Inactivation of the p14ARF, p15INK4B and p16INK4A genes is a frequent event in human oral squamous cell carcinomas

Shintani, Satoru; Nakahara, Yuuji; Mihara, Mariko; Ueyama, Yoshiya; Matsumura, Tomohiro

doi:10.1016/s1368-8375(00)00142-1

Cited by 100 publications

(70 citation statements)

References 13 publications

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“…26 In oral tumors, the promoters of several tumorsuppressor genes, such as p16, p15, p14 and E-cadherin, are highly methylated in addition to a rare gene mutation in human OSCCs. 23,27,28 In the present study, we found an association between methylation and suppression of ATP2A2 gene expression in tumor tissues and OSCC-derived cell lines. Treatment of OSCC-derived cell lines showing ATP2A2 methylation with a demethylating agent was effective for restoration or significant upregulation of ATP2A2 protein expression.…”

Section: Discussionsupporting

confidence: 65%

Sarcoendoplasmic reticulum Ca²⁺ ATPase type 2 downregulated in human oral squamous cell carcinoma

Endo

Uzawa

Mochida

et al. 2004

Intl Journal of Cancer

104

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Mice with a heterozygous deletion of the Atp2a2 gene (Atp2a2 ؉/-) encoding SERCA2 spontaneously develop SCCs of the skin and upper digestive tract, including the oral cavity. To elucidate the contribution of ATP2A2 to human oral carcinogenesis, we analyzed genetic and epigenetic changes as well as mRNA and protein expression in primary OSCCs and OPLs. With the exception of one OSCC-derived cell line showing a 12 bp deletion of ATP2A2, we found no mutations in the coding sequence of the gene in primary OSCCs (n ‫؍‬ 52), OPLs (n ‫؍‬ 32) and cell lines (n ‫؍‬ 8). In immunohistochemistry, however, high frequencies of ATP2A2 downregulation were evident not only in primary OSCCs (42%, 42/100) but also in OPLs (31%, 10/32). Real-time quantitative RT-PCR data were consistent with the protein expression status. Aberrant DNA methylation within ATP2A2 also was detected in 9 of 30 ATP2A2-downregulated OSCCs. Moreover, restoration or elevated expression of the ATP2A2 protein was induced in most of the cell lines showing ATP2A2 methylation after treatment with 5-aza-2 -dC, a DNA demethylating agent. These results suggest that inactivation of the ATP2A2 gene is a frequent and early event during oral carcinogenesis and that loss of expression may be regulated partly by an epigenetic mechanism.

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Section: Discussionsupporting

confidence: 65%

Sarcoendoplasmic reticulum Ca²⁺ ATPase type 2 downregulated in human oral squamous cell carcinoma

Endo

Uzawa

Mochida

et al. 2004

Intl Journal of Cancer

104

View full text Add to dashboard Cite

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“…In this context, with accumulating knowledge of the mechanisms of inactivation of tumour-suppressor genes, abnormal methylation at the promoters of tumour-suppressor genes is another mechanism that suppresses gene activity (Jones and Laird, 1999). In oral tumours, the promoters of several tumoursuppressor genes, that is, p16, p15, p14, and E-cadherin, are highly methylated in addition to a rare gene mutation in human OSCCs (Saito et al, 1998;Miracca et al, 1999;Shintani et al, 2001). In the present study, we found an association between methylation and suppression of CKMT1 gene expression in OSCC-derived cell lines.…”

Section: Discussionmentioning

confidence: 99%

Ubiquitous mitochondrial creatine kinase downregulated in oral squamous cell carcinoma

et al. 2006

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In this study, we performed two-dimensional electrophoresis (2-DE) and matrix-assisted laser desorption/ionisation time of fly mass spectrometry to identify the protein(s) associated with the development of oral squamous cell carcinomas (OSCCs) by comparing patterns of OSCC-derived cell lines with normal oral keratinocytes (NOKs), and found that downregulation of ubiquitous mitochondrial creatine kinase (CKMT1) could be a good candidate. Decreased levels of CKMT1 mRNA and protein were detected in all OSCC-derived cell lines examined (n ¼ 9) when compared to those in primary normal oral keratinocytes. Although no sequence variation in the coding region of the CKMT1 gene with the exception of a nonsense mutation in exon 8 was identified in these cell lines, we found a frequent hypermethylation in the CpG island region. CKMT1 expression was restored by experimental demethylation. In addition, when we transfected CKMT1 into the cell lines, they showed an apoptotic phenotype but no invasiveness. In clinical samples, high frequencies of CKMT1 downregulation were detected by immunohistochemistry (19 of 52 (37%)) and quantitative real-time RT -PCR (21 of 50 (42%)). Furthermore, the CKMT1 expression status was significantly correlated with tumour differentiation (Po0.0001). These results suggest that the CKMT1 gene is frequently inactivated during oral carcinogenesis and that an epigenetic mechanism may regulate loss of expression, which may lead to block apoptosis.

