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iNature
Glioblastoma (GBM) is the most common and deadly primary brain tumor
in adults.
Despite some progress in diagnosis and treatment, the prognosis for patients with GBM remains poor
.
GBM is classified by the WHO as a grade IV (highest grade) neurological tumor, and the median survival of patients diagnosed is only 14 to 16 months
.
Numerous studies have shown the presence of subsets of cancer stem cells in GBM, called glioma stem cells (GSCs).
GSCs have super self-renewal and multidirectional differentiation ability, which is closely related
to tumorigenesis, continuous growth and recurrence.
Ribosomes are ribonucleoprotein particles composed of ribosomal RNA and ribosomal proteins in cells, which are molecular machines for protein synthesis in cells, and their function is to convert the genetic code into amino acid sequences and synthesize protein polypeptide chains
according to the instructions of mRNA 。 The generation of ribosomes is mainly carried out in the nucleoli of the nucleus, first rDNA transcription produces 45S pre-rRNA, and then three types of ribosome RNA are generated by shearing processing, which are 28S, 18S and 5.
8S rRNA, and then assembled with other components into ribosomal size subunits, transported to the cytoplasm to finally form ribosomes, which serve as factories for protein synthesis
.
Ribosomes are closely related
to cell growth, proliferation, differentiation and the occurrence of cancer.
Tumor cells, including cancer stem cells, are abnormally activated by the ribosome biogenesis pathway, which promotes the rapid proliferation
of tumor cells.
However, in GSCs, the molecular mechanisms that control abnormal activation of the ribosome biogenesis pathway are still not well understood
.
On December 15, 2022, the research group of Tao Weiwei, College of Biomedicine and Health and College of Life Science and Technology, Huazhong Agricultural University, cooperated with the Bosden research group of the Department of Cancer Biology at the Lerner Institute of Cleveland Clinic in the United States and published a report entitled " NIR Drives Glioblastoma Growth by Promoting Ribosomal DNA Transcription in Glioma Stem Cells In the paper, the researchers found that the NIR (Novel INHAT Repressor) protein is mainly localized in the nucleola of glioma stem cells, and promotes protein synthesis by activating ribosomal DNA (rDNA) transcription, thereby promoting the self-renewal of GSCs and the malignant growth of GBM, which will provide potential drug targets and intervention strategies
for the treatment of GBM.
in GBM tissues.
Analyzing GBM-related clinical databases, the researchers found that high expression of the NIR gene predicted a poorer
prognosis for GBM patients.
Further studies found that NIR was mainly expressed in glioma stem cells (GSCs) and localized within
the nucleolar of GSCs.
Phenotypic analysis found that NIR is essential for the proliferation and self-renewal of GSCs, and NIR promotes GSCs rDNA transcription and rRNA synthesis (Figure 1A-B), which in turn affects protein synthesis (Figure 1C-D).
The researchers also found that NIR plays an important role in maintaining the size of the nucleoli.
Figure 1.
NIR regulates glioma stem cell (GSCs) rDNA transcription and protein synthesis
.
A-B, EU (5-Ethynyl uridine) incorporation experiments showed that knockdown NIR inhibited rDNA transcription and rRNA synthesis of GSCs.
C-D, OPP (O-Propargyl-puromycin) incorporation experiments showed that knocking down NIR inhibited protein synthesis
of GSCs.
Animal results also confirmed that NIR promoted intracranial growth of GBM, knocked down NIR inhibited cell proliferation in vivo, the number of GSCs, and the transcription
of ribosomal DNA.
Through co-immunoprecipitation combined with liquid chromatography-mass spectrometry, the researchers found that NIR can interact
with two important nucleolar transcription factors, NCL and NPM1.
Moreover, NIR does not affect the expression
of NCL or NPM1.
Further mechanistic studies have found that NIR forms protein complexes with NCL and NPM1 and binds to the promoter of rDNA, promoting rDNA transcription and rRNA synthesis
.
Increased rRNA content increases ribosome assembly, which increases protein synthesis, leading to rapid proliferation, self-renewal, and malignant growth of GBMs (Figure 2).
Figure 2.
Interestingly, NIR promotes glioma stem cell ribosome biogenesis Interestingly, previously reported that NIR is a transcriptional inhibitor that performs specific functions
by inhibiting the transcription of downstream target genes.
Our study confirms that in GSCs, NIR is a transcriptional activator that activates the transcription
of downstream rDNA.
Thus, NIR performs different functions in different cells, allowing it to act as a transcription activator or transcription inhibitor
.
In summary, the study found for the first time that NIR is highly expressed in GBM and GSCs, while expression is low
in normal brain tissue and neural precursor cells.
NIR as a key transcription factor promotes abnormal activation
of the ribogenetic pathway of GSCs.
GSCs promote the transcription of ribosomal DNA and the assembly of ribosomes through high NIR expression, which in turn promotes the malignant proliferation and self-renewal
of GSCs.
Therefore, targeting NIR or blocking the binding of NIR to NCL/NPM1 may become a potential GBM drug development strategy
.
The study was conducted in collaboration with Huazhong Agricultural University, Cleveland Clinic and the University of Pittsburgh
.
Professor Tao Weiwei of Huazhong Agricultural University and Professor Bao Shiden of Cleveland Clinic are co-corresponding authors, and Professor Tao Weiwei is the first author
.
Lei Hong, Luo Wenlong, Ling Peng and Guo Mengyue, master's and doctoral students in Tao Weiwei's research group, participated in part of the research
.
Professor Dong Zhiqiang and Professor Xu Shutong of Huazhong Agricultural University, Professor Zeng Liang of Wuhan Tongji Hospital, Professor Wang Xiuxing of Nanjing Medical University, Professor Jeremy Rich of the University of Pittsburgh, and Dr.
Wu Qiulian also participated in some of the research
.
Professor Zhou Wenchao of the University of Science and Technology of China, researcher Man Jianghong, researcher of the Military Medical Research Institute of the Academy of Military Sciences, and Professor Yu Xingjiang of Huazhong University of Science and Technology also gave a lot of valuable suggestions and help
to the subject.
It is reported that Tao Weiwei's research group has been recruiting postdoctoral fellows and scientific research assistants
for a long time.
We sincerely welcome outstanding doctoral and master's students with molecular biology, cell biology, tumor biology or neurobiology backgrounds to join
.
Original link: https://doi.
org/10.
1093/neuonc/noac272
—END—
The content is [iNature]
