PROX1 is a transcriptional regulator of MMP14

Gramolelli, Silvia; Cheng, Jianpin; Martínez-Corral, Inés; Vähä‐Koskela, Markus; Elbasani, Endrit; Kaivanto, Elisa; Rantanen, Ville; Tuohinto, Krista; Hautaniemi, Sampsa; Bower, Mark; Haglund, Caj; Alitalo, Kari; Mäkinen, Taija; Petrova, Tatiana V.; Lehti, Kaisa; Ojala, Päivi M.

doi:10.1038/s41598-018-27739-w

Cited by 28 publications

(39 citation statements)

References 58 publications

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“…PROX1 has been shown to have both oncogenic and tumor suppressive functions [12]. For instance, PROX1 functions as a tumor promoter in hepatocellular carcinoma (HCC) [13,14], while it potentially has an anti-tumor effect of PROX1 in BC as it suppresses BC cell invasion [15]. These findings suggest that the interaction between hsa-miR-423-5p and PROX1 may be important in BC.…”

Section: Introductionmentioning

confidence: 99%

RETRACTED ARTICLE: Long non-coding RNA LINC00968 reduces cell proliferation and migration and angiogenesis in breast cancer through up-regulation of PROX1 by reducing hsa-miR-423-5p

et al. 2019

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Background: Breast cancer (BC) is a common invasive malignancy in women with unclear etiology. A recent study suggested that long non-coding RNA (lncRNA), LINC00968 had a tumor-promoting effect in cancer. However, the role of LINC00968 in BC remains unclear. Therefore, we conducted the present study to determine the effect of LINC00968 in BC and its underlying mechanism. Methods: The expression of LINC00968 and hsa-miR-423-5p in BC tissues and cells was determined using reverse transcription quantitative polymerase chain reaction and western blot analysis. Dual luciferase reporter, RNA pull-down and RNA immunoprecipitation assays were used to determine the relationship among LINC00968, PROX1 and hsa-miR-423-5p. Gain-and loss-function approaches were utilized to examine the effects of LINC00968, PROX1 and hsa-miR-423-5p on cell proliferation, migration, tube formation in vitro; and tumor growth and angiogenesis in vivo. Results: LINC00968 expression reduced while hsa-miR-423-5p increased in BC tissues relative to adjacent normal tissues. Overexpression of LINC00968 was observed to inhibit BC cell proliferation, migration and tube formation abilities in vitro as well as tumor growth in vivo through inhibition of hsa-miR-423-5p. And hsa-miR-423-5p mediated BC cellular functions and tumor growth through down-regulating PROX1. LINC00968 was identified as a competing endogenous RNA to upregulate PROX1 by downregulating hsa-miR-423-5p. More importantly, it was found that LINC00968 increased PROX1 expression in vivo in a concentration-dependent manner. Conclusion: Taken together, this study suggests that LINC00968 inhibits the progression of BC through impeding hsa-miR-423-5p-mediated PROX1 inhibition. LINC00968 may be a potential therapeutic target for BC therapy that warrants further studies.

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Section: Introductionmentioning

confidence: 99%

RETRACTED ARTICLE: Long non-coding RNA LINC00968 reduces cell proliferation and migration and angiogenesis in breast cancer through up-regulation of PROX1 by reducing hsa-miR-423-5p

et al. 2019

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“…The PROX1 target gene Mmp14 induces tumor fibrosis and chemoresistance. PROX1 is a transcriptional repressor shown previously to directly repress annexin A1 (ANXA1) in Apc-deficient mouse intestinal stem cells (29) and matrix metalloproteinase 14 (MMP14) in human liver, colon, and breast cancer cell lines (48). Accordingly, the expression of both genes was increased in cultured Prox1deficient organoids and tumors ( Figure 5A).…”

Section: Resultsmentioning

confidence: 71%

Antiangiogenic immunotherapy suppresses desmoplastic and chemoresistant intestinal tumors in mice

Ragusa

Prat-Luri

González-Loyola

et al. 2020

Journal of Clinical Investigation

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“…PROX1 was recently shown to suppress MMP14 expression in breast cancer, as well as hepatocellular and colorectal carcinoma; here we showed that survival is worse specifically among those gastric cancer patients with a high MMP14 and a low PROX1 expression. 21 To further explore the connection between MMP14 and PROX1 in gastric cancer, we proceeded by studying the expression levels in cell lines. Cell lines, intestinal MKN-7, intestinal MKN-28, diffuse TMK-1, and AGS (unknown histological type) were studied using immunofluorescence ( Figure 3A).…”

Section: Immunofluorescence Immunoblot and Sirna Transfection Anamentioning

confidence: 99%

High tissue MMP14 expression predicts worse survival in gastric cancer, particularly with a low PROX1

et al. 2019

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Matrix metalloproteinase 14 (MMP14), a membrane‐associated matrix metalloproteinase, has been shown to influence the invasion and metastasis of several solid tumors. Prospero homeobox protein 1 (PROX1), involved in the development and cell fate determination, is also expressed in malignant diseases functioning either as a tumor‐suppressing or oncogenic factor. In certain cancers PROX1 appears to transcriptionally suppress MMP14 expression. This study, therefore, aimed to explore the association between MMP14 and PROX1 and understand their potential as prognostic biomarkers in gastric cancer. The cohort consisted of 313 individuals operated for gastric adenocarcinoma between 2000 and 2009 in the Department of Surgery, Helsinki University Hospital. MMP14 and PROX1 expressions were studied using immunohistochemistry in the patient sample and using immunoblotting and immunofluorescence in gastric cancer cell lines. We generated survival curves using the Kaplan‐Meier method, determining significance via the log‐rank test. A high MMP14 expression associated with being ≥67 years (P = .041), while a positive nuclear PROX1 expression associated with tumors of a diffuse histological type (P = .041) and a high cytoplasmic PROX1 expression (P < .001). Five‐year disease‐specific survival among patients with a high MMP14 expression was 35.9% (95% confidence interval [CI] 24.9‐46.9), compared to 45.3% (95% CI 38.0‐52.6) for patients with a low MMP14 (P = .030). Survival was worse specifically among those with a high MMP14 and absent nuclear PROX1 expression (hazard ratio [HR] 1.65; 95% CI 1.09‐2.51; P = .019). Thus, this study confirms that a high MMP14 expression predicts a worse survival in gastric cancer, revealing for the first time that survival is particularly worse when PROX1 is low.

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PROX1 is a transcriptional regulator of MMP14

Cited by 28 publications

References 58 publications

RETRACTED ARTICLE: Long non-coding RNA LINC00968 reduces cell proliferation and migration and angiogenesis in breast cancer through up-regulation of PROX1 by reducing hsa-miR-423-5p

RETRACTED ARTICLE: Long non-coding RNA LINC00968 reduces cell proliferation and migration and angiogenesis in breast cancer through up-regulation of PROX1 by reducing hsa-miR-423-5p

Antiangiogenic immunotherapy suppresses desmoplastic and chemoresistant intestinal tumors in mice

High tissue MMP14 expression predicts worse survival in gastric cancer, particularly with a low PROX1

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