Stem cell self-renewal factors Bmi1 and HMGA2 in head and neck squamous cell carcinoma: clues for diagnosis

Abstract

Head and neck squamous cell carcinoma (HNSCC) includes both morphological and functional cellular heterogeneity, as would be expected if it arose from dysregulated stem or progenitor cells as opposed to the simple clonal expansion of a mutated cell; however, stemness molecule expression levels and distribution in HNSCC remain unclear. To clarify this, stemness molecule expressions were determined in HNSCC, as well as their properties and prognosis. Two protooncogenic chromatin regulators, Bmi-1 and high-mobility-group A2 (Hmga2), were identified in 12 pair cases of HNSCC tumor regions by comparison with their non-cancerous background tissues using cDNA microarray. Both Bmi-1 and Hmga2 are known to promote stem cell self-renewal by negatively regulating the expressions of Ink4a and Arf tumor suppressors. Despite similar targets, Bmi-1 protein was expressed in an early cancerous region and HMGA2 protein was expressed in a region showing more progression. Similarly, Bmi1 expression had no significance with regard to overall survival (P ¼ 0.67), whereas HMGA2 expression was associated with decreased overall survival (P ¼ 0.05). Quantitative realtime reverse transcription polymerase chain reaction analyses also correlated with protein levels. These findings suggest that Bmi-1 is an early detection marker to distinguish cancerous from non-cancerous regions, whereas HMGA2 is presumed to be a tumor prognosis marker. Among our HNSCC analyses, these stemness molecules expressed fewer primitive rare cells in the tumor than all other cells in the tumor. HNSCC cells with high expression of stemness molecules partly behave like stem cells. Head and neck squamous cell carcinoma (HNSCC) is typically associated with virus infection, persistent chronic inflammation, and tobacco and alcohol use. Survival rates have changed in the last 40 years because of reductions in these factors; 1 however, the mortality rate remains high because advanced and recurrent locoregional control is difficult in many cases. Better understanding of the biology of HNSCC is required to define relevant targets and to develop novel therapeutic approaches. HNSCCs have both morphological and functional cellular heterogeneity, as would be expected if they arose from dysregulated stem or progenitor cells as opposed to the simple clonal expansion of a mutated cell. 2 Recently, numerous reports have shown support for the 'cancer stem cell' theory in many types of tumor, including HNSCC. 3,4,5 Acute and chronic myeloid leukemias follow the cancer stem cell model. Both tumors show robustly hematopoietic hierarchical organization in the tumor cells; 6,7 however, for solid cancers such as squamous cell carcinoma, it is not clear how generalizable the cancer stem cell model is. Not all cancer cells have the same capacity to proliferate. 8 In some cancers, most cancer cells appear to have limited ability to proliferate, while in the same tumors, stochastic minority populations of stemness molecules highly expressed in cancer as a 'stem-like cancer' retain the capacity...

shRNA targeting Bmi-1 sensitizes CD44+ nasopharyngeal cancer stem-like cells to radiotherapy

“…However, the interaction between radioresistance and CSCs and its underlying mechanisms have not been previously explored. B-cell-specific Moloney murine leukemia virus integration site 1 (Bmi-1), a member of the Polycomb family of transcriptional repressors, is essential for maintaining the self-renewal and differentiation of human stem cells (4)(5)(6)(7). Bmi-1 has been demonstrated to be overexpressed in various of tumors (8), such as lung (9), breast (10) and prostate cancer (11), esophageal carcinoma (12) and NPC (13).…”

Silencing of Bmi-1 Gene Enhances Chemotherapy Sensitivity in Human Glioblastoma Cells

“…BMI1 is a polycomb group epigenetic gene silencer that is highly expressed in various types of human cancers [14–16,20]. In addition, it is involved in the development and progression of cancers [21,22].…”

“…The abnormal expression of the BMI1 gene is tightly related with occurrence, progression, invasion, metastasis, and prognosis of tumors [11–13]. BMI1 has been reported to act as a key biomarker for the prognosis of various kinds of cancer, including head and neck squamous cell carcinoma, colorectal cancer, and lung adenocarcinoma [14–16]. Therefore, the objective of this study was to first determine the correlation between the abnormal expression of BMI1 and the carcinogenesis and development of human gliomas, and then to search for its possible influence on chemotherapy sensitivity of human glioma U251 cells.…”

Beyond transcription factors: how oncogenic signalling reshapes the epigenetic landscape

“…BMI1 plays an important role in hematopoietic and neural stem cell self-renewal 55, 56 , and upregulation of BMI1 has been detected in AML and chronic myeloid leukemia (CML) 57 , as well as many solid tumors, including squamous cell carcinomas 58 , neuroblastoma 59 and bladder cancer 60 . The oncogenic potential of BMI1 has been associated with its ability to repress the CDKN2A locus, blocking the expression of the two proteins encoded by this locus, the cyclin-dependent kinase 4 (CDK4) and CDK6 inhibitors p16 INK4A , and the p53 activator p14 ARF (p19 ARF in mouse) 61 .…”