Loss of cytoskeleton protein ADD3 promotes tumor growth and angiogenesis in glioblastoma multiforme

Kiang, Karrie Mei Yee; Zhang, Pingde; Li, Ning; Zhu, Zhiyuan; Jin, Ling; Leung, Gilberto Ka-Kit

doi:10.1016/j.canlet.2020.01.007

Cited by 18 publications

(22 citation statements)

References 29 publications

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“…While most cell-based studies suggest an oncogenic behavior, different papers on glioma tumor specimens, in agreement with our data, relate ADD3 downregulation to progression [43,44] and to migration [45]. Other cancer that shows EGFR amplification, such as non-small cell lung cancer, shares this ADD3 infraexpression associated with cell migration [47]. We suggest that the use of such easy techniques as MLPA to assess ADD3 SCNA could be considered for diagnostic routines to better tailor clinical decisions as an independent prognostic factor and to delve deeper into the GB classification of patients.…”

Section: Discussionsupporting

confidence: 89%

Identification of New Genetic Clusters in Glioblastoma Multiforme: EGFR Status and ADD3 Losses Influence Prognosis

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San-Miguel

Megías

et al. 2020

Cells

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Glioblastoma multiforme (GB) is one of the most aggressive tumors. Despite continuous efforts to improve its clinical management, there is still no strategy to avoid a rapid and fatal outcome. EGFR amplification is the most characteristic alteration of these tumors. Although effective therapy against it has not yet been found in GB, it may be central to classifying patients. We investigated somatic-copy number alterations (SCNA) by multiplex ligation-dependent probe amplification in a series of 137 GB, together with the detection of EGFRvIII and FISH analysis for EGFR amplification. Publicly available data from 604 patients were used as a validation cohort. We found statistical associations between EGFR amplification and/or EGFRvIII, and SCNA in CDKN2A, MSH6, MTAP and ADD3. Interestingly, we found that both EGFRvIII and losses on ADD3 were independent markers of bad prognosis (p = 0.028 and 0.014, respectively). Finally, we got an unsupervised hierarchical classification that differentiated three clusters of patients based on their genetic alterations. It offered a landscape of EGFR co-alterations that may improve the comprehension of the mechanisms underlying GB aggressiveness. Our findings can help in defining different genetic profiles, which is necessary to develop new and different approaches in the management of our patients.

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Section: Discussionsupporting

confidence: 89%

Identification of New Genetic Clusters in Glioblastoma Multiforme: EGFR Status and ADD3 Losses Influence Prognosis

Navarro

San-Miguel

Megías

et al. 2020

Cells

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“…Compared with MXI1 , less is known about the role of ADD3 in cancer. We reported previously on the putative tumor-suppressive function of ADD3 in GBM ( 22 ). It is by chance mapped to chromosome 10q25.2, where LOH frequently occurs.…”

Section: Discussionmentioning

confidence: 99%

“…It is by chance mapped to chromosome 10q25.2, where LOH frequently occurs. ADD3 was found to be significantly downregulated in GBM, and such loss was associated with enhanced tumor growth ( 22 ). In this study, we were able to demonstrate the mechanism by which ADD3 was downregulated in gliomas as being most likely due to LOH with copy number deletions.…”

Section: Discussionmentioning

confidence: 99%

“…Alteration of ADD3 may also modulate the tumor microenvironment mediated by changes in focal adhesion as well as cell–cell contacts ( 32 , 33 ). It was found that ADD3-deficient GBM cells were able to elicit pro-angiogenic signals to stimulate VEGFR expression in endothelial cells ( 22 ). All of these could be the potential mechanisms and the pathophysiological consequences that underlie allelic loss of ADD3 in malignant gliomas, particularly during disease progression.…”

Section: Discussionmentioning

confidence: 99%

“…ADD3 is located on chromosome 10q25.1-25.2, which is known to be a functional tumor suppressor region. While it primarily functions as a cytoskeleton protein, ADD3 is characterized as a negative regulator of tumor growth and is negatively associated with malignant phenotypes such as angiogenesis in GBM ( 22 ). However, the basis behind ADD3 downregulation has not been identified for which both genetic and epigenetic modifications should be taken into consideration when studying its functional characteristics in cancer cells.…”

Section: Introductionmentioning

confidence: 99%

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ADD3 Deletion in Glioblastoma Predicts Disease Status and Survival

2021

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Loss of heterozygosity (LOH) on chromosome 10 frequently occurs in gliomas. Whereas genetic loci with allelic deletion often implicate tumor suppressor genes, a putative tumor suppressor Adducin3 (ADD3) mapped to chromosome 10q25.2 was found to be preferentially downregulated in high-grade gliomas compared with low-grade lesions. In this study, we unveil how the assessment of ADD3 deletion provides clinical significance in glioblastoma (GBM). By deletion mapping, we assessed the frequency of LOH in forty-three glioma specimens using five microsatellite markers spanning chromosome 10q23-10qter. Data were validated in The Cancer Genome Atlas (TCGA) cohort with 203 GBM patients. We found that allelic loss in both D10S173 (ADD3/MXI1 locus) and D10S1137 (MGMT locus) were positively associated with tumor grading and proliferative index (MIB-1). However, LOH events at only the ADD3/MXI1 locus provided prognostic significance with a marked reduction in patient survival and appeared to have diagnostic potential in differentiating high-grade gliomas from low-grade ones. Furthermore, we showed progressive loss of ADD3 in six out of seven patient-paired gliomas with malignant progression, as well as in recurrent GBMs. These findings suggest the significance of ADD3/MXI1 locus as a promising marker that can be used to refine the LOH10q assessment. Data further suggest the role of ADD3 as a novel tumor suppressor, whereby the loss of ADD3 is indicative of a progressive disease that may at least partially account for rapid disease progression in GBM. This study revealed for the first time the downregulation of ADD3 on the genetic level resulting from copy number deletion.

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Insights into the antitumor mechanism of ginsenosides Rg3

Liu

et al. 2021

Mol Biol Rep

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Loss of cytoskeleton protein ADD3 promotes tumor growth and angiogenesis in glioblastoma multiforme

Cited by 18 publications

References 29 publications

Identification of New Genetic Clusters in Glioblastoma Multiforme: EGFR Status and ADD3 Losses Influence Prognosis

Identification of New Genetic Clusters in Glioblastoma Multiforme: EGFR Status and ADD3 Losses Influence Prognosis

ADD3 Deletion in Glioblastoma Predicts Disease Status and Survival

Insights into the antitumor mechanism of ginsenosides Rg3

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