Cyclin D1 overexpression in hepatocellular carcinoma

Joo, Mee; Kang, Yun Kyung; Kim, Miran; Lee, Hye Kyung; Jang, Ja‐June

doi:10.1034/j.1600-0676.2001.021002089.x

Cited by 91 publications

(86 citation statements)

References 23 publications

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“…In addition, we show that loss of ELF results in cell-cycle deregulation, as evident by an increase in cyclin D1, Cdk4, c-Myc and MDM2 levels in elf þ /À HCC specimens. Increased expression of protein or mRNA levels of cyclin D1 and Cdks, c-Myc, and MDM2 in chronic hepatitis or HCCs has also been observed by several other groups (Ito et al, 1999;Joo et al, 2001;Sundarrajan et al, 2002;Ueta et al, 2002;Zhang et al, 2002;Masaki et al, 2003).…”

Section: Discussionmentioning

confidence: 55%

Disruption of transforming growth factor-β signaling through β-spectrin ELF leads to hepatocellular cancer through cyclin D1 activation

et al. 2007

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Transforming growth factor-b (TGF-b) signaling members, TGF-b receptor type II (TBRII), Smad2, Smad4 and Smad adaptor, embryonic liver fodrin (ELF), are prominent tumor suppressors in gastrointestinal cancers. Here, we show that 40% of elf þ /À mice spontaneously develop hepatocellular cancer (HCC) with markedly increased cyclin D1, cyclin-dependent kinase 4 (Cdk4), c-Myc and MDM2 expression. Reduced ELF but not TBRII, or Smad4 was observed in 8 of 9 human HCCs (Po0.017). ELF and TBRII are also markedly decreased in human HCC cell lines SNU-398 and SNU-475. Restoration of ELF and TBRII in SNU-398 cells markedly decreases cyclin D1 as well as hyperphosphorylated-retinoblastoma (hyperphosphorylated-pRb). Thus, we show that TGF-b signaling and Smad adaptor ELF suppress human hepatocarcinogenesis, potentially through cyclin D1 deregulation. Loss of ELF could serve as a primary event in progression toward a fully transformed phenotype and could hold promise for new therapeutic approaches in human HCCs.

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Section: Discussionmentioning

confidence: 55%

Disruption of transforming growth factor-β signaling through β-spectrin ELF leads to hepatocellular cancer through cyclin D1 activation

et al. 2007

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“…The tumor data are quite striking as mice injected with cells expressing the shRNA against PAK5 had no visible tumors in contrast to the control mice ( Figure 3D). Genetic evidence supports a role for Cyclin D1 and beta-catenin activation in HCC [21][22][23][24][25][26] , and our results indicated that silencing of PAK5 gene expression significantly decreased Cyclin D1 and beta-catenin mRNA and protein, although the exact mechanism requires further study. This result is consistent with the reduced tumorigenicity of HepG2 cells upon PAK5 gene silencing.…”

Section: Discussionmentioning

confidence: 67%

“…In addition, the fraction of cells in the S phase decreased upon PAK5 gene silencing. All PAK5 gene silencing suppresses hepatocellular cancer related gene expression Genes encoding Cyclin D1 and beta-catenin have been implicated in hepatocellular carcinoma [21][22][23][24][25][26] . To determine whether PAK5 gene silencing affects the expression of these genes, HepG2 cells were transfected with the Lv-PAK5-shRNAs or control Lv-scr-shRNA as before, and the expression of Cyclin D1 and beta-catenin were analyzed by qPCR and Western blotting.…”

Section: Effects Of Pak5 Gene Silencing On Cell Functionmentioning

confidence: 99%

P21-activated kinase 5 plays essential roles in the proliferation and tumorigenicity of human hepatocellular carcinoma

