DARPP-32 expression arises after a phase of dysplasia in oesophageal squamous cell carcinoma

Ebihara, Yuma; Miyamoto, Masaki; Fukunaga, Akira; Kato, Kentaro; Shichinohe, Toshiaki; Kawarada, Yo; Kurokáwa, Tomonori; Cho, Y; Murakami, Soichi; Uehara, Hirofumi; Kaneko, Hiroyuki; Hashimoto, Hiroyuki; Murakami, Yoshihiro; Itoh, Tomoo; Okushiba, Shunichi; Kondo, Satoshi; Katoh, Hiroyuki

doi:10.1038/sj.bjc.6601899

Cited by 30 publications

(32 citation statements)

References 21 publications

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“…We have observed a similar trend for Darpp-32 and t-Darpp overexpression in a small number of common adenocarcinomas, including breast, colon, lung, and prostate (8). However, a recent study has shown that esophageal squamous cell carcinomas frequently overexpress Darpp-32 but not t-Darpp (9). In a related study, amplification and overexpression of ERBB2, which coincides at the same locus as DARPP-32 (17q12q21), was found in f10% of both diffuse-type and intestinal-type gastric cancers (31).…”

Section: Discussionsupporting

confidence: 73%

“…We have recently cloned DARPP-32 (AF464196) and its novel truncated isoform t-DARPP (AY070271) from adenocarcinoma of the stomach with 17q amplicon (6,7). In addition, we and others have recently documented the overexpression of Darpp-32 in a variety of common adenocarcinomas, such as those of the colon, esophagus, breast, and prostate (8,9).…”

Section: Introductionmentioning

confidence: 73%

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Darpp-32: a Novel Antiapoptotic Gene in Upper Gastrointestinal Carcinomas

Belkhiri¹,

Zaika²,

Pidkovka³

et al. 2005

Cancer Research

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We show the molecular mechanisms involved in Darpp-32 overexpression and its biological role in upper gastrointestinal adenocarcinomas (UGC). A tumor tissue array of 377 samples was developed and used to detect DARPP-32 DNA amplification and protein overexpression, which occurred in 32% and 60% of UGCs, respectively. Concomitant overexpression of mRNA for Darpp-32 and its truncated isoform t-Darpp was observed in 68% of tumors (P < 0.001). When Darpp-32 and t-Darpp were overexpressed in AGS and RKO gastrointestinal cells, up to a 4-fold reduction in the apoptosis rate was observed (terminal deoxynucleotidyl transferase-mediated nick-end labeling and Annexin V assays) in response to camptothecin, sodium butyrate, and ceramide. However, the introduction of mutations in phosphorylation sites abrogated this effect. Expression of Darpp-32 and t-Darpp preserved the mitochondrial transmembrane potential and was associated with increased levels of Bcl2 protein. A reversal of Bcl2 protein level was obtained using small interfering RNAs for Darpp-32 and t-Darpp. Luciferase assays using the p53 and p21 reporter plasmids and probing of immunoblots with antibodies specific for p53 transcriptional targets, such as Hdm2 and p21, indicated that neither Darpp-32 nor t-Darpp interfere with p53 function. Altogether, we show more frequent mRNA and protein overexpression of Darpp-32 than DNA amplification, suggesting that, in addition to amplification, transcriptional or posttranscriptional mechanisms may play an important role. The expression of Darpp-32 and t-Darpp is associated with a potent antiapoptotic advantage for cancer cells through a p53-independent mechanism that involves preservation of mitochondrial potential and increased Bcl2 levels. (Cancer Res 2005; 65(15): 6583-92)

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Section: Discussionsupporting

confidence: 73%

Section: Introductionmentioning

confidence: 73%

Darpp-32: a Novel Antiapoptotic Gene in Upper Gastrointestinal Carcinomas

Belkhiri¹,

Zaika²,

Pidkovka³

et al. 2005

Cancer Research

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“…We previously identified PPP1R1B/DARPP-32 as a cancer gene (29). PPP1R1B/DARPP-32 is now known to be overexpressed in several tumors, such as adenocarcinomas of the breast, colon, esophagus, and stomach (33)(34)(35)(36). We recently showed that PPP1R1B/DARPP-32 is a novel cancer gene with a potent antiapoptotic potential that may contribute to the drug resistance and poor outcome phenotype in UGCs (37).…”

