Inhibition of heat shock protein 90 suppresses squamous carcinogenic progression in a mouse model of esophageal cancer

Wang, Shaoxiang; Du, Zhan; Luo, Jie; Xiao, Wang; Li, Haiying; Liu, Yuting; Zhang, Yong; Ma, Jiwei; Xiao, Weiwei; Wang, Yifei; Zhong, Xueyun

doi:10.1007/s00432-014-1896-8

Cited by 17 publications

(10 citation statements)

References 39 publications

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“…In patients receiving early comprehensive treatment, the 5-year relative survival rate of esophageal carcinoma approaches 90%. However, the overall 5-year survival rate of patients with esophageal carcinoma remains poor as it is most commonly diagnosed at an advanced stage (with lymph node metastases) and only few symptoms appear at an early stage (3,4). Therefore, there is an urgent requirement for novel and reliable biomarkers that facilitate the detection of preneoplastic esophageal carcinoma lesions.…”

Section: Introductionmentioning

confidence: 99%

Possible tumor suppressive role of the miR-144/451 cluster in esophageal carcinoma as determined by principal component regression analysis

Gao

Liu

Liao

et al. 2016

Molecular Medicine Reports

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MicroRNA (miRNA) clusters are expressed universally across different types of organisms, and an accumulating number of studies have demonstrated that miRNA clusters function more efficiently compared with single miRNAs during the development of certain cancer types. miRNA clusters may have increased stability and reliability over individual miRNAs as diagnostic or therapeutic biomarkers. In the present study, the expression levels of mature miRNAs within the miR-144/451 cluster were examined using stem‑loop reverse transcription‑quantitative polymerase chain reaction in 102 patients pathologically diagnosed with esophageal carcinoma. Bioinformatics tools were used to identify a possible miRNA‑mediated network of the miR‑144/451 cluster. The expression levels of hsa‑miR‑451a, hsa‑miR‑144‑3p and hsa‑miR‑144‑5p in tumor tissues were significantly lower compared with those in adjacent non‑tumor tissues (P<0.05). Pearson correlation analysis demonstrated that the expression levels of individual miR‑144/451 cluster members were correlated with each other, except for the pair of hsa‑miR‑144‑3p and hsa‑miR‑4732‑3p. In particular, hsa‑miR‑144‑5p expression was highly associated with hsa-miR-4732‑5p and hsa-miR-451a expression levels, with correlation coefficients of 0.729 and 0.608, respectively. Furthermore, the low expression levels of hsa‑miR‑144‑3p [odds ratio (OR), 0.85; P<0.05] and hsa-miR-144-5p (OR, 0.84; P<0.05) were determined to be risk factors for esophageal carcinoma development. Kyoto Encyclopedia of Genes and Genomes pathway analysis demonstrated that miRNAs forming the miR‑144/451 cluster may cooperate to regulate the cell cycle. Therefore, the miR‑144/451 cluster may serve an important role in the progression of esophageal carcinoma and may be considered as a biomarker for the detection of esophageal carcinoma at an early stage.

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Section: Introductionmentioning

confidence: 99%

Possible tumor suppressive role of the miR-144/451 cluster in esophageal carcinoma as determined by principal component regression analysis

Gao

Liu

Liao

et al. 2016

Molecular Medicine Reports

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“…Figure 3 B showed that A-P as chiRNA dramatically increased 4NQO-induced ESCC initiation (the number of tumors) compared with WT mice. As previously described, the esophageal wall of WT mice was thick, rough, and lost proper organization at the end of the 16-week 4NQO treatment [ 20 , 21 ]. However, with identical treatment, the esophagi form mice expressing A-P as chiRNA deteriorated rapidly and exhibited multiple visible lesions (>1 mm diameter).…”

Section: Resultsmentioning

confidence: 94%

Generation and Application of Inducible Chimeric RNA ASTN2-PAPPAas Knockin Mouse Model

Luo

Yao

et al. 2022

Cells

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Chimeric RNAs (chiRNAs) play many previously unrecognized roles in different diseases including cancer. They can not only be used as biomarkers for diagnosis and prognosis of various diseases but also serve as potential therapeutic targets. In order to better understand the roles of chiRNAs in pathogenesis, we inserted human sequences into mouse genome and established a knockin mouse model of the tamoxifen-inducible expression of ASTN2-PAPPA antisense chimeric RNA (A-PaschiRNA). Mice carrying the A-PaschiRNA knockin gene do not display any apparent abnormalities in growth, fertility, histological, hematopoietic, and biochemical indices. Using this model, we dissected the role of A-PaschiRNA in chemical carcinogen 4-nitroquinoline 1-oxide (4NQO)-induced carcinogenesis of esophageal squamous cell carcinoma (ESCC). To our knowledge, we are the first to generate a chiRNA knockin mouse model using the Cre-loxP system. The model could be used to explore the roles of chiRNA in pathogenesis and potential targeted therapies.

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“…Many studies have demonstrated that HSP90 is associated with the pathogenesis, poor prognosis and resistance to therapy of various human cancers [10, 11, 16, 17]. HSP90 target proteins are known to contribute to nearly every aspect of the oncogenic process including immortality, survival, anti-apoptosis, genomic instability, neoangiogenesis and metastasis [18–20].…”

Section: Discussionmentioning

confidence: 99%

Small molecule inhibitor screening identifified HSP90 inhibitor 17-AAG as potential therapeutic agent for gallbladder cancer

et al. 2017

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Gallbladder cancer (GBC) is a lethal cancer with poor prognosis associated with high invasiveness and poor response to chemotherapy and radiotherapy. New therapeutic approaches are urgently needed in order to improve survival and response rates of GBC patients. We screened 130 small molecule inhibitors on a panel of seven GBC cell lines and identified the HSP90 inhibitor 17-AAG as one of the most potent inhibitory drugs across the different lines. We tested the antitumor efficacy of 17-AAG and geldanamycin (GA) in vitro and in a subcutaneous preclinical tumor model NOD-SCID mice. We also evaluated the expression of HSP90 by immunohistochemistry in human GBC tumors.In vitro assays showed that 17-AAG and GA significantly reduced the expression of HSP90 target proteins, including EGFR, AKT, phospho-AKT, Cyclin B1, phospho-ERK and Cyclin D1. These molecular changes were consistent with reduced cell viability and cell migration and promotion of G2/M cell cycle arrest and apoptosis observed in our in vitro studies.In vivo, 17-AAG showed efficacy in reducing subcutaneous tumors size, exhibiting a 69.6% reduction in tumor size in the treatment group compared to control mice (p < 0.05).The HSP90 immunohistochemical staining was seen in 182/209 cases of GBC (87%) and it was strongly expressed in 70 cases (33%), moderately in 58 cases (28%), and weakly in 54 cases (26%).Our pre-clinical observations strongly suggest that the inhibition of HSP90 function by HSP90 inhibitors is a promising therapeutic strategy for gallbladder cancer that may benefit from new HSP90 inhibitors currently in development.

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Inhibition of heat shock protein 90 suppresses squamous carcinogenic progression in a mouse model of esophageal cancer

Abstract: Our in vivo findings support the contribution of Hsp90 to ESCC progression, which was achieved by stimulating apoptosis and inhibition of cell proliferation, and provide a strong rationale for further evaluation of Hsp90 inhibitors for treating ESCC.

Cited by 17 publications

References 39 publications

Possible tumor suppressive role of the miR-144/451 cluster in esophageal carcinoma as determined by principal component regression analysis

Possible tumor suppressive role of the miR-144/451 cluster in esophageal carcinoma as determined by principal component regression analysis

Generation and Application of Inducible Chimeric RNA ASTN2-PAPPAas Knockin Mouse Model

Small molecule inhibitor screening identifified HSP90 inhibitor 17-AAG as potential therapeutic agent for gallbladder cancer

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