Numb-like (NumbL) downregulation increases tumorigenicity, cancer stem cell-like properties and resistance to chemotherapy

Abstract

NumbL, or Numb-like, is a close homologue of Numb, and is part of an evolutionary conserved protein family implicated in some important cellular processes. Numb is a protein involved in cell development, in cell adhesion and migration, in asymmetric cell division, and in targeting proteins for endocytosis and ubiquitination. NumbL exhibits some overlapping functions with Numb, but its role in tumorigenesis is not fully known. Here we showed that the downregulation of NumbL alone is sufficient to increase NICD nuclear translocation and induce Notch pathway activation. Furthermore, NumbL downregulation increases epithelial-mesenchymal transition (EMT) and cancer stem cell (CSC)-related gene transcripts and CSC-like phenotypes, including an increase in the CSC-like pool. These data suggest that NumbL can act independently as a tumor suppressor gene. Furthermore, an absence of NumbL induces chemoresistance in tumor cells. An analysis of human tumors indicates that NumbL is downregulated in a variable percentage of human tumors, with lower levels of this gene correlated with worse prognosis in colon, breast and lung tumors. Therefore, NumbL can act as an independent tumor suppressor inhibiting the Notch pathway and regulating the cancer stem cell pool.

NAMPT Is a Potent Oncogene in Colon Cancer Progression that Modulates Cancer Stem Cell Properties and Resistance to Therapy through Sirt1 and PARP

“…It has been proposed that CICs are primarily responsible for tumor relapse and poor therapeutic responses, as CICs are able to reconstitute entire tumors. To analyze the cancer-initiating cell properties induced by NAMPT, we cultured cells at low densities to form independent colonies comprising individual clones, which were previously classified as holoclones, meroclones, and paraclones based on their ability to reconstitute tumors from a single cell (16)(17)(18)(19). Holoclones are believed to be derived from stem cells, whereas paraclones are differentiated cells that are incapable of reconstituting a culture ( Fig.…”

Numb prevents a complete EMT by modulating Notch signalling

“…S22-S23). This selective inhibition of Notch-Jagged signallingan axis involved in drug resistance and colonization 8,38,39 may help rationalize, at least in part, multiple experimental observations, such as (a) Numb and/or Fringe is/are often lost in many cancer types, including aggressive ones such as basal-like breast cancer (BLBC) [40][41][42] , (b) Numbl knockdown increases chemoresistance and tumorigenic properties in cell lines of different origins -HeLa (cervix), T47D (breast) and AX (sarcoma) 43 , and (c) lunatic fringe (Lfng) suppresses in vitro tumorsphere formation in prostate cancer DU145 cells 40 .…”

Cancer stem cells as targets for immunotherapy

“…Its close homologue, Numb-like (NumbL), is able to regulate the CSC/TIC pool by inhibiting the Notch pathway. 125 Numb-1-and Notchspecific T-cells eliminated luminal CSC/TIC-like cells in a breast cancer model. 126 In a gynaecological cancer (endometrioid adenocarcinoma), ALDH high cells preferentially expressed Hsp27, the over-expression of which is associated with poor prognosis.…”

“…Numb is lost in differentiating tumour cells, due to exaggerated ubiquitination and subsequent proteasomal degradation, but its expression is maintained in stem‐like cells. Its close homologue, Numb‐like (NumbL), is able to regulate the CSC/TIC pool by inhibiting the Notch pathway . Numb‐1‐ and Notch‐specific T‐cells eliminated luminal CSC/TIC‐like cells in a breast cancer model .…”