Pin1 positively affects tumorigenesis of esophageal squamous cell carcinoma and correlates with poor survival of patients

Lin, Fengyi; Lee, Yu Cheng; Tsai, Chen Hsun; Yao, Yun; Cheng, Hongye; Lai, Wu‐Wei; Wang, Yi‐Ching; Sheu, Bor Shyang; Lu, Pei Jung

doi:10.1186/s12929-014-0075-1

Cited by 14 publications

(10 citation statements)

References 10 publications

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“…In this study, we found that Pin1 is a direct target of 6,7,4 0 -THIF for the suppression of esophageal cancer cell growth. Upregulation of Pin1 levels has been observed clinically and is closely correlated with poor survival of esophageal cancer patients (28). Indeed, we confirmed an overexpression of the Pin1 protein in esophageal cancer cells compared with normal cells (Supplementary Fig.…”

Section: Introductionsupporting

confidence: 79%

“…Even though the actual bioactive compounds in soy isoflavones are their metabolites (12), only a few studies have begun to reveal the physiologic activities and identify their modes of action (14)(15)(16). In the case of esophageal cancer, Pin1 has been clearly correlated with prognosis and poor survival of patients (28). Because Pin1 regulates oncogenes, such as c-Jun, p63a, p63nerb B2 (22, 40), the poor prognosis for patients with esophageal cancer was assumed to be associated with Pin1-related oncogene activation.…”

Section: Discussionmentioning

confidence: 99%

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The Prolyl Isomerase Pin1 Is a Novel Target of 6,7,4′-Trihydroxyisoflavone for Suppressing Esophageal Cancer Growth

Lim

Lee

Duan

et al. 2017

Cancer Prevention Research

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Intake of soy isoflavones is inversely associated with the risk of esophageal cancer. Numerous experimental results have supported the anticancer activity of soy isoflavones. This study aimed to determine the anti-esophageal cancer activity of 6,7,4'-trihydroxyisoflavone (6,7,4'-THIF), a major metabolite of daidzein, which is readily metabolized in the human body. Notably, 6,7,4'-THIF inhibited proliferation and increased apoptosis of esophageal cancer cells. On the basis of a virtual screening analysis, Pin1 was identified as a target protein of 6,7,4'-THIF. Pull-down assay results using 6,7,4'-THIF Sepharose 4B beads showed a direct interaction between 6,7,4'-THIF and the Pin1 protein. Pin1 is a critical therapeutic and preventive target in esophageal cancer because of its positive regulation of β-catenin and cyclin D1. The 6,7,4'-THIF compound simultaneously reduced Pin1 isomerase activity and the downstream activation targets of Pin1. The specific inhibitory activity of 6,7,4'-THIF was analyzed using Neu/Pin1 wild-type (WT) and Neu/Pin1 knockout (KO) MEFs. 6,7,4'-THIF effected Neu/Pin1 WT MEFs, but not Neu/Pin1 KO MEFs. Furthermore, the results of a xenograft assay using Neu/Pin1 WT and KO MEFs were similar to those obtained from the assay. Overall, we found that 6,7,4'-THIF specifically reduced Pin1 activity in esophageal cancer models. Importantly, 6,7,4'-THIF directly bound to Pin1 but not FKBP or cyclophilin A, the same family of proteins. Because Pin1 acts like an oncogene by modulating various carcinogenesis-related proteins, this study might at least partially explain the underlying mechanism(s) of the anti-esophageal cancer effects of soy isoflavones..

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Section: Introductionsupporting

confidence: 79%

Section: Discussionmentioning

confidence: 99%

The Prolyl Isomerase Pin1 Is a Novel Target of 6,7,4′-Trihydroxyisoflavone for Suppressing Esophageal Cancer Growth

Lim

Lee

Duan

et al. 2017

Cancer Prevention Research

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“…PIN1 is a central controller in the regulation of proline‐directed phosphorylation, which is a common event relating to tumorigenesis . Overactivation or upregulation of PIN1 contributes to carcinogenesis in the majority of human tumors, including PDAC, whereas alteration of PIN1 single nucleotide polymorphisms (SNP) at the promoter region has inverse results . In addition, PIN1 is likely to be an indispensable orchestrator in the process of oncogene‐driven carcinogenesis .…”

