Changes in Retinoblastoma Cell Adhesion Associated with Optic Nerve Invasion

Laurie, Nikia A.; Mohan, Ashwin; McEvoy, Justina; Reed, Damon R.; Zhang, Jiakun; Schweers, Brett; Ajioka, Itsuki; Valentine, Virginia; Johnson, Dianna A.; Ellison, David H.; Dyer, Michael A.

doi:10.1128/mcb.00374-09

Cited by 33 publications

(36 citation statements)

References 25 publications

(45 reference statements)

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“…Both KDM5A shRNA and PGC-1α overexpression resulted in reduced cell growth in osteosarcoma, cervical carcinoma, retinoblastoma, and SCLC cell lines. Differentiation of retinoblastoma cell lines is manifested in increased cell adhesion and requires special techniques that were not applied in our analysis by light microscope (Laurie et al 2009). However, in cases with the KDM5A knockdown, we recorded increased MFN2 expression, indicating that retinoblastoma cells respond to KDM5A loss by increasing mitochondrial fusion protein similar to other cell types.…”

Section: Discussionmentioning

confidence: 99%

Increased mitochondrial function downstream from KDM5A histone demethylase rescues differentiation in pRB-deficient cells

et al. 2015

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The retinoblastoma tumor suppressor protein pRb restricts cell growth through inhibition of cell cycle progression. Increasing evidence suggests that pRb also promotes differentiation, but the mechanisms are poorly understood, and the key question remains as to how differentiation in tumor cells can be enhanced in order to diminish their aggressive potential. Previously, we identified the histone demethylase KDM5A (lysine [K]-specific demethylase 5A), which demethylates histone H3 on Lys4 (H3K4), as a pRB-interacting protein counteracting pRB's role in promoting differentiation. Here we show that loss of Kdm5a restores differentiation through increasing mitochondrial respiration. This metabolic effect is both necessary and sufficient to induce the expression of a network of cell typespecific signaling and structural genes. Importantly, the regulatory functions of pRB in the cell cycle and differentiation are distinct because although restoring differentiation requires intact mitochondrial function, it does not necessitate cell cycle exit. Cells lacking Rb1 exhibit defective mitochondria and decreased oxygen consumption. Kdm5a is a direct repressor of metabolic regulatory genes, thus explaining the compensatory role of Kdm5a deletion in restoring mitochondrial function and differentiation. Significantly, activation of mitochondrial function by the mitochondrial biogenesis regulator Pgc-1α (peroxisome proliferator-activated receptor γ-coactivator 1α; also called PPARGC1A) a coactivator of the Kdm5a target genes, is sufficient to override the differentiation block. Overexpression of Pgc-1α, like KDM5A deletion, inhibits cell growth in RB-negative human cancer cell lines. The rescue of differentiation by loss of KDM5A or by activation of mitochondrial biogenesis reveals the switch to oxidative phosphorylation as an essential step in restoring differentiation and a less aggressive cancer phenotype.

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Section: Discussionmentioning

confidence: 99%

Increased mitochondrial function downstream from KDM5A histone demethylase rescues differentiation in pRB-deficient cells

et al. 2015

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“…It is noted that the adherent cells lacked the astrocyte marker GFAP, yet this was consistent with the progressive loss of GFAP in freshly explanted Pax2 ϩ retinal astrocytes under the same tissue culture conditions (data not shown). As these cells grew quite robustly, it is plausible that adherent cells that were previously cultured from retinoblastomas 34 or from mouse retinal tumors 46 constituted a similar retinal astrocyte population.…”

Section: Retinoblastoma Glia Have Properties Of Non-neoplastic Retinamentioning

confidence: 99%

Tumor-Associated Retinal Astrocytes Promote Retinoblastoma Cell Proliferation Through Production of IGFBP-5

Lee

Offor

et al. 2010

The American Journal of Pathology

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“…Laurie et al proved this association at molecular basis, and their "detailed analysis of these cells as they were propagated in culture from the primary tumor shows that changes in cadherin-mediated cell adhesion are associated with retinoblastoma invasion of the optic nerve prior to metastasis. In addition, the same changes in cadherin-mediated cell adhesion correlate with the invasive properties of the human retinoblastoma cell lines isolated decades ago, providing a molecular mechanism for these earlier observations" [18]. In another study, it was seen that relating the RB gene expression with the clinico-pathologic features of the tumor tissues, and found that the tumor with invasion of choroid, optic nerve and retinal pigment epithelium, had relatively higher gene expression, when compared with the tumor with only choroidal invasion [19].…”

Section: Discussionmentioning

confidence: 82%

Prognostic significance of retinoblastoma gene mutation in retinoblastoma eye with respect to pathological risk factors

Khan¹,

Mehboob²,

Bukhari³

2013

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Retinoblastoma (Rb) was reported firstly by Benedict is the commonest pediatric intraocular malignant tumor in children younger than 5 years of age. The study was conducted to detect the RB-1 gene for prognostic evaluation in retinoblastoma and to see the frequency of RB-1 gene in our population. This was a retrospective descriptive analytical study. Five years biopsies (January, 2006 to December 2011) of the retinoblastoma, from the Pathology department, was retrieved to see optic nerve involvement in all the retrieved specimens. The study was taken to see the mutation of RB1 gene by immunohistochemistry and PCR. The study plan was approved from Institutional Review Board (IRB) of the University. All the cases showed positivity of abnormal Rb-1 gene proteins expression by Immunohistochemistry staining. On PCR, 51/52 (98%) tumors expressed gene mutation as compared to 100% expression shown by IHC. Out of these, 28/51 (55%) cases showed ONI and ODI with positivity for mutated RB gene. A positive association was seen among RB gene mutation with ONI and ODI (p = 0.05). There were 33/51 (65%) cases who did not show any EOE but showed PCR positivity for RB gene mutation. While there were 18/51 (35%) cases who showed EOE and positivity of PCR for Rb-1 gene mutation and a positive association was seen with EOE and gene mutation (p = 0.005). The most common sequence of mutation was on 13 with 33 cases for double mutation, 12 cases for single and 6 patients for triple pattern of mutation. Most of the double and triple sequences of mutations were associated with ONI, ODI and EOE. We concluded that mutation of RB-1 gene is responsible in causation of the tumors with a positive association with tumor size and tumor extension (optic nerve, and extraocular extension), and mutation affects patients with all ages, both gender and unilateral and bilateral tumors.

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Changes in Retinoblastoma Cell Adhesion Associated with Optic Nerve Invasion

Cited by 33 publications

References 25 publications

Increased mitochondrial function downstream from KDM5A histone demethylase rescues differentiation in pRB-deficient cells

Increased mitochondrial function downstream from KDM5A histone demethylase rescues differentiation in pRB-deficient cells

Tumor-Associated Retinal Astrocytes Promote Retinoblastoma Cell Proliferation Through Production of IGFBP-5

Prognostic significance of retinoblastoma gene mutation in retinoblastoma eye with respect to pathological risk factors

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