Cyclin D3 is dispensable for human diffuse large B-cell lymphoma survival and growth: evidence for redundancy with cyclin E

Gumina, Maria R.; Xu, Chenjia; Chiles, Thomas C.

doi:10.4161/cc.9.4.10783

Cited by 10 publications

(9 citation statements)

References 33 publications

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“…Although high-level p16 expression normally halts cellular proliferation by inhibiting the ability of cyclin D/CDK4/6 complexes to phosphorylate and inactivate pRb [ 33 ], human melanomas and DLBCLs can escape the effect of p16 by inducing cyclin E expression [ 56 , 57 ]. High-level c-Myc expression (which activates cyclin E expression) can also bypass the p16 effect [ 58 ].…”

Section: Resultsmentioning

confidence: 99%

An EBNA3C-deleted Epstein-Barr virus (EBV) mutant causes B-cell lymphomas with delayed onset in a cord blood-humanized mouse model

et al. 2018

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EBV causes human B-cell lymphomas and transforms B cells in vitro. EBNA3C, an EBV protein expressed in latently-infected cells, is required for EBV transformation of B cells in vitro. While EBNA3C undoubtedly plays a key role in allowing EBV to successfully infect B cells, many EBV+ lymphomas do not express this protein, suggesting that cellular mutations and/or signaling pathways may obviate the need for EBNA3C in vivo under certain conditions. EBNA3C collaborates with EBNA3A to repress expression of the CDKN2A-encoded tumor suppressors, p16 and p14, and EBNA3C-deleted EBV transforms B cells containing a p16 germline mutation in vitro. Here we have examined the phenotype of an EBNAC-deleted virus (Δ3C EBV) in a cord blood-humanized mouse model (CBH). We found that the Δ3C virus induced fewer lymphomas (occurring with a delayed onset) in comparison to the wild-type (WT) control virus, although a subset (10/26) of Δ3C-infected CBH mice eventually developed invasive diffuse large B cell lymphomas with type III latency. Both WT and Δ3C viruses induced B-cell lymphomas with restricted B-cell populations and heterogeneous T-cell infiltration. In comparison to WT-infected tumors, Δ3C-infected tumors had greatly increased p16 levels, and RNA-seq analysis revealed a decrease in E2F target gene expression. However, we found that Δ3C-infected tumors expressed c-Myc and cyclin E at similar levels compared to WT-infected tumors, allowing cells to at least partially bypass p16-mediated cell cycle inhibition. The anti-apoptotic proteins, BCL2 and IRF4, were expressed in Δ3C-infected tumors, likely helping cells avoid c-Myc-induced apoptosis. Unexpectedly, Δ3C-infected tumors had increased T-cell infiltration, increased expression of T-cell chemokines (CCL5, CCL20 and CCL22) and enhanced type I interferon response in comparison to WT tumors. Together, these results reveal that EBNA3C contributes to, but is not essential for, EBV-induced lymphomagenesis in CBH mice, and suggest potentially important immunologic roles of EBNA3C in vivo.

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Section: Resultsmentioning

confidence: 99%

An EBNA3C-deleted Epstein-Barr virus (EBV) mutant causes B-cell lymphomas with delayed onset in a cord blood-humanized mouse model

et al. 2018

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“…Cyclin D3 gene is amplified in bladder carcinoma in situ [ 3 ]. Genomic changes disrupting the expression of Cyclin D3 are associated with aberrant growth of several human B-lymphoid malignancies [ 4 ]. Targeting Cyclin D3 by miR-138 could induce cell cycle arrest in hepatocellular carcinoma [ 5 ].…”