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“…However, mounting evidence accumulated recently reveals an important function of p14 ARF in blocking tumorigenesis in humans. By assaying deletion of the exon 1b (specific for p14 ARF ) or methylation of p14 ARF promoter, inactivation of p14 ARF has been detected in 33% of colon carcinomas (Burri et al, 2001), 25% of oligodendrogliomas (Watanabe et al, 2001), 14% of breast cancers (Ho et al, 2001), 26.5% of oral squamous cell carcinomas and 32-58% of gliomas (Ichimura et al, 2000;Shintani et al, 2001). Mechanistically, p14 ARF bridges the RB and p53 tumor suppressors .…”

Section: Discussionmentioning

confidence: 99%

ATM activity contributes to the tumor-suppressing functions of p14ARF

Chen

et al. 2004

Oncogene

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P14/p19 ARF (ARF) plays a major role in the activation of p53 by oncogenic signals. The biochemical basis of this has not been fully elucidated. We report here that forced expression of p14 ARF enhances phosphorylation of p53 serine 15 (p53S15) in NIH3T3, IMR90 and MCF7 cells. Ectopic expression of the oncogenes c-myc, E2F1 and E1A, all of which activate p53 at least partially via ARF, lead to p53S15 phosphorylation in IMR90 cells. In addition, ectopic expression of p53 also results in p53S15 phosphorylation, suggesting that this is a common event in the ARFp53 tumor suppression system. Furthermore, p53-, p14 ARF -, c-myc-and E2F1-, but not E1A-, induced p53S15 phosphorylation was substantially reduced in AT fibroblasts (GM05823). Downregulation of ATM in MCF7 cells using RNA interference (RNAi) technology significantly attenuated p14 ARF -and p53-induced phosphorylation of p53S15. Ectopically expressed ARF in NIH3T3 cells induced ATM nuclear foci and activated ATM kinase. Functionally, ectopic expression of p14 ARF and c-myc inhibited the proliferation of IMR90 but not ATM null GM05823 cells, and p14 ARF -induced inhibition of MCF7 cell proliferation was significantly attenuated by downregulation of ATM by RNAi. Taken together, these data show a functional role for ATM in ARF-mediated tumor suppression.

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Inactivation of the p14ARF, p15INK4B and p16INK4A genes is a frequent event in human oral squamous cell carcinomas

Cited by 100 publications

References 13 publications

Sarcoendoplasmic reticulum Ca²⁺ ATPase type 2 downregulated in human oral squamous cell carcinoma

Sarcoendoplasmic reticulum Ca²⁺ ATPase type 2 downregulated in human oral squamous cell carcinoma

Ubiquitous mitochondrial creatine kinase downregulated in oral squamous cell carcinoma

ATM activity contributes to the tumor-suppressing functions of p14ARF

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Inactivation of the p14ARF, p15INK4B and p16INK4A genes is a frequent event in human oral squamous cell carcinomas

Cited by 100 publications

References 13 publications

Sarcoendoplasmic reticulum Ca2+ ATPase type 2 downregulated in human oral squamous cell carcinoma

Sarcoendoplasmic reticulum Ca2+ ATPase type 2 downregulated in human oral squamous cell carcinoma

Ubiquitous mitochondrial creatine kinase downregulated in oral squamous cell carcinoma

ATM activity contributes to the tumor-suppressing functions of p14ARF

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Product

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Sarcoendoplasmic reticulum Ca²⁺ ATPase type 2 downregulated in human oral squamous cell carcinoma

Sarcoendoplasmic reticulum Ca²⁺ ATPase type 2 downregulated in human oral squamous cell carcinoma