Estrogen receptor beta reduces colon cancer metastasis through a novel miR-205 - PROX1 mechanism

Nguyen-Vu, Trang; Wang, Jun; Mesmar, Fahmi; Mukhopadhyay, Srijita; Saxena, Ashish; McCollum, Catherine W.; Gustafsson, Jan Åke; Bondesson, Maria; Williams, Cecilia

doi:10.18632/oncotarget.9895

Cited by 48 publications

(42 citation statements)

References 38 publications

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“…Overexpression of PROX1 has been shown to enhance colon cancer progression in vivo ; indeed, it has been associated with transition from benign adenoma to carcinoma, and silencing of this transcription factor inhibits the growth of human colorectal tumor xenografts [91]. We have demonstrated that PROX1 is repressed by ERβ, through the regulation of microRNA miR-205, and results in a repression of metastatic potential of CRC cells [92]. This pathway was confirmed in clinical specimens and could be recapitulated in intestine-specific ERβ knockout mice [92].…”

Section: The Molecular Mechanism Of Action Of Erβ In Colon Epithelmentioning

confidence: 99%

“…We have demonstrated that PROX1 is repressed by ERβ, through the regulation of microRNA miR-205, and results in a repression of metastatic potential of CRC cells [92]. This pathway was confirmed in clinical specimens and could be recapitulated in intestine-specific ERβ knockout mice [92]. In summary, a number of studies support that the molecular mechanism whereby ERβ protects against tumorigenesis by enhancing DNA repair and apoptosis while repressing oncogene expression, proliferation and metastasis (Figure 1).…”

Section: The Molecular Mechanism Of Action Of Erβ In Colon Epithelmentioning

confidence: 99%

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Estrogen receptor beta as target for colorectal cancer prevention

et al. 2016

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Colorectal cancer (CRC) is a leading cause of death in the United States. Despite its slow development and the capacity for early diagnosis, current preventive approaches are not sufficient. However, a role for estrogen has been demonstrated in multiple epidemiologic studies, which may benefit CRC prevention. A large body of evidence from preclinical studies indicates that expression of the estrogen receptor beta (ERβ/ESR2) demonstrates an inverse relationship with the presence of colorectal polyps and stage of tumors, and can mediate a protective response. Natural compounds, including phytoestrogens, or synthetic ERβ selective agonists, can activate or upregulate ERβ in the colon and promote apoptosis in preclinical models and in clinical experience. Importantly, this activity has been associated with a reduction in polyp formation and, in rodent models of CRC, has been shown to lower incidence of colon adenocarcinoma. Collectively, these findings indicate that targeted activation of ERβ may represent a novel clinical approach for management of colorectal adenomatous polyps and prevention of colorectal carcinoma in patients at risk for this condition. In this review, we discuss the potential of new chemopreventive or dietary approaches based on estrogen signaling.

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Section: The Molecular Mechanism Of Action Of Erβ In Colon Epithelmentioning

confidence: 99%

Section: The Molecular Mechanism Of Action Of Erβ In Colon Epithelmentioning

confidence: 99%

Estrogen receptor beta as target for colorectal cancer prevention

et al. 2016

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“…Further, estrogen through estrogen receptor β (ERβ/ESR2) appears to reduce the risk of CRC development (reviewed in []). Our previous cell‐based analyses have shown that re‐introduction of ERβ into CRC cells exhibits anti‐proliferative functions, represses oncogenes, and mediates anti‐inflammatory signaling . Studies in mice have generated support in vivo for such a preventive role .…”

Section: Introductionmentioning

confidence: 99%

“…However, whether intestinal ERβ affects the microbiota of the gut has not been investigated. To explore the effect of ERβ in the intestines, we have generated intestine‐specific knockout of ERβ (referred to as ERβKO Vil or simply KO in the remainder of the text) . Here, we characterize how the microbiota composition is affected by AOM/DSS‐driven colitis and CRC development in mice with and without intestinal ERβ.…”

Section: Introductionmentioning

confidence: 99%

Colitis‐induced colorectal cancer and intestinal epithelial estrogen receptor beta impact gut microbiota diversity

