EXTL3 could serve as a potential biomarker of prognosis and immunotherapy for prostate cancer and its potential mechanisms

Chang, Ping‐An; Chen, Shenglan; Chang, Xiumei; Zhu, Jiaxi; Tang, Qingsheng; Ma, Limin

doi:10.1186/s40001-022-00740-w

Cited by 9 publications

(11 citation statements)

References 58 publications

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“…4C ). Interestingly, the most significantly upregulated genes in Ppm1d T/+ AML ( Zbed3, Runx3, Marcks, Extl3, Pcbp4, Igf2bp3, Plch1 , and Gdf6 ) were previously associated with AML and cancer progression [ 52 – 58 ]. We compared the expression of these genes in AML patients versus healthy samples using the TNM database [ 42 ], and noted that PLCH1 , ZBED3 , IGF2BP3 , INSM1 , and SLC17A8 were elevated in leukemic patients in comparison to healthy samples (Fig.…”

Section: Resultsmentioning

confidence: 99%

Ppm1d truncating mutations promote the development of genotoxic stress-induced AML

Burocziova,

Danek,

Oravetzova

et al. 2023

Leukemia

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Hematopoietic stem cells (HSCs) ensure blood cell production during the life-time of an organism, and to do so they need to balance self-renewal, proliferation, differentiation, and migration in a steady state as well as in response to stress or injury. Importantly, aberrant proliferation of HSCs leads to hematological malignancies, and thus, tight regulation by various tumor suppressor pathways, including p53, is essential. Protein phosphatase magnesium-dependent 1 delta (PPM1D) is a negative regulator of p53 and promotes cell survival upon induction of genotoxic stress. Truncating mutations in the last exon of PPM1D lead to the production of a stable, enzymatically active protein and are commonly associated with clonal hematopoiesis. Using a transgenic mouse model, we demonstrate that truncated PPM1D reduces self-renewal of HSCs in basal conditions but promotes the development of aggressive AML after exposure to ionizing radiation. Inhibition of PPM1D suppressed the colony growth of leukemic stem and progenitor cells carrying the truncated PPM1D, and remarkably, it provided protection against irradiation-induced cell growth. Altogether, we demonstrate that truncated PPM1D affects HSC maintenance, disrupts normal hematopoiesis, and that its inhibition could be beneficial in the context of therapy-induced AML.

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Section: Resultsmentioning

confidence: 99%

Ppm1d truncating mutations promote the development of genotoxic stress-induced AML

Burocziova,

Danek,

Oravetzova

et al. 2023

Leukemia

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“…Zhong et al found an up-regulation of COL6A2, which could be a factor in poor prognosis in metastatic ccRCC [31]. Exostosin-like glycosyltransferase 3 (EXTL3), belonging to the EXT family, takes a crucial part in predicting the prognosis of various cancers and immune defciencies [32], but its role in ccRCC remains unknown. HEAT repeat containing 6 (HEATR6) is part of a highly expressed breast cancer amplicon.…”

Section: Discussionmentioning

confidence: 99%

SLC9A1 Binding mTOR Signaling Pathway-Derived Risk Score Predicting Survival and Immune in Clear Cell Renal Cell Carcinoma

