Esophagin and proliferating cell nuclear antigen (PCNA) are biomarkers of human esophageal neoplastic progression

Kimos, Martha; Wang, Suna; Borkowski, Andrew; Yang, Guang; Yang, Chung S.; Perry, Kellie; Olaru, Andreea; Deacu, Elena; Sterian, Anca; Cottrell, John R.; Papadimitriou, J; Sisodia, Lopa; Selaru, Florin M.; Mori, Yuriko; Xu, Yan; Yin, Jing; Abraham, John M.; Meltzer, Stephen J.

doi:10.1002/ijc.20267

Cited by 75 publications

(37 citation statements)

References 8 publications

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“…Overexpression of PCNA, a biomarker for cell proliferation (Kimos et al 2004), was observed in 87.76% (43/49) of the tumor tissues compared with the adjacent…”

Section: Correlation Between Level Of Ezrin Protein and Cell Prolifermentioning

confidence: 99%

Altered Expression of Ezrin in Esophageal Squamous Cell Carcinoma

Zeng

et al. 2006

J Histochem Cytochem.

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Ezrin is a membrane-cytoskeletal linker belonging to the ezrin-radixin-moesin (ERM) family and has been suggested to be involved in tumorigenesis. In this study we investigated ezrin expression pattern in normal esophageal mucosa and esophageal squamous cell carcinoma (ESCC) and the correlation with clinical characteristics. Immunohistochemical staining showed a tendency for ezrin to translocate from membrane to cytoplasm in the progression from normal epithelium to invasive carcinoma of the esophagus. By Western blot, we found that ezrin expression was downregulated in 13 ESCC specimens and upregulated in 36 others. Moreover, quantitative real-time RT-PCR demonstrated that ezrin mRNA level in normal esophageal mucosa was 3.60 ± 3.60 times that in ESCC ( p<0.001). Proliferating cell nuclear antigen (PCNA) expression level was higher in ezrin downregulated group compared with that in ezrin upregulated group ( p<0.05). However, there was no significant association between ezrin expression and clinical characteristics. The results suggested that the localization of ezrin by immunohistochemistry may be useful in the diagnosis of ESCC, and ezrin may play a suppressive role in the tumorgenesis of ESCC.

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“…Overexpression of PCNA, a biomarker for cell proliferation (Kimos et al 2004), was observed in 87.76% (43/49) of the tumor tissues compared with the adjacent…”

Section: Correlation Between Level Of Ezrin Protein and Cell Prolifermentioning

confidence: 99%

Altered Expression of Ezrin in Esophageal Squamous Cell Carcinoma

Zeng

et al. 2006

J Histochem Cytochem.

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“…Expression levels of PCNA correlate positively with other pathological indices in prostate cancer (Mulligan et al, 1997) and can serve as an independent prognosis marker (Miyamoto et al, 2006). Overexpression of PCNA is also a reliable biomarker for other tumor types (Kimos et al, 2004;Cappello et al, 2006;Stuart-Harris et al, 2008). These findings suggest that PCNA could be a valuable target for cancer therapy.…”

Section: Introductionmentioning

confidence: 98%

“…PCNA gene deregulation and post-translational modulation are hallmarks of malignant cells. Tumor cells, regardless of their origins, express higher levels of PCNA (Celis and Olsen, 1994;Kallakury et al, 1999;Kimos et al, 2004;Malkas et al, 2006;Miyamoto et al, 2006;Naryzhny and Lee, 2007;Eltz et al, 2008;Naryzhny, 2008;Stuart-Harris et al, 2008;Zhong et al, 2008;Stoimenov and Helleday, 2009). Expression levels of PCNA correlate positively with other pathological indices in prostate cancer (Mulligan et al, 1997) and can serve as an independent prognosis marker (Miyamoto et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

Small-Molecule Targeting of Proliferating Cell Nuclear Antigen Chromatin Association Inhibits Tumor Cell Growth

