Expression of D-type cyclins in colon cancer and in cell lines from colon carcinomas

Mermelshtein, A; Gerson, Ariela; Walfisch, Shlomo; Delgado, Bertha; Shechter-Maor, G; Delgado, Jorge; Fich, Alexander; Gheber, Larisa

doi:10.1038/sj.bjc.6602709

Cited by 93 publications

(80 citation statements)

References 38 publications

(57 reference statements)

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“…A previous study has shown that overexpression of cyclin D2 in gastric cancer correlates with disease progression and poor prognosis. 17 In this study, we showed that one common polymorphism in 5¢-UTR (rs1049606) and CCND2-ht1 [T-C-T-A-T] were associated with HBV clearance. Although it was difficult to determine as to which polymorphism is causal, the association signal of ht1 [T-C-T-A-T] was equivalent to the effect of rs1049606 as 490% of ht1 [T-C-T-A-T] were tagged by rs1049606 (Figure 1b).…”

Section: ) the Ht1 [T-c-t-a-t]mentioning

confidence: 70%

CCND2 polymorphisms associated with clearance of HBV Infection

et al. 2010

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Cyclin D2s (CCND2s) are members of the D-type cyclin family. They interact and construct complexes with cyclin-dependent kinase (CDK)4 or 6. The cyclin D2/CDK4 or CDK6 complexes have key roles in controlling the progression of cell cycle from the Gap 1 (G1) phase to the synthesis (S) phase. Overexpression of cyclin D2 is associated with the development of tumors. In this study, we identified 16 sequence variants of CCND2 polymorphisms through direct DNA sequencing in 24 individuals, and 5 common variants were selected for genotyping in larger-scale subjects (n¼1100). Genetic associations of those polymorphisms with hepatitis B virus (HBV) clearance and hepatocellular carcinoma (HCC) outcome among patients with HBV were analyzed. Although no significant association was observed between the polymorphisms and HCC outcome among HBV patients, one common polymorphism in the 5¢-untranslated region (that is, rs1049606) and the most common haplotype (CCND-ht1 [T-C-T-A-T]), however, were significantly associated with HBV clearance (odds ratio¼0.69, P¼0.0002, P corr ¼0.001 and odds ratio¼1.37, P¼0.0009, P corr ¼0.004, respectively). The minor allele frequency of rs1049606 among the spontaneously recovered (SR) group was significantly higher than that of the chronic carrier (CC) group (frequency¼0.403 vs 0.336, P¼0.0002). In contrast, the frequency of CCND-ht1was higher among the CC group than among the SR group (frequency¼0.429 vs 0.374, P¼0.0009). The information identified in this study might provide valuable insights into generating strategies for control of HBV.

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Section: ) the Ht1 [T-c-t-a-t]mentioning

confidence: 70%

CCND2 polymorphisms associated with clearance of HBV Infection

et al. 2010

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“…It could be shown that Cyclin D2 along with other Cyclins (D1, D3) is overexpressed in colon tumors and colon cancer cells like HT29 cells (Mermelshtein et al 2005). Cole et al (2010) could demonstrate that Cyclin D2 expression is up-regulated immediately after APC loss.…”

Section: Discussionmentioning

confidence: 99%

Influence of miRNA-106b and miRNA-135a on butyrate-regulated expression of p21 and Cyclin D2 in human colon adenoma cells

et al. 2015

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Epigenetic and posttranslational modifications of the expression of cell cycle-relevant genes or proteins like p21, e.g., by miRNAs are crucial mechanisms in the development or prevention of colon cancer. The present study investigated the influence of butyrate and trichostatin A (TSA) as histone deacetylase inhibitors on the expression of colon cancer-relevant miRNA (miR-135a, miR-135b, miR-24, miR-106b, miR-let-7a) in LT97 colon adenoma cells as a model of an early stage of colon carcinogenesis. The impact of distinct miRNAs (miR-106b, miR-135a) on butyrate-mediated regulation of p21 and Cyclin D2 gene and protein expression as well as the effect on LT97 cell proliferation (non-transfected, miR-106b and miR-135a mimic transfected) was analyzed. Butyrate and partial TSA reduced the expression of miR-135a, miR-135b, miR-24 and miR-let-7a (*0.5-fold, 24 h) and miR-24, miR-106b and miR-let-7a (*0.5-0.7-fold, 48 h) in LT97 cells. Levels of p21 mRNA and protein were significantly increased by butyrate and TSA (*threefold and 4.5-fold, respectively, 24 h) in non-transfected but not in miR-106b transfected LT97 cells. Levels of Cyclin D2 mRNA were significantly reduced by butyrate and TSA (*0.3-fold, 24 h) in non-transfected and miR-135a-transfected LT97 cells, whereas protein levels were predominantly not influenced. MiR-106b and miR-135a significantly reduced butyrate-/TSA-mediated inhibition of LT97 cell proliferation (72 h). These results indicate that butyrate is able to modify colon cancer-relevant miRNAs like miR-106b and miR-135a which are involved in the regulation of cell cycle-relevant genes like p21 and might influence inhibition of adenoma cell proliferation.

