Microglia-Specific Expression of HEXA and HEXB Leads to Poor Prognosis in Glioblastoma Patients

Abstract

Glioblastoma multiforme (GBM) is one of the deadliest cancers in brain. There have been few treatment advances for GBM despite increasing scientific understanding of this disease. β-hexosaminidase (Hex) is an important enzyme system in human body, encoded by two genes, HEXA and HEXB, are closely related to central nervous system (CNS) diseases such as Sandhoff disease (SD) and Tay-Sachs disease (TSD). However, the expression pattern and function of HEXA and HEXB in GBM remains unclear. Here, we found that both the mRNA and protein expression levels of HEXA and HEXB were significantly upregulated in GBM patient samples. The results from single-cell RNA-sequencing (scRNA-seq) database and double immunostaining showed that HEXA and HEXB were specifically expressed in microglia in GBM patient samples. Furthermore, our in vitro experiments revealed that conditioned media from HEXA and HEXB knockdown-microglia cells could inhibit the proliferation and migration of GBM cells. Finally, according to survival analysis based on online database, higher expression of HEXA and HEXB was associated with poor prognosis in GBM patients. In conclusion, these results suggest that microglial HEXA and HEXB play fundamental role in GBM progression, and they will be potential biomarkers for GBM.

Oxidative stress induces extracellular vesicle release by upregulation of HEXB to facilitate tumour growth in experimental hepatocellular carcinoma

“…In humans, HEXB is an important lysosomal enzyme involved in the degradation of various cellular substrates (Jia et al., 2021 ). Accumulating studies have shown that HEXB is associated with various central nervous system diseases (Kostallari et al., 2021 ; Sierksma et al., 2020 ).…”

“…Previous studies have shown that HEXB is highly expressed in several cancers, such as laryngeal cancer (Olszewska et al., 2009 ) and glioblastoma multiforme (Jia et al., 2021 ). However, the precise mechanisms underlying the high level of HEXB in cancer cells still require further clarification.…”

Established and emerging techniques for the study of microglia: visualization, depletion, and fate mapping

“…Notably, it was not detected in CNS-associated macrophages according to Masuda et al (2020) ; however, it has been identified in non-CNS cells, such as Ly6C + monocytes obtained from the bone marrow ( Hickman et al, 2013 ; Monaghan et al, 2019 ; Masuda et al, 2020 ; Shah et al, 2022 ). HEXB may also play a role in pathology, with elevated gene expression of HEXB associated with poor prognosis in human glioblastoma ( Jia et al, 2021 ). Although HEXB immunostaining has been utilized in combination with TMEM119 to directly identify microglia ( Jia et al, 2021 ), Hexb -based gene reporter and fate mapping tools, have also recently provided important insights into the behavior and functions of microglia in vivo ( Masuda et al, 2020 ).…”

“…HEXB may also play a role in pathology, with elevated gene expression of HEXB associated with poor prognosis in human glioblastoma ( Jia et al, 2021 ). Although HEXB immunostaining has been utilized in combination with TMEM119 to directly identify microglia ( Jia et al, 2021 ), Hexb -based gene reporter and fate mapping tools, have also recently provided important insights into the behavior and functions of microglia in vivo ( Masuda et al, 2020 ). Additionally, the promoter region of Hexb has recently been characterized, enabling the study of Hexb as a potential target for microglia-targeted gene therapies in humans ( Shah et al, 2022 ).…”

Contribution of “Genuine Microglia” to Alzheimer's Disease Pathology

“…More critically, another advanced single-cell technology, namely cytometry by time of flight (CyTOF), showed that TMEM119 and P2RY12 were expressed on microglia isolated from postmortem human brains and were absent from myeloid cells in human blood and cerebrospinal fluid (Bottcher et al, 2019 ). Accordingly, in humans, it is tempting to regard TMEM119 and P2RY12 as the most reliable markers that can identify “genuine microglia” in humans, while Siglech (sialic-acid-binding immunoglobulin-like lectin-h) (Bedard et al, 2007 ; Konishi et al, 2017 ) and Hexb (beta-hexosaminidase subunit beta) (Masuda et al, 2020 ; Jia et al, 2021 ) are also considered as microglia-enriched genes ( Table 1 ).…”