Wang

2023

Journal of Oncology

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Objective. Clear cell renal cell carcinoma (ccRCC) is one of the common renal cell carcinomas (RCC) with a high risk of recurrence. Considering that SLC9A1 is involved in various cellular physiological processes and probably mediates the course of mTOR signaling in tumors, this study constructed a risk model for SLC9A1 combined with mTOR signaling in ccRCC, aiming at better predicting the prognosis of patients. Methods. ccRCC expression matrices were downloaded from TCGA and ICGC databases to compare the expression of SLC9A1 in TCGA, and qRT-PCR was adopted to validate the SLC9A1 expression in different RCC cells and normal kidney cells. The CIBERSORT and ESTIMATE algorithms were used to assess samples for immunity. mTOR signaling-associated genes were downloaded from the KEGG website, and then the genes were adopted to screen genes associated with SLC9A1 expression and mTOR signaling pathway colleagues, based on which univariate COX regression and lasso regression Cox analyses were conducted to construct a ccRCC prognostic risk model. ROC curves and nomograms were used to assess the validity of the models. Results. ccRCC tumor samples showed lower SLC9A1 expression than normal samples, as also evidenced by qRT-PCR. The SLC9A1 expression was highly correlated with tumor immunity. Totally, 564 key genes associated with both SLC9A1 expression and mTOR signaling were screened out, and the risk model consisting of 11 gene signatures was constructed in ccRCC based on the 564 genes. Since patients at a high risk had poorer survival outcomes, the high-risk group presented poorer immunotherapy outcomes. Moreover, a higher clinical grade of patients suggested a higher risk score. The risk score can serve as one independent prognostic factor for the prognosis prediction of ccRCC patients. Conclusion. An extremely promising prognostic indicator for ccRCC based on SLCA9A1 and mTOR signaling has been constructed to provide reference for clinical treatment.

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“…EXTL3 can be used as an anticancer gene and is significantly associated with seven signaling pathways in prostate cancer. Therefore, EXTL3 is a potential biomarker for evaluating prognosis and immunotherapy in prostate cancer (Chang et al., 2022). The reported EXTL3 variants were primarily distributed in the EXT domain, affecting the assembly of HS, intercellular communication and biological signal transduction, resulting in defects in the growth and development of the central nervous system and immune system, and abnormal skeletal development.…”

Section: Discussionmentioning

confidence: 99%

Immune skeletal dysplasia with neurodevelopmental abnormalities caused by a novel variant of EXTL3 gene in a Chinese family

Tian,

Zhang,

Zhang

et al. 2023

Molec Gen & Gen Med

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BackgroundImmune skeletal dysplasia with neurodevelopmental abnormalities (ISDNA) is an extremely rare, autosomal recessive genetic disorder characterized by various skeletal abnormalities, neurodevelopmental deficits, and abnormal immune system function. ISDNA is caused by variation in the exostosin‐like 3 (EXTL3) gene, located on chromosome 8p21.2, whose primary function is the biosynthesis of heparan sulfate (HS) skeleton structure. Only a few variations in the EXTL3 gene have been discovered so far. In these years of development, many pathogenic variants in genetic diseases with genetic and phenotypic heterogeneity have been investigated using whole‐exome sequencing (WES) technology.MethodsIn this research, a novel EXTL3 variant was first detected in a patient using WES, which was validated from Sanger sequencing in this family. Family history and clinical information were then collected through comprehensive medical examinations and genetic counseling. In silico prediction was then utilized to confirm the pathogenicity of the variant.ResultsA novel homozygous variant, NM_001440: c.2015G>A (p.Arg672Gln) in the EXTL3 gene, was identified using WES, which has never been reported before. Sanger sequencing was performed to confirm that the variant segregated with the disease within the family.ConclusionThis research identified a novel pathogenic variant in the EXTL3 gene responsible for ISDNA in a Chinese family. It showed the potential diagnostic role of WES in ISDNA, expanded the EXTL3 gene variation spectrum, and demonstrated that the diagnosis of ISDNA using WES is feasible and effective. More comprehensive genetic counseling and precise prenatal diagnosis for the next pregnancy can also be provided to families with genetic disorders.

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EXTL3 could serve as a potential biomarker of prognosis and immunotherapy for prostate cancer and its potential mechanisms

Cited by 9 publications

References 58 publications

Ppm1d truncating mutations promote the development of genotoxic stress-induced AML

Ppm1d truncating mutations promote the development of genotoxic stress-induced AML

SLC9A1 Binding mTOR Signaling Pathway-Derived Risk Score Predicting Survival and Immune in Clear Cell Renal Cell Carcinoma

Immune skeletal dysplasia with neurodevelopmental abnormalities caused by a novel variant of EXTL3 gene in a Chinese family

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