Membranous type matrix metalloproteinase 16 induces human prostate cancer metastasis

Jiang, Chunwa; Wang, Juanjing; Dong, Chen; Wei, Wei; Jiang, Li; Li, Xiaomeng

doi:10.3892/ol.2017.6536

Cited by 11 publications

(13 citation statements)

References 33 publications

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“…MMPs are a family of proteolytic enzymes that play a crucial role in cancer metastasis by degrading the extracellular matrix, along with a variety of cell surface receptors and signaling molecules (44). Jiang et al reported that high expression of MMP16 is associated with advanced prostate tumor stage and PCa metastasis (45). Knockdown of MMP16 in PC3 cells led to decreased migratory and invasive properties of PC3 cells (45).…”

Section: Discussionmentioning

confidence: 99%

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Role of a novel race-related tumor suppressor microRNA located in frequently deleted chromosomal locus 8p21 in prostate cancer progression

et al. 2019

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Abstract The prostate cancer (PCa) genome is characterized by deletions of chromosome 8p21–22 region that increase significantly with tumor grade and are associated with poor prognosis. We proposed and validated a novel, paradigm-shifting hypothesis that this region is associated with a set of microRNA genes—miR-3622, miR-3622b, miR-383—that are lost in PCa and play important mechanistic roles in PCa progression and metastasis. Extending our hypothesis, in this study, we evaluated the role of a microRNA gene located in chromosome 8p—miR-4288—by employing clinical samples and cell lines. Our data suggests that (i) miR-4288 is widely downregulated in primary prostate tumors and cell lines; (ii) miR-4288 expression is lost in metastatic castration-resistant PCa; (ii) miR-4288 downregulation is race-related PCa alteration that is prevalent in Caucasian patients and not in African Americans; (iii) in Caucasians, miR-4288 was found to be associated with increasing tumor grade and high serum prostate-specific antigen, suggesting that miR-4288 downregulation/loss may be associated with tumor progression specifically in Caucasians; (iv) miR-4288 possess significant potential as a molecular biomarker to predict aggressiveness/metastasis; and (v) miR-4288 is anti-proliferative, is anti-invasive and inhibits epithelial-to-mesenchymal transition; and (vi) miR-4288 directly represses expression of metastasis/invasion-associated genes MMP16 and ROCK1. Thus, the present study demonstrates a tumor suppressor role for a novel miRNA located with a frequently lost region in PCa, strengthening our hypothesis that this locus is causally related to PCa disease progression via loss of microRNA genes. Our study suggests that miR-4288 may be a novel biomarker and therapeutic target, particularly in Caucasians.

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Section: Discussionmentioning

confidence: 99%

“…Jiang et al reported that high expression of MMP16 is associated with advanced prostate tumor stage and PCa metastasis (45). Knockdown of MMP16 in PC3 cells led to decreased migratory and invasive properties of PC3 cells (45). ROCK1 is an effector kinase of the small GTPase RhoA (46).…”

Section: Discussionmentioning

confidence: 99%

Role of a novel race-related tumor suppressor microRNA located in frequently deleted chromosomal locus 8p21 in prostate cancer progression

et al. 2019

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“…Beside the PMD-associated DMS, we also identified DMS with focal changes in methylation in gene promoter regions. The gene of matrix metalloproteinase 16 (MMP16), a proteolytic enzyme involved in the development of PCa progression and metastases [23], is located in a frequent PMD. However, we identified cg12818557 located in the promoter region of MMP16 as a strong predictor, with almost 20% methylation gain in the poor compared to the good prognosis group.…”

