Bmi-1 expression modulates non-small cell lung cancer progression

Abstract

y These authors equally contributed to this work.Keywords: Bmi-1, EMT, invasion, metastasis, NSCLC, progression Abbreviations: NSCLC, non-small cell lung cancer; EMT, epithelial-mesenchymal transition; Bmi-1, B lymphoma Mo-MLV insertion region 1 homolog; IHC, immunohistochemistry; FBS, fetal calf serum; qRT-PCR, quantitative real-time PCR.Previous studies indicate that the role of B lymphoma Mo-MLV insertion region 1 homolog (Bmi-1) is responsible for multiple cancer progression. However, Bmi-1 in controlling gene expression in non-small cell lung cancer (NSCLC) development is not well explored. Here we report that the Bmi-1 level is highly increased in primary NSCLC tissues compared to matched adjacent non-cancerous tissues and required for lung tumor growth in xenograft model. Furthermore, we also demonstrate that Bmi-1 level is lower in matched involved lymph node cancerous tissues than the respective primary NSCLC tissues. We find that Bmi-1 does not affect cell cycle and apoptosis in lung cancer cell lines as it does not affect the expression of p16/p19, Pten, AKT and P-AKT. Mechanistic analyses note that reduction of Bmi-1 expression inversely regulates invasion and metastasis of NSCLC cells in vitro and in vivo, followed by induction of epithelial-mesenchymal transition (EMT). Using genome microarray assays, we find that RNAi-mediated silence of Bmi-1 modulates some important molecular genetics or signaling pathways, potentially associated with NSCLC development. Taken together, our findings disclose for the first time that Bmi-1 level accumulates strongly in early stage and then declines in late stage, which is potentially important for NSCLC cell invasion and metastasis during progression.

Prognostic Significance of BMI-1 But Not MEL-18 Expression in Pulmonary Squamous Cell Carcinoma

“…It has also been reported that BMI-1 repression induces epithelialmesenchymal transition and progression of lung cancer in vitro. In our study, overall survival in lung squamous cell carcinoma was inversely correlated with BMI-1 expression, and these results were supported by a previous report (18). In another report, BMI-1 mRNA expression in early stage breast cancer was higher than in late stage and was inversely related with lymph node metastasis (21).…”

“…These results suggested that BMI-1 may cause carcinogenesis in early events, but not late stage progression, but this remains controversial. Another study of BMI-1 expression in lung cancer showed significant correlation with early and decline in late stages of disease, which is negatively correlated with nodal involvement (18). They reported that silencing of BMI-1 expression induced invasiveness and metastasis in human lung cancer cell lines in vitro.…”

Doublecortin-Like Kinase 1 (DCLK1) Regulates B Cell-Specific Moloney Murine Leukemia Virus Insertion Site 1 (Bmi-1) and is Associated with Metastasis and Prognosis in Pancreatic Cancer

“…Indeed, accumulating evidence demonstrates that Bmi-1 is upregulated in malignant tumors and is correlated with disease progression [22][23][24]. In addition, it has been shown that Bmi-1 induces EMT, an important mechanism in the initial step of metastasis [25,26].…”

Long non‑coding RNA CCAT1 enhances human non‑small cell lung cancer growth through downregulation of microRNA‑218

“…B lymphoma Mo-MLV insertion region 1 homolog (BMI-1) is a component of polycomb repressive complex 1 (PRC1) (27). In NSCLC, BMI-1 has been demonstrated as an oncogene due to its functions in tumor proliferation, invasion and chemoresistance (28,29). In the present study, it was found that the expression of BMI-1 was downregulated by CCAT1 silencing in NSCLC cells.…”