis of patients with pancreatic cancer (36). Furthermore, BMI1 functioned as an oncogene in pancreatic cancer by promoting chemoresistance, invasion and tumorigenesis of pancreatic cancer (37). The results of the present study were in accordance with the aforementioned results.…”

BMI-1, a promising therapeutic target for human cancer

“…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)(24)(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).…”

“…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)(18)(19)(20)40).…”