EPCR promotes breast cancer progression by altering SPOCK1/testican 1-mediated 3D growth

Perurena, Naiara; Zandueta, Carolina; Martínez-Canarias, Susana; Moreno, Haritz; Vicent, Silvestre; Almeida, Ana S.; Guruceaga, Elizabeth; Gomis, Roger R.; Santisteban, Marta; Egeblad, Mikala; Hermida, José; Lecanda, Fernando

doi:10.1186/s13045-017-0399-x

Cited by 22 publications

(23 citation statements)

References 38 publications

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“…For example, SPOCK1 has already been reported to promote glioma cell proliferation, migration, and invasion 53 . Silencing EPCR resulted in a reduction of SPOCK1 which reduced primary tumor growth of breast cancer 54 . SPOCK1 functioned as an oncogene through multiple signaling pathways, such as ERK/AKT pathways 55 and mTOR-S6K pathways 56 .…”

Section: Discussionmentioning

confidence: 99%

NR2C2-uORF targeting UCA1-miR-627-5p-NR2C2 feedback loop to regulate the malignant behaviors of glioma cells

et al. 2018

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Accumulating evidence has highlighted the potential role of non-coding RNAs (ncRNAs) and upstream open-reading frames (uORFs) in the biological behaviors of glioblastoma. Here, we elucidated the function and possible molecular mechanisms of the effect of some ncRNAs and NR2C2-uORF on the biological behaviors of gliomas. Quantitative real-time PCR was conducted to profile the cell expression of lnc-UCA1 and microRNA-627-5p (miR-627-5p) in glioma tissues and cells. Western blot assay was used to determine the expression levels of NR2C2, SPOCK1, and NR2C2-uORF in glioma tissues and cells. Stable knockdown of lnc-UCA1 or overexpression of miR-627-5p in glioma cell lines (U87 and U251) were established to explore the function of lnc-UCA1 and miR-627-5p in glioma cells. Further, Dual luciferase report assay was used to investigate the correlation between lnc-UCA1 and miR-627-5p. Cell Counting Kit-8, transwell assays, and flow cytometry were used to investigate lnc-UCA1 and miR-627-5p function including cell proliferation, migration and invasion, and apoptosis, respectively. ChIP assays were used to ascertain the correlations between NR2C2 and SPOCK1 as well as NR2C2 between lnc-UCA1. This study confirmed that lnc-UCA1 was up-regulated in glioma tissues and cells. UCA1 knockdown inhibited the malignancies of glioma cells by reducing proliferation, migration, and invasion, but inducing apoptosis. We found that lnc-UCA1 acted as miR-627-5p sponge in a sequence-specific manner. Meanwhile, upregulated lnc-UCA1 inhibited miR-627-5p expression. In addition, miR-627-5p targeted 3′UTR of NR2C2 and down-regulated its expression. Moreover, UCA1 knockdown impaired NR2C2 expression by upregulating miR-627-5p. An uORF was identified in mRNA 5'UTR of NR2C2 and overexpression of whom negatively regulated NR2C2 expression. Remarkably, lnc-UCA1 knockdown combined with uORF overepression and NR2C2 knockdown led to severe tumor suppression in vivo. This study demonstrated that the NR2C2-uORF impaired the pivotal roles that UCA1-miR-627-5p-NR2C2 feedback loop had in regulating the malignancies of glioma cells by targeting NR2C2 directly. And this may provide a potential therapeutic strategy for treating glioma.

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Section: Discussionmentioning

confidence: 99%

NR2C2-uORF targeting UCA1-miR-627-5p-NR2C2 feedback loop to regulate the malignant behaviors of glioma cells

et al. 2018

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“…Endometrial and ovarian cancers exhibit low FSTL1 levels; moreover, ectopic FSTL1 expression exerts anti-neoplastic activity by inducing apoptosis (58). Among SPOCK isoforms (SPOCK1-3), SPOCK1 is upregulated in different tumor types, and its expression positively correlates with invasive/metastatic potential and hence poor prognosis (59)(60)(61). However, in brain tumors, expression of all SPOCK family members decreases with increasing tumor grade (62).…”

Section: Expression Of Mcps In Cancermentioning

confidence: 99%

The Matrix Revolution: Matricellular Proteins and Restructuring of the Cancer Microenvironment

et al. 2020

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The extracellular matrix (ECM) surrounding cells is indispensable for regulating their behavior. The dynamics of ECM signaling are tightly controlled throughout growth and development. During tissue remodeling, matricellular proteins (MCPs) are secreted into the ECM. These factors do not serve classical structural roles, but rather regulate matrix proteins and cell-matrix interactions to influence normal cellular functions. In the tumor microenvironment, it is becoming increasingly clear that aberrantly expressed MCPs can support multiple hallmarks of carcinogenesis by interacting with various cellular components that are coupled to an array of downstream signals. Moreover, MCPs also reorganize the biomechanical properties of the ECM to accommodate metastasis and tumor colonization. This realization is stimulating new research on MCPs as reliable and accessible biomarkers in cancer, as well as effective and selective therapeutic targets. Research.

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“…A previous study revealed that deregulating the expression of SPOCK1 suppressed colorectal cancer (CRC) proliferation in vitro and vivo, SPOCK1 was involved in CRC malignant features (7). Notably, SPOCK1 was altered by EPCR to mediate 3D growth consequently promoted breast cancer progression (40). Here, we detected the variation on BC cells by modifying SPOCK1 expression, which revealed that SPOCK1 overexpression improved the proliferative and metastatic properties of BC cells and suppression of SPOCK1 got the opposite effect.…”

Section: Discussionmentioning

confidence: 73%

SPOCK1 promotes breast cancer progression via interacting with SIX1 and activating AKT/mTOR signaling pathway

Zhang

et al. 2019

Preprint

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SPOCK1 is highly expressed in many types of cancer, which has been recognized as a promoter of cancer progression, while its regulatory mechanism remains to be clear in breast cancer (BC). This study aimed to explore the precise function of SPOCK1 in BC progression and the mechanism by which SPOCK1 was involved in cell proliferation and epithelial-mesenchymal transition (EMT).Immunohistochemistry (IHC) and database analysis displayed that high expression of SPOCK1 was positively associated with histological grade, lymph node metastasis (LN) and poor clinical prognosis in BC. A series of assays both in vitro and in vivo elucidated that altering SPOCK1 level led to distinctly changes in BC cell proliferation and metastasis. Investigations of potential mechanisms revealed that SPOCK1 interacted with SIX1 could enhance cell proliferation, cell cycle and EMT process by activating the AKT/mTOR pathway, whereas inhibition of AKT/mTOR pathway or depletion of SIX1 reversed the effects of SPOCK1 overexpression.Furthermore, SPOCK1 and SIX1 were highly expressed in BC and might indicate poor prognoses. Altogether, SPOCK1/SIX1 promoted BC progression by activating AKT/mTOR pathway to accelerