Methylation of the SPARC gene promoter and its clinical implication in pancreatic cancer

Gao, Jun; Song, Jiahui; Huang, Haojie; Li, Zhao‐Shen; Du, Yiqi; Cao, Jia; Li, Minghui; Lv, Shunli; Han, Lin; Yang, Gong

doi:10.1186/1756-9966-29-28

Cited by 40 publications

(38 citation statements)

References 34 publications

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“…63), it was not surprising to find increased SPARC levels in early stages of differentiation of growth-arrested nonproliferating fibroblasts and macrophages in response to inflammatory stimuli (Supplemental Figures 5 and 6) and hence, the lack of cancerous compartment. Our findings regarding SPARC protein expression in the human bladder tumor and carcinogenesis model in the Sparc +/+ mice may explain the apparently paradoxical reports in which expression of SPARC protein in cancer is decreased due to promoter methylation, while being overexpressed in the tumor associated stroma (26,(50)(51)(52)(53)(54)(55)(56). In our study, we show that SPARC protein expression increased in fibroblasts and macrophages in vitro in response to stimulation by cancer cells, the prototype ROS, and H 2 O 2 as well as 8-isoprostane, another marker of oxidative tissue damage that further contributes to inflammation and ROS production.…”

Section: Discussionmentioning

confidence: 54%

Loss of SPARC in bladder cancer enhances carcinogenesis and progression

Said¹,

Frierson²,

Sänchez‐Carbayo³

et al. 2013

J. Clin. Invest.

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Secreted protein acidic and rich in cysteine (SPARC) has been implicated in multiple aspects of human cancer. However, its role in bladder carcinogenesis and metastasis are unclear,with some studies suggesting it may be a promoter and others arguing the opposite. Using a chemical carcinogenesis model in Sparc-deficient mice and their wild-type littermates, we found that loss of SPARC accelerated the development of urothelial preneoplasia (atypia and dysplasia), neoplasia, and metastasis and was associated with decreased survival. SPARC reduced carcinogen-induced inflammation and accumulation of reactive oxygen species as well as urothelial cell proliferation. Loss of SPARC was associated with an inflammatory phenotype of tumor-associated macrophages and fibroblasts, with concomitant increased activation of urothelial and stromal NF-κB and AP1 in vivo and in vitro. Syngeneic spontaneous and experimental metastasis models revealed that tumorand stroma-derived SPARC reduced tumor growth and metastasis through inhibition of cancer-associated inflammation and lung colonization. In human bladder tumor tissues, the frequency and intensity of SPARC expression were inversely correlated with disease-specific survival. These results indicate that SPARC is produced by benign and malignant compartments of bladder carcinomas where it functions to suppress bladder carcinogenesis, progression, and metastasis.

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Section: Discussionmentioning

confidence: 54%

Loss of SPARC in bladder cancer enhances carcinogenesis and progression

Said¹,

Frierson²,

Sänchez‐Carbayo³

et al. 2013

J. Clin. Invest.

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“…SPARC-null mice develop mild thrombocytopenia and exhibit an impaired ability to form BFU-E colonies. 18 SPARC is also a candidate tumor suppressor as methylation of the SPARC promoter has been observed in both lung and pancreatic cancers 90,91 and is often associated with breast cancer cell invasion. 92 The human APC (adenomatous polyposis coli) gene is located on chromosome 5q22, in close proximity to the region that is deleted in 5q-syndrome.…”

Section: Mds Mouse Models Of Chromosomal Deletions: Candidate Genes Fmentioning

confidence: 99%

Engineering mouse models with myelodysplastic syndrome human candidate genes; how relevant are they?

2012

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Myelodysplastic syndromes represent particularly challenging hematologic malignancies that arise from a large spectrum of genetic events resulting in a disease characterized by a range of different presentations and outcomes. Despite efforts to classify and identify the key genetic events, little improvement has been made in therapies that will increase patient survival. Animal models represent powerful tools to model and study human diseases and are useful pre-clinical platforms. In addition to enforced expression of candidate oncogenes, gene inactivation has allowed the consequences of the genetic effects of human myelodysplastic syndrome to be studied in mice. This review aims to examine the animal models expressing myelodysplastic syndrome-associated genes that are currently available and to highlight the most appropriate model to phenocopy myelodysplastic syndrome disease and its risk of transformation to acute myelogenous leukemia. ©2013 Ferrata Storti Foundation. This is an open-access paper. doi:10.3324/haematol.2012.069385 ABSTRACTMouse models myelodysplastic syndrome human candidate genes haematologica | 2013; 98 (1) 11 Figure 1. Mouse models to study malignant hematologic disease. Several strategies can be employed to create mouse models of disease. Candidate genes can be introduced into the germline under the control of appropriate promoters to drive expression in certain cell compartments. Knock-out strategies create gene deficient mice, whilst knock-in strategies use the endogenous promoters; but again these tend to be conditional systems requiring specific promoters to determine in which cell the genes are introduced. Transduction of bone marrow and reinfusion is a powerful tool. Xenograft models are theoretically the best if the techniques involved can be improved.

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“…SPARC, also called osteonectin/BM40, is highly expressed at the interface of the tumor and stroma, and methylation and subsequent gene silencing of SPARC were recently reported to be common in pancreatic tumor cells. [74][75][76] It has been hypothesized that GP-60 (Caveolin-1), a scaffolding protein found in the plasma membrane, facilitates transcytosis of nab-paclitaxel across the endothelial barrier; SPARC then mediates accumulation of nabpaclitaxel in the interstitial space adjacent to the tumor cell. 77 In a small study of patients with head and neck cancers, clinical benefits with nabpaclitaxel correlated with SPARC expression, supporting the hypothesis.…”

Section: Investigational Treatmentsmentioning

confidence: 99%