Ibrahim

Hugerth

Hases

et al. 2019

Intl Journal of Cancer

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Chronic inflammation of the colon (colitis) is a risk factor for colorectal cancer (CRC). Hormone‐replacement therapy reduces CRC incidences, and the estrogen receptor beta (ERβ/ESR2) has been implicated in this protection. Gut microbiota is altered in both colitis and CRC and may influence the severity of both. Here we test the hypothesis that intestinal ERβ impacts the gut microbiota. Mice with and without intestine‐specific deletion of ERβ (ERβKO Vil ) were generated using the Cre‐LoxP system. Colitis and CRC were induced with a single intraperitoneal injection of azoxymethane (AOM) followed by administration of three cycles of dextran sulfate sodium (DSS) in drinking water. The microbiota population were characterized by high‐throughput 16S rRNA gene sequencing of DNA extracted from fecal samples ( N = 39). Differences in the microbiota due to AOM/DSS and absence of ERβ were identified through bioinformatic analyses of the 16S‐Seq data, and the distribution of bacterial species was corroborated using qPCR. We demonstrate that colitis‐induced CRC reduced the gut microbiota diversity and that loss of ERβ enhanced this process. Further, the Bacteroidetes genus Prevotellaceae_ UCG_001 was overrepresented in AOM/DSS mice compared to untreated controls (3.5‐fold, p = 0.004), and this was enhanced in females and in ERβKO Vil mice. Overall, AOM/DSS enriched for microbiota impacting immune system diseases and metabolic functions, and lack of ERβ in combination with AOM/DSS enriched for microbiota impacting carbohydrate metabolism and cell motility, while reducing those impacting the endocrine system. Our data support that intestinal ERβ contributes to a more favorable microbiome that could attenuate CRC development.

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“…While they found high miR205 expression in non-metastatic tissue, miR205 was absent in metastatic tissue [29]. Furthermore, over-expression of miR205 resulted in reduced invasiveness and metastatic potential in prostate and colon cancer cells [30,31]. Regarding BTC, a study by Okamoto et al demonstrated that over-expression of miR205 enhanced sensitivity to the standard chemotherapeutic Gemcitabine, which, again, categorizes miR205 as a tumor suppressor miR in this particular case [32].…”

Section: Discussionmentioning

confidence: 99%

Relevance of MicroRNA200 Family and MicroRNA205 for Epithelial to Mesenchymal Transition and Clinical Outcome in Biliary Tract Cancer Patients

Urbas

Mayr

Klieser

et al. 2016

IJMS

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Extensive stromal interaction is one reason for the dismal outcome of biliary tract cancer (BTC) patients. Epithelial to mesenchymal transition (EMT) is involved in tumor invasion and metastasis and is partly regulated by microRNAs (miRs). This study explores the expression of anti-EMT miR200 family (miR141, −200a/b/c, −429) and miR205 as well as the EMT-related proteins E-cadherin and vimentin in a panel of BTC cell lines and clinical specimens by quantitative real-time polymerase chain reaction, Western blot and immunohistochemistry, respectively. MicroRNA expression was correlated to (i) the expression patterns of E-cadherin and vimentin; (ii) clinicopathological characteristics; and (iii) survival data. MicroRNA-200 family and miR205 were expressed in all BTC cells and clinical specimens. E-cadherin and vimentin showed a mutually exclusive expression pattern in both, in vitro and in vivo. Expression of miR200 family members positively correlated with E-cadherin and negatively with vimentin expression in BTC cells and specimens. High expression of miR200 family members (but not miR205) and E-cadherin was associated with longer survival, while low miR200 family and high vimentin expression was a predictor of unfavorable survival. Overall, the current study demonstrates the relevance of the miR200 family in EMT of BTC tumors and suggests these miRs as predictors for positive outcome.

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Estrogen receptor beta reduces colon cancer metastasis through a novel miR-205 - PROX1 mechanism

Cited by 48 publications

References 38 publications

Estrogen receptor beta as target for colorectal cancer prevention

Estrogen receptor beta as target for colorectal cancer prevention

Colitis‐induced colorectal cancer and intestinal epithelial estrogen receptor beta impact gut microbiota diversity

Relevance of MicroRNA200 Family and MicroRNA205 for Epithelial to Mesenchymal Transition and Clinical Outcome in Biliary Tract Cancer Patients

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