Fang¹,

Jiang

et al. 2013

Acta Pharmacol Sin

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Aim: To investigate the roles of P21-activated kinase 5 (PAK5) in proliferation and tumorigenicity of human hepatocellular carcinoma (HCC). Methods: HCC and matched paraneoplastictis tissue samples were obtained from 30 patients. Human HCC cell lines SMMC7721, HepG2, Hep3B, SK-HEP-1, Huh-7, and liver cell line HL-7702 were examined. The expression of PAK5 gene was studied using real-time qPCR and Western blotting. Cell proliferation was quantified with the MTT assay. Cell cycle was analyzed with flow cytometry. The tumorigenicity of Lv-shRNA-transfected HepG2 cells was evaluated in BALB/cA nude mice. Results: The mRNA level of PAK5 was significantly higher in 25 out of 30 HCC samples compared to the matched paraneoplastic tissues. The HCC cell lines showed varying expression of PAK5 protein, and the highest level was found in the HepG2 cells. PAK5 gene silencing in HepG2 cells markedly reduced the cell proliferation and colony formation, and induced cell cycle arrest in the G 1 phase. Furthermore, PAK5 gene silencing suppressed the tumor formation in nude mice, and significantly decreased the expression of HCCrelated genes Cyclin D1 and beta-catenin. Conclusion: PAK5 may play essential roles in the initiation and progression of human HCC. Thus, it may be an effective therapeutic target or perhaps serve as a clinical diagnostic or prognostic marker in human HCC.

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“…23 Loss of transforming growth factor beta signaling frequently occurs in HCCs, 24 suggesting that KLF6 inactivation or down-regulation could affect this pathway. Overexpression of cyclins has also been observed frequently in HCC cases, 25 and we recently demonstrated that KLF6 can bind and inactivate cyclin D1 and converge with the Rb pathway. 26 KLF6 may also up-regulate the insulin-like growth factor 1 receptor, 27 the loss of which could contribute to HCC.…”

Section: Discussionmentioning

confidence: 99%

Frequent inactivation of the tumor suppressor Kruppel-like factor 6 ( KLF6 ) in hepatocellular carcinoma

et al. 2004

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Hepatocellular carcinoma (HCC) is a leading cause of cancer death worldwide, reflecting incomplete characterization of underlying mechanisms and lack of early detection. Krüppel-like factor 6 (KLF6) is a ubiquitously expressed zinc finger transcription factor that is deregulated in multiple cancers through loss of heterozygosity (LOH) and/or inactivating somatic mutation. We analyzed the potential role of the KLF6 tumor suppressor gene in 41 patients who had HCC associated with hepatitis C virus (16 patients), hepatitis B virus (12 patients, one of whom was coinfected with hepatitis C virus), and other etiologies (14 patients) by determining the presence of LOH and mutations. Overall, LOH and/or mutations were present in 20 (49%) of 41 tumors. LOH of the KLF6 gene locus was present in 39% of primary HCCs, and the mutational frequency was 15%. LOH and/or mutations were distributed across all etiologies of HCC evaluated, including patients who did not have cirrhosis. Functionally, wild-type KLF6 decreased cellular proliferation of HepG2 cells, while patient-derived mutants did not. In conclusion, we propose that KLF6 is deregulated by loss and/or mutation in HCC, and its inactivation may contribute to pathogenesis in a significant number of these tumors.

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Cyclin D1 overexpression in hepatocellular carcinoma

Abstract: Our results suggest that cyclin D1 overexpression may be an early event in hepatocarcinogenesis and that it plays a role in tumor differentiation. In addition, cyclin D1 expression is not correlated with tumor cell proliferation in HCCs.

Cited by 91 publications

References 23 publications

Disruption of transforming growth factor-β signaling through β-spectrin ELF leads to hepatocellular cancer through cyclin D1 activation

Disruption of transforming growth factor-β signaling through β-spectrin ELF leads to hepatocellular cancer through cyclin D1 activation

P21-activated kinase 5 plays essential roles in the proliferation and tumorigenicity of human hepatocellular carcinoma

Frequent inactivation of the tumor suppressor Kruppel-like factor 6 ( KLF6 ) in hepatocellular carcinoma

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