Section: Introductionmentioning

confidence: 99%

Targeting PIN1 exerts potent antitumor activity in pancreatic ductal carcinoma via inhibiting tumor metastasis

Chen

Wen

et al. 2019

Cancer Science

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The human prolyl isomerase PIN1, best known for its association with carcinogenesis, has recently been indicated in the disease of pancreatic ductal adenocarcinoma (PDAC). However, the functions of PIN1 and the feasibility of targeting PIN1 in PDAC remain elusive. For this purpose, we examined the expression of PIN1 in cancer, related paracarcinoma and metastatic cancer tissues by immunohistochemistry and analyzed the associations with the pathogenesis of PDAC in 173 patients. The functional roles of PIN1 in PDAC were explored in vitro and in vivo using both genetic and chemical PIN1 inhibition. We showed that PIN1 was upregulated in pancreatic cancer and metastatic tissues. High PIN1 expression is significantly association with poor clinicopathological features and shorter overall survival and disease‐free survival. Further stratified analysis showed that PIN1 phenotypes refined prognostication in PDAC. Inhibition of PIN1 expression with RNA interference or with all trans retinoic acid decreased not only the growth but also the migration and invasion of PDAC cells through regulating the key molecules of multiple cancer‐driving pathways, simultaneously resulting in cell cycle arrest and mesenchymal‐epithelial transition in vitro. Furthermore, genetic and chemical PIN1 ablation showed dramatic inhibition of the tumorigenesis and metastatic spread and then reduced the tumor burden in vivo. We provided further evidence for the use of PIN1 as a promising therapeutic target in PDAC. Genetic and chemical PIN1 ablation exerted potent antitumor effects through blocking multiple cancer‐driving pathways in PDAC. More potent and specific PIN1 targeted inhibitors could be exploited to treat this aggressive cancer.

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“…[1][2][3][4][5] Up-regulation of Pin1 has been observed in many types of cancers including lung, breast, esophageal squamous cell carcinoma (ESCC) and prostate cancers, and is generally regarded as a biomarker for poor prognosis. 6,7 Several studies have reported possible mechanisms of Pin1 up-regulation. For example, increased Pin1 level was found to be increased through the oncogenic Neu/Ras pathway via E2F to promote tumorigenesity in mammary epithelial cells.…”

Section: Introductionmentioning

confidence: 99%

Landscape of Pin1 in the cell cycle

Lin

Lee

et al. 2015

Exp Biol Med (Maywood)

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Pin1 is a peptidyl-prolyl isomerase which plays a critical role in many diseases including cancer and Alzheimer's disease. The essential role of Pin1 is to affect stability, localization or function of phosphoproteins by catalyzing structural changes. Among the collection of Pin1 substrates, many have been shown to be involved in regulating cell cycle progression. The cell cycle disorder caused by dysregulation of these substrates is believed to be a common phenomenon in cancer. A number of recent studies have revealed possible functions of several important Pin1-binding cell cycle regulators. Investigating the involvement of Pin1 in the cell cycle may assist in the development of future cancer therapeutics. In this review, we summarize current knowledge regarding the network of Pin1 substrates and Pin1 regulators in cell cycle progression. In G1/S progression, cyclin D1, RB, p53, p27, and cyclin E are all well-known cell cycle regulators that are modulated by Pin1. During G2/M transition, our lab has shown that Aurora A suppresses Pin1 activity through phosphorylation at Ser16 and cooperates with hBora to modulate G2/M transition. We conclude that Pin1 may be thought of as a molecular timer which modulates cell cycle progression networks.

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Pin1 positively affects tumorigenesis of esophageal squamous cell carcinoma and correlates with poor survival of patients

Cited by 14 publications

References 10 publications

The Prolyl Isomerase Pin1 Is a Novel Target of 6,7,4′-Trihydroxyisoflavone for Suppressing Esophageal Cancer Growth

The Prolyl Isomerase Pin1 Is a Novel Target of 6,7,4′-Trihydroxyisoflavone for Suppressing Esophageal Cancer Growth

Targeting PIN1 exerts potent antitumor activity in pancreatic ductal carcinoma via inhibiting tumor metastasis

Landscape of Pin1 in the cell cycle

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