The role of NUMB/NUMB isoforms in cancer stem cells

Abstract

Cancer stem cells (CSCs) are a subpopulation of cancer that can self-renew and differentiate into large tumor masses. Evidence accumulated to date shows that CSCs affect tumor proliferation, recurrence, and resistance to chemotherapy. Recent studies have shown that, like stem cells, CSCs maintain cells with self-renewal capacity by means of asymmetric division and promote cell proliferation by means of symmetric division. This cell division is regulated by fate determinants, such as the NUMB protein, which recently has also been confirmed as a tumor suppressor. Loss of NUMB expression leads to uncontrolled proliferation and amplification of the CSC pool, which promotes the Notch signaling pathway and reduces the expression of the p53 protein. NUMB genes are alternatively spliced to produce six functionally distinct isoforms. An interesting recent discovery is that the protein NUMB isoform produced by alternative splicing of NUMB plays an important role in promoting carcinogenesis. In this review, we summarize the known functions of NUMB and NUMB isoforms related to the proliferation and generation of CSCs.

miR-31-NUMB Cascade Modulates Monocarboxylate Transporters to Increase Oncogenicity and Lactate Production of Oral Carcinoma Cells

“…Although the entire NUMB protein was required for the binding of NUMB with mGluR5 [28], during transdifferentiation from mesodermal cells to endothelial progenitor cells, the splicing factor mediated the induction of NUMB_S isoforms to regulate Notch signaling [27]. The present study demonstrated, for the first time, the presence of Numb4 and MCT1/MCT4 complexes, which may trigger proteasome degradation, although the PTB and PRR domains were absent in Numb4 [12]. As NUMB does not possess ubiquitin ligase activity [18], further studies are required to elucidate the interaction sites in the NUMB protein and the mechanisms of ubiquitin ligase recruitment for degradation.…”

“…NUMB is an adaptor protein that plays multifaceted roles in modulating cell functions, including neurogenesis, symmetric cell division in the stemness process, epithelialmesenchymal transition, and oncogenesis [12][13][14][15]. NUMB participates in the process of ubiquitin degradation by binding with ubiquitin ligase Itch to breakdown Notch or Gli [16][17][18].…”

“…The suppressor roles of NUMB against OSCC have been identified in previous studies [14,23], but its downstream effectors remain to be elucidated. The distinct functions mediated by six NUMB isoforms resulting from alternative splicing have been actively investigated [12,27]. We discovered that the NUMB isoforms Numb1 to Numb4 were capable of suppressing OSCC pathogenesis [23].…”

A new insight into the diverse facets of microRNA-31 in oral squamous cell carcinoma

“…In conclusion sensitivity towards DDP of OSCC cells is enhanced by CASC2 by the upregulation of KANK1 via miR-31-5p. An adaptive protein that plays multifarious part in various cell functions including oncogenesis is NUMB [28,29]. It is said to be a regulator of cell fate as it asymmetrically partitions at mitosis [30] and a tumor protein p53 regulator [31] and an endocytic protein as well [32].…”

Alternative splicing variant of NRP/B promotes tumorigenesis of gastric cancer

“…However, there are some disadvantages to alternative splicing. Among them, is the association of alternative splicing with cancer development ( 2 - 6 ). Generally, eight common traits are needed for cancer development ( 7 ): resistance to cell death ( 8 ), proliferative signaling ( 9 ), acquisition of the ability to invade normal tissue and metastasize ( 10 ), the induction of angiogenesis ( 11 ), the enabling of replicative immortality ( 12 ), the reprogramming of energy metabolism ( 13 ), the evasion of growth suppressors ( 14 ), and the avoidance of immune destruction ( 15 ).…”