P53 mutation is a rare event in Merkel cell carcinoma of the head and neck

Lill, Claudia; Schneider, Sven; Item, Chike B.; Loewe, Robert; Houben, Roland; Halbauer, Daniel; Heiduschka, Gregor; Brunner, Markus; Thurnher, Dietmar

doi:10.1007/s00405-011-1529-7

Cited by 15 publications

(13 citation statements)

References 31 publications

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“…We found that RFS was significantly longer in patients with HCC wild-type TP53 with PIN1 expression. Similar to our result, Lill et al have demonstrated that high expression of PIN1 is a good prognostic factor in patients with Merkel cell carcinoma, which shows infrequent TP53 mutation (22,28). Girardini et al have reported that OS is significantly decreased in patients with breast cancer expressing high levels of PIN1 and mutant TP53 compared to that of patients with low PIN1 expression and mutant or wild-type TP53 (14).…”

Section: Discussionsupporting

confidence: 91%

PIN1 in hepatocellular carcinoma is associated with TP53 gene status

et al. 2016

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Phosphorylation of proteins on serine/threonine residues that precede proline (pSer/Thr-Pro) is specifically catalyzed by the peptidyl-prolyl cis-trans isomerase PIN1. PIN1-mediated prolyl-isomerization induces cell cycle arrest and growth inhibition through the regulation of target proteins, including TP53. We examined whether PIN1 acts in a different manner according to TP53 gene status in hepatocellular carcinoma (HCC). We investigated the expression of PIN1 and TP53 proteins in 119 HCC tissue samples. We also analyzed PIN1 expression in combination with TP53 gene mutation and its correlation with the clinical outcome. In addition, we used synthetic small interfering RNA to silence PIN1 gene expression in TP53 wild-type and TP53 mutant HCC cell lines, and then evaluated cell proliferation, migration and invasion. Expression of PIN1 was strongly associated with expression of TP53 protein or TP53 mutation of HCC samples. PIN1 and TP53 expression in TP53 mutant HCC cell lines was higher than that in TP53 wild-type HCC cell lines. Silencing of PIN1 in HLE cells containing mutant TP53 significantly decreased cell proliferation, migration and invasion. In contrast to PIN1 silencing in HLE cells, PIN1 silencing in HepG2 cells containing functional wild-type TP53 resulted in enhanced tumor cell proliferation. HCC patients bearing PIN1 expression with wild-type TP53 were predicted to demonstrate favorable relapse-free survival. Our results suggest that PIN1 plays a role in cancer cell proliferation, migration and invasion in a different manner according to the TP53 gene mutation status in HCC. In particular, interaction of PIN1 with mutant TP53 can act as a tumor promoter and increase its oncogenic activities in HCC.

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Section: Discussionsupporting

confidence: 91%

PIN1 in hepatocellular carcinoma is associated with TP53 gene status

et al. 2016

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“…Notably, the MKL1 cell line had been reported to express wildtype p53 transcript (39). Other studies have reported infrequent p53 mutations (24,40,41). A pre vious study found p53 mutations in 11 of 23 MCC tumors that had no detectable large T antigen expression by immunohistochemistry using CM2B4 antibody and absence of p53 mutations in 16 large T antigen-positive MCC tumors (42).…”

Section: Discussionmentioning

confidence: 95%

“…To date, few mutations in known oncogenes or tumor suppressors have been reported in MCC. Inactivating muta tions in the p53 tumor suppressor gene (TP53) have been reported to occur rarely in MCC (23,24). In addition, activating mutations in PIK3CA have also been reported in a few MCC tumors (25,26).…”

Section: Introductionmentioning

confidence: 99%

Improved detection suggests all Merkel cell carcinomas harbor Merkel polyomavirus