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“…Elevated CCND2 levels are observed in various cancers and are implicated in cell proliferation. 38,39 It was interesting to notice that miR-1 and -206 can also regulate CCND2 transcript and protein levels. Overexpression of miR-1 showed strong promyogenic effect in RMS cells and downregulated expression of CCND2 transcript levels.…”

Section: Discussionmentioning

confidence: 99%

Downregulation of microRNAs miR-1, -206 and -29 stabilizes PAX3 and CCND2 expression in rhabdomyosarcoma

Sarver

Alamgir

et al. 2012

Laboratory Investigation

101

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Elevated levels of PAX3 and cell proliferation genes are characteristic features of rhabdomyosarcoma (RMS). We hypothesize that the increased levels of these genes are stabilized due to downregulation of specific miRNAs. In this study, we show that downregulation of miR-1, -206 and -29 stabilizes the expression of PAX3 and CCND2 in both embryonal (ERMS) and alveolar (ARMS) RMS types. Ectopic expression of miR-1 and 206 in JR1, an ERMS cell line, show significant downregulation of PAX3 protein expression, whereas overexpression of these miRNAs in Rh30, an ARMS cell line, did not show any effect in PAX3 protein levels. In ARMS, PAX3 forms a fusion transcript with FOXO1 and the resultant loss of PAX3 3 0 UTR in the fusion transcript indicate an oncogenic mechanism to evade miRNA-mediated regulation of PAX3. Further, we show that miR-1, -206 and -29 can regulate the expression of CCND2, a cell cycle gene. In addition to CCND2, miR-29 also targets E2F7, another cell cycle regulator. Cell function analysis shows that overexpression of miR-29 downregulates the expression of these cell cycle genes, induces partial G1 arrest leading to decreased cell proliferation. Taken together our data suggest that the RMS state is stabilized by the deregulation of multiple miRNAs and their target genes, supporting a tumor suppressor role for these miRNA. KEYWORDS: cell cycle genes; miRNAs; PAX3; regulatory networks; rhabdomyosarcoma Rhabdomyosarcoma (RMS) is a malignant striated muscle tumor that accounts for B3% of all childhood cancers. 1 RMS arises from primitive muscle cells and tumors show varying degrees of skeletal muscle differentiation that serves to define their classification as either embryonal (ERMS) or alveolar (ARMS) types. 2,3 ERMS, the most common type has features of embryonic muscle and are generally associated with favorable prognosis. In contrast, ARMS display poor muscle differentiation and are associated with poor outcomes. 4 Most ARMS cases are characterized by chromosomal translocation t(2;13) or t(1;13) involving genes PAX3-FKHR or PAX7-FKHR, respectively. 5 Regulatory disruptions in growth and differentiation pathways of myogenic precursor cells have been implicated in RMS development. Genes involved with muscle cell differentiation and cell proliferation have been associated with RMS development and metastasis. 6-11 Gene expression profiles comparing PAX-FOXO1-positive ARMS vs translocation-negative ERMS have identified genes relevant to tumorigenic process of ARMS and ERMS. 12 microRNAs (miRNAs) have been implicated in RMS. [13][14][15] miRNAs are small (18-22 nucleotides) evolutionarily conserved, non-coding RNAs that post-transcriptionally regulate gene expression through mRNA degradation, translation inhibition or chromatin-based silencing mechanisms. 16 Each miRNA can potentially regulate hundreds of targets either directly or indirectly. miRNAs have been shown to be deregulated in many types of cancers. 17 As a consequence, miRNAs from tumor tissue have been proposed for use in the diagnosis, classif...

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Expression of D-type cyclins in colon cancer and in cell lines from colon carcinomas

Cited by 93 publications

References 38 publications

CCND2 polymorphisms associated with clearance of HBV Infection

CCND2 polymorphisms associated with clearance of HBV Infection

Influence of miRNA-106b and miRNA-135a on butyrate-regulated expression of p21 and Cyclin D2 in human colon adenoma cells

Downregulation of microRNAs miR-1, -206 and -29 stabilizes PAX3 and CCND2 expression in rhabdomyosarcoma

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