Tan¹,

Wortman²,

Dillehay³

et al. 2012

Mol Pharmacol

116

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Proliferating cell nuclear antigen (PCNA), a potential anticancer target, forms a homotrimer and is required for DNA replication and numerous other cellular processes. The purpose of this study was to identify novel small molecules that modulate PCNA activity to affect tumor cell proliferation. An in silico screen of a compound library against a crystal structure of PCNA and a subsequent structural similarity search of the ZINC chemical database were carried out to derive relevant docking partners. Nine compounds, termed PCNA inhibitors (PCNA-Is), were selected for further characterization. PCNA-I1 selectively bound to PCNA trimers with a dissociation constant (K d ) of ϳ0.2 to 0.4 M. PCNA-Is promoted the formation of SDSrefractory PCNA trimers. PCNA-I1 dose-and time-dependently reduced the chromatin-associated PCNA in cells. Consistent with its effects on PCNA trimer stabilization, PCNA-I1 inhibited the growth of tumor cells of various tissue types with an IC 50 of ϳ0.2 M, whereas it affected the growth of nontransformed cells at significantly higher concentrations (IC 50 , ϳ1.6 M). Moreover, uptake of BrdU was dose-dependently reduced in cells treated with PCNA-I1. Mechanistically the PCNA-Is mimicked the effect of PCNA knockdown by siRNA, inducing cancer cell arrest at both the S and G 2 /M phases. Thus, we have identified a class of compounds that can directly bind to PCNA, stabilize PCNA trimers, reduce PCNA association with chromatin, and inhibit tumor cell growth by inducing a cell cycle arrest. They are valuable tools in studying PCNA function and may be useful for future PCNA-targeted cancer therapy.

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“…Tumor cells, regardless of their origin, express high levels of PCNA, presumably to accommodate their high degree of uncontrolled replication (21). For these reasons, PCNA is a reliable diagnostic and prognostic biomarker (21)(22)(23)(24)(25)(26)(27)(28).…”

Section: Introductionmentioning

confidence: 99%

Antitumor Effects of a Novel Small Molecule Targeting PCNA Chromatin Association in Prostate Cancer

Dillehay

Dong

2014

Molecular Cancer Therapeutics

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Proliferating cell nuclear antigen (PCNA) plays an essential role in DNA replication and repair. Tumor cells express high levels of PCNA, identifying it as a potentially ideal target for cancer therapy. Previously, we identified nine compounds termed PCNA inhibitors (PCNA-Is) that bind directly to PCNA, stabilize PCNA trimer structure, reduce chromatin-associated PCNA, and selectively inhibit tumor cell growth. Of these compounds, PCNA-I1 is most potent. The purposes of this study were to further investigate the effects of targeting PCNA chromatin association on DNA damage and cytotoxicity and to evaluate the therapeutic potential of PCNA-I1 against tumors in mice. Given the important roles of tumor suppressor p53 in regulating sensitivity of tumor cells to chemotherapeutics, we performed studies in two human prostate cancer cell lines differing in p53 expression: LNCaP cells (wild-type p53) and PC-3 cells (p53-null). PCNA-I1 induced DNA damage and apoptosis in both LNCaP and PC-3 cells and enhanced DNA damage and apoptosis triggered by cisplatin. PCNA-I1 also induced autophagy in PC-3 cells. A short-term pretreatment with PCNA-I1 reduced colony formation by 50% in both cell lines. These data suggest that, unlike many other cytotoxic drugs, the effects of PCNA-I1 on tumor cells do not depend on expression of p53. Intravenous administrations of PCNA-I1 significantly retarded growth of LNCaP tumors of in nude mice without causing detectable effects on mouse body weight and hematology profiles. These data provide proof of concept that targeting PCNA chromatin association could be a novel and effective therapeutic approach for treatment of cancer. Mol Cancer Ther; 13(12); 2817-26. Ó2014 AACR.

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Esophagin and proliferating cell nuclear antigen (PCNA) are biomarkers of human esophageal neoplastic progression

Cited by 75 publications

References 8 publications

Altered Expression of Ezrin in Esophageal Squamous Cell Carcinoma

Altered Expression of Ezrin in Esophageal Squamous Cell Carcinoma

Small-Molecule Targeting of Proliferating Cell Nuclear Antigen Chromatin Association Inhibits Tumor Cell Growth

Antitumor Effects of a Novel Small Molecule Targeting PCNA Chromatin Association in Prostate Cancer

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