Rodig¹,

Cheng²,

Wardzala³

et al. 2012

J. Clin. Invest.

196

176

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“…These results indicate that the MCC-specific truncations of MCPyV large T antigen do not result in loss of p53 binding activity. It should be noted that most MCC tumors contain wild-type p53, although it is not known if p53 function is perturbed in MCC containing wild-type p53 (5,43,44). Although MCPyV T antigens do not bind to p53, they may serve to indirectly inactivate p53 function.…”

Section: Discussionmentioning

confidence: 99%

Merkel Cell Polyomavirus Large T Antigen Has Growth-Promoting and Inhibitory Activities

Cheng

Rozenblatt-Rosen

Paulson

et al. 2013

J Virol

109

145

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cMerkel cell carcinoma (MCC) is a rare and aggressive form of skin cancer. In at least 80% of all MCC, Merkel cell polyomavirus (MCPyV) DNA has undergone clonal integration into the host cell genome, and most tumors express the MCPyV large and small T antigens. In all cases of MCC reported to date, the integrated MCPyV genome has undergone mutations in the large T antigen. These mutations result in expression of a truncated large T antigen that retains the Rb binding or LXCXE motif but deletes the DNA binding and helicase domains. However, the transforming functions of full-length and truncated MCPyV large T antigen are unknown. We compared the transforming activities of full-length, truncated, and alternatively spliced 57kT forms of MCPyV large T antigen. MCPyV large T antigen could bind to Rb but was unable to bind to p53. Furthermore, MCPyV-truncated large T antigen was more effective than full-length and 57kT large T antigen in promoting the growth of human and mouse fibroblasts. In contrast, expression of the MCPyV large T antigen C-terminal 100 residues could inhibit the growth of several different cell types. These data imply that the deletion of the C terminus of MCPyV large T antigen found in MCC serves not only to disrupt viral replication but also results in the loss of a distinct growth-inhibitory function intrinsic to this region. Merkel cell carcinoma (MCC) is an aggressive skin cancer with an annual incidence of 3 per million in the United States (1). Risk factors for developing MCC include advanced age, prolonged UV exposure, and immunosuppression due to HIV, hematologic malignancy, or solid-organ transplantation (2, 3). Recently, Merkel cell polyomavirus (MCPyV) was discovered to be clonally integrated in at least 80% of MCC, raising the possibility that this pathogen contributes to carcinogenesis (4, 5).MCPyV is a typical polyomavirus with a circular, doublestranded DNA genome containing an early region that expresses large and small T antigens, a late region that encodes 3 viral coat proteins, VP1, VP2, and VP3, and a regulatory region that contains the origin of replication and a bidirectional promoter for the early and late genes. MCPyV was the fifth polyomavirus identified in humans, preceded by BKPyV, JCPyV, KIPyV, and WUPyV (6-9). Since then, 6 additional human polyomaviruses have been discovered, including HPyV6, HPyV7, TSPyV, HPyV9, MWPyV, and STLPyV (10-15). Although JCPyV and BKPyV have been detected in a variety of human cancers (16, 17), Merkel cell polyomavirus is the only polyomavirus DNA clonally integrated in human cancer. Expression of Merkel large and small T antigens can be detected in most MCC specimens (5, 18, 19).The T antigens from several polyomaviruses have oncogenic activity. Notably, the simian virus 40 (SV40) large and small T antigens can transform a variety of rodent and human cells. Expression of SV40 large and small T antigens, together with human telomerase reverse transcriptase and an oncogenic form of H-RAS, can fully transform normal human fibroblasts (20,21)...

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P53 mutation is a rare event in Merkel cell carcinoma of the head and neck

Cited by 15 publications

References 31 publications

PIN1 in hepatocellular carcinoma is associated with TP53 gene status

PIN1 in hepatocellular carcinoma is associated with TP53 gene status

Improved detection suggests all Merkel cell carcinomas harbor Merkel polyomavirus

Merkel Cell Polyomavirus Large T Antigen Has Growth-Promoting and Inhibitory Activities

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