Section: Resultsmentioning

confidence: 99%

Random forest-based modelling to detect biomarkers for prostate cancer progression

et al. 2019

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BackgroundThe clinical course of prostate cancer (PCa) is highly variable, demanding an individualized approach to therapy. Overtreatment of indolent PCa cases, which likely do not progress to aggressive stages, may be associated with severe side effects and considerable costs. These could be avoided by utilizing robust prognostic markers to guide treatment decisions.ResultsWe present a random forest-based classification model to predict aggressive behaviour of prostate cancer. DNA methylation changes between PCa cases with good or poor prognosis (discovery cohort with n = 70) were used as input. DNA was extracted from formalin-fixed tumour tissue, and genome-wide DNA methylation differences between both groups were assessed using Illumina HumanMethylation450 arrays. For the random forest-based modelling, the discovery cohort was randomly split into a training (80%) and a test set (20%). Our methylation-based classifier demonstrated excellent performance in discriminating prognosis subgroups in the test set (Kaplan-Meier survival analyses with log-rank p value < 0.0001). The area under the receiver operating characteristic curve (AUC) for the sensitivity analysis was 95%. Using the ICGC cohort of early- and late-onset prostate cancer (n = 222) and the TCGA PRAD cohort (n = 477) for external validation, AUCs for sensitivity analyses were 77.1% and 68.7%, respectively. Cancer progression-related DNA hypomethylation was frequently located in ‘partially methylated domains’ (PMDs)—large-scale genomic areas with progressive loss of DNA methylation linked to mitotic cell division. We selected several candidate genes with differential methylation in gene promoter regions for additional validation at the protein expression level by immunohistochemistry in > 12,000 tissue micro-arrayed PCa cases. Loss of ZIC2 protein expression was associated with poor prognosis and correlated with significantly shorter time to biochemical recurrence. The prognostic value of ZIC2 proved to be independent from established clinicopathological variables including Gleason grade, tumour stage, nodal stage and prostate-specific-antigen.ConclusionsOur results highlight the prognostic relevance of methylation loss in PMD regions, as well as of several candidate genes not previously associated with PCa progression. Our robust and externally validated PCa classification model either directly or via protein expression analyses of the identified top-ranked candidate genes will support the clinical management of prostate cancer.

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“…Similarly, our data indicate that Wnt3A treatment of DCIS cells resulted in increased MMP16 mRNA levels. The effect of MMP16 on cancer progression has been reported in multiple cancers, such as prostate cancer, colon cancer and melanoma, where it promotes migration, invasion, and metastasis 53,54 . Higher levels of MMP16 are detected in cancer tissues compared to normal tissues and they are also associated with poor prognosis 53 .…”

Section: Discussionmentioning

confidence: 99%

BCL9/STAT3 regulation of transcriptional enhancer networks promote DCIS progression

Elsarraj

Limback

et al. 2020

npj Breast Cancer

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The molecular processes by which some human ductal carcinoma in situ (DCIS) lesions advance to the more aggressive form, while others remain indolent, are largely unknown. Experiments utilizing a patient-derived (PDX) DCIS Mouse INtraDuctal (MIND) animal model combined with ChIP-exo and RNA sequencing revealed that the formation of protein complexes between B Cell Lymphoma-9 (BCL9), phosphoserine 727 STAT3 (PS-727-STAT3) and non-STAT3 transcription factors on chromatin enhancers lead to subsequent transcription of key drivers of DCIS malignancy. Downregulation of two such targets, integrin β3 and its associated metalloproteinase, MMP16, resulted in a significant inhibition of DCIS invasive progression. Finally, in vivo targeting of BCL9, using rosemary extract, resulted in significant inhibition of DCIS malignancy in both cell line and PDX DCIS MIND animal models. As such, our studies provide compelling evidence for future testing of rosemary extract as a chemopreventive agent in breast cancer.npj Breast Cancer (2020) 6:12 ; https://doi.

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Membranous type matrix metalloproteinase 16 induces human prostate cancer metastasis

Cited by 11 publications

References 33 publications

Role of a novel race-related tumor suppressor microRNA located in frequently deleted chromosomal locus 8p21 in prostate cancer progression

Role of a novel race-related tumor suppressor microRNA located in frequently deleted chromosomal locus 8p21 in prostate cancer progression

Random forest-based modelling to detect biomarkers for prostate cancer progression

BCL9/STAT3 regulation of transcriptional enhancer networks promote DCIS progression

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