Section: Discussionmentioning

confidence: 99%

Molecular Dissection of 17q12 Amplicon in Upper Gastrointestinal Adenocarcinomas

Maqani

Belkhiri

Moskaluk

et al. 2006

Molecular Cancer Research

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DNA amplification at 17q is frequently detected in upper gastrointestinal adenocarcinomas (UGC; stomach and esophagus). In this study, we did fluorescence in situ hybridization on a tissue microarray that contained 304 UGCs and 89 normal stomach samples using a f168-kb BAC clone (CTD-2019C10) that maps to 17q12-q21.1. This 168-kb region contains the following genes: PPP1R1B/DARPP-32, STARD3, TCAP, PNMT, PERLD1, ERBB2, C17orf37, and GRB7 as well as the first two exons of ZNFN1A3. DNA amplification (z5 signals) was detected in 85 of 282 (30%) of UGCs, and high-level amplification (z10 signals) was seen in 28 of 282 (10%) of all tumors. Adenocarcinomas of gastroesophageal junction and lower esophagus had the highest frequency of amplification (45%) compared with stomach tumors (27%; P = 0.04). On the other hand, 38% of tumors with intestinal-type morphology had amplification compared with 26% of diffuse-type tumors (P = 0.02). We further did quantitative real-time reverse transcription-PCR on 74 frozen tissue samples from UGCs for 11 genes located within or adjacent to the boundaries of this f168-kb genomic region. These genes include all 9 genes that are fully or partially located inside the CTD-2019C10 clone as well as 2 additional adjacent genes (NEUROD and TOP2A). Overexpression of PPP1R1B/DARPP-32, TCAP, and TOP2A was seen in approximately half of the tumors, whereas STARD3 and ZNFN1A3 were rarely overexpressed (12%). Interestingly, there was a statistical correlation between expression of all 8 genes that map between PPP1R1B/DARPP-32 and GRB7, whereas expression of NEUROD, ZNFN1A3, and TOP2A that are partially inside or adjacent to the boundaries of the CTD-2019C10 clone did not correlate with the expression of any of these 8 genes. These data show a transcriptionally active oncogenomic region bounded by PPP1R1B/DARPP-32 and GRB7 in UGCs and provide further insight into expression levels of several critical genes. (Mol Cancer Res 2006;4(7):449 -55)

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“…We have identified a truncated isoform of Darpp-32, t-Darpp, as a novel gene that is expressed in cancer (8). t-Darpp is overexpressed in several common adenocarcinomas, such as those of the colon, esophagus, breast, and prostate (9)(10)(11)(12)(13)(14). We have reported that overexpression of t-Darpp provides antiapoptotic potential to cancer cells in a p53-independent mechanism (15).…”

Section: Introductionmentioning

confidence: 99%

t-Darpp Promotes Cancer Cell Survival by Up-regulation of Bcl2 through Akt-Dependent Mechanism

et al. 2008

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t-Darpp is a cancer-related truncated isoform of Darpp-32 (dopamine and cyclic-AMP-regulated phosphoprotein of M r 32,000). We detected overexpression of t-Darpp mRNA in two thirds of gastric cancers compared with normal samples (P = 0.004). Using 20 Mmol/L ceramide treatment as a model for induction of apoptosis in AGS cancer cells, we found that expression of t-Darpp led to an increase in Bcl2 protein levels and blocked the activation of caspase-3 and caspase-9. The MitoCapture mitochondrial apoptosis and cytochrome c release assays indicated that t-Darpp expression enforces the mitochondrial transmembrane potential and protects against ceramide-induced apoptosis. Interestingly, the expression of t-Darpp in AGS cells led to z2-fold increase in Akt kinase activity with an increase in protein levels of p-Ser 473 Akt and p-Ser 9 GSK3B. These findings were further confirmed using tetracycline-inducible AGS cells stably expressing t-Darpp. We also showed transcriptional up-regulation of Bcl2 using the luciferase assay with Bcl2 reporter containing P1 full promoter, quantitative reverse transcription-PCR, and t-Darpp small interfering RNA. The Bcl2 promoter contains binding sites for cyclic AMP-responsive element binding protein CREB/ATF1 transcription factors and using the electrophoretic mobility shift assay with a CREB response element, we detected a stronger binding in t-Darpp-expressing cells. The t-Darpp expression led to an increase in expression and phosphorylation of CREB and ATF-1 transcription factors that were required for up-regulating Bcl2 levels. Indeed, knockdown of Akt, CREB, or ATF1 in t-Darppexpressing cells reduced Bcl2 protein levels. In conclusion, the t-Darpp/Akt axis underscores a novel oncogenic potential of t-Darpp in gastric carcinogenesis and resistance to druginduced apoptosis. [Cancer Res 2008;68(2):395-403]

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DARPP-32 expression arises after a phase of dysplasia in oesophageal squamous cell carcinoma

Cited by 30 publications

References 21 publications

Darpp-32: a Novel Antiapoptotic Gene in Upper Gastrointestinal Carcinomas

Darpp-32: a Novel Antiapoptotic Gene in Upper Gastrointestinal Carcinomas

Molecular Dissection of 17q12 Amplicon in Upper Gastrointestinal Adenocarcinomas

t-Darpp Promotes Cancer Cell Survival by Up-regulation of Bcl2 through Akt-Dependent Mechanism

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