Section: Introductionmentioning

confidence: 99%

Cyclin D3 predicts disease-free survival in breast cancer

et al. 2015

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BackgroundCyclin D3, which induces progression through the G1 phase of the cell cycle, is a regulator of Cyclin-dependent kinases 4 and 6. Previous studies revealed that abnormal expression of Cyclin D3 was found in many different cancers. However, the role of Cyclin D3 in breast cancer (BC) remains unknown. The aim of this study is to examine the expression pattern of Cyclin D3 in BC and to evaluate its biological role and clinical significance in prognosis prediction. The mechanism involved is also evaluated.MethodsImmunohistochemical staining was used to detect the expression of Cyclin D3. qRT-PCR was used to detect the mRNA level of Cyclin D3 in BC tissues and BC cell lines. Transwell assay was used to examine the role of Cyclin D3 in the migration and invasion of BC cells. Mass Spectrometry was used to search for the interacting protein with Cyclin D3. Co-Immunoprecipitation assay and GST-Pull Down assay were used to validate the interaction of Cyclin D3 and its interaction protein.ResultsThrough detecting Cyclin D3 expression in 243 breast cancer patients’ tissue array, we found Cyclin D3 expression was correlated with ER status (p = 0.000), PR status (p = 0.001), HER2 status (p = 0.002) and tumor differentiation (p = 0.045). The Kaplan–Meier survival curves indicated that the disease free survival (DFS) was significantly poor in high Cyclin D3 expression BC patients (p = 0.004). Furthermore, expression of Cyclin D3 was significantly associated with BC prognosis and was shown to be an independent prognostic marker in breast cancer (p = 0.028). By IHC staining and qPCR detection, Cyclin D3 expression was found to be down-regulated both in BC tissues and in BC cell lines compared with the corresponding normal controls. Further investigation showed Cyclin D3 was involved in the metastasis of BC cells and physically interacted with actin in vivo and in vitro.ConclusionOur studies revealed that Cyclin D3 was upregulated in breast cancer and represented a novel predictor of BC prognosis.Electronic supplementary materialThe online version of this article (doi:10.1186/s12935-015-0245-6) contains supplementary material, which is available to authorized users.

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“…Actually, a previous study on B-cell lymphoma has already indirectly suggested the possible existence of cyclin-independent functions of CDK4. 56,57 Warenius et al have also reported that the hexapeptide (PRGPRP) at the 251-256th AA has killing effects on cancer cells. 58 Probably the growth arrest and apoptotic effects of the ΔE2 and the wt may be attributed to this C-terminal region.…”

Section: Cdk4 May Have Functions Independent Of Binding To Ccnd and Rbmentioning

confidence: 99%

Cyclin-dependent kinase 4 may be expressed as multiple proteins and have functions that are independent of binding to CCND and RB and occur at the S and G₂/M phases of the cell cycle

et al. 2013

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Cyclin D3 is dispensable for human diffuse large B-cell lymphoma survival and growth: evidence for redundancy with cyclin E

Cited by 10 publications

References 33 publications

An EBNA3C-deleted Epstein-Barr virus (EBV) mutant causes B-cell lymphomas with delayed onset in a cord blood-humanized mouse model

An EBNA3C-deleted Epstein-Barr virus (EBV) mutant causes B-cell lymphomas with delayed onset in a cord blood-humanized mouse model

Cyclin D3 predicts disease-free survival in breast cancer

Cyclin-dependent kinase 4 may be expressed as multiple proteins and have functions that are independent of binding to CCND and RB and occur at the S and G₂/M phases of the cell cycle

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Cyclin D3 is dispensable for human diffuse large B-cell lymphoma survival and growth: evidence for redundancy with cyclin E

Cited by 10 publications

References 33 publications

An EBNA3C-deleted Epstein-Barr virus (EBV) mutant causes B-cell lymphomas with delayed onset in a cord blood-humanized mouse model

An EBNA3C-deleted Epstein-Barr virus (EBV) mutant causes B-cell lymphomas with delayed onset in a cord blood-humanized mouse model

Cyclin D3 predicts disease-free survival in breast cancer

Cyclin-dependent kinase 4 may be expressed as multiple proteins and have functions that are independent of binding to CCND and RB and occur at the S and G2/M phases of the cell cycle

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Cyclin-dependent kinase 4 may be expressed as multiple proteins and have functions that are independent of binding to CCND and RB and occur at the S and G₂/M phases of the cell cycle