The polarity protein Par3 coordinates positively self-renewal and negatively invasiveness in glioblastoma

Abstract

Glioblastoma (GBM) is a brain malignancy characterized by invasiveness to the surrounding brain tissue and by stem-like cells, which propagate the tumor and may also regulate invasiveness. During brain development, polarity proteins, such as Par3, regulate asymmetric cell division of neuro-glial progenitors and neurite motility. We, therefore, studied the role of the Par3 protein (encoded by PARD3) in GBM. GBM patient transcriptomic data and patient-derived culture analysis indicated diverse levels of expression of PARD3 across and independent from subtypes. Multiplex immunolocalization in GBM tumors identified Par3 protein enrichment in SOX2-, CD133-, and NESTIN-positive (stem-like) cells. Analysis of GBM cultures of the three subtypes (proneural, classical, mesenchymal), revealed decreased gliomasphere forming capacity and enhanced invasiveness upon silencing Par3. GBM cultures with suppressed Par3 showed low expression of stemness (SOX2 and NESTIN) but higher expression of differentiation (GFAP) genes. Moreover, Par3 silencing reduced the expression of a set of genes encoding mitochondrial enzymes that generate ATP. Accordingly, silencing Par3 reduced ATP production and concomitantly increased reactive oxygen species. The latter was required for the enhanced migration observed upon silencing of Par3 as anti-oxidants blocked the enhanced migration. These findings support the notion that Par3 exerts homeostatic redox control, which could limit the tumor cell-derived pool of oxygen radicals, and thereby the tumorigenicity of GBM.

PARD3 drives tumorigenesis through activating Sonic Hedgehog signalling in tumour-initiating cells in liver cancer

“…Although PARD3 expression is differentially regulated in human cancers, and PARD3 may function as either an oncogene or tumour suppressor depending on cancer subtype or stage [ 22 ], a recent study showed that in human glioblastoma, PARD3 was enriched in NESTIN-positive stem cells. Similar to our findings, silencing PARD3 was found to lead to a defect in glioma sphere formation in vitro, suggesting that the self-renewal capacity of TICs was lost upon PARD3 silencing [ 41 ]. By single-cell analysis, we showed that in an early established HCC tumour, PARD3 was enriched in cancer cells expressing CD133, the cell surface marker of liver cancer stem cells.…”

“…Similar to our findings, silencing Fig. 7 Mechanisms involved in the regulation of PARD3 on TICs in hepatocarcinogenesis PARD3 was found to lead to a defect in glioma sphere formation in vitro, suggesting that the self-renewal capacity of TICs was lost upon PARD3 silencing [41]. By singlecell analysis, we showed that in an early established HCC tumour, PARD3 was enriched in cancer cells expressing CD133, the cell surface marker of liver cancer stem cells.…”

“…Interestingly, our data and previous study suggested that PARD3 is differentially expressed in stem-like cancer cells and differentiated cancer cells. Mahsa et al reported PARD3 protein enrichment in SOX2-, CD133-, and NESTIN-positive stem like glioblastoma cells [ 41 ]. Our scRNA sequencing analysis demonstrated a positive correlation between the expression of PARD3 and CD133 in the cancer stem cell lineage with highly activated SHH signalling (Fig.…”

Weighted Correlation Network Analysis of Cancer Stem Cell-Related Prognostic Biomarkers in Esophageal Squamous Cell Carcinoma

“… 39 Zhou et al 40 reported that loss of Par3 promoted prostatic tumorigenesis. Nevertheless, Dadras et al 41 showed that Par3 participated in homeostatic redox control and limited invasiveness of glioblastoma.…”

Partition defective 3 promotes TAZ nuclear localization and promotes Amphiregulin transcription to promote liver hepatocellular carcinoma cell invasion, migration and epithelial mesenchymal

“…Therefore, PARD3 was con rmed to have invasion and migration inhibitory effects possibly through regulating cell polarity (Dadras, et al 2021). However, studies have also shown that PARD3 acts as an oncogene in ovarian cancer (Nakamura, et al 2016), prostate cancer (Zhou, et al 2017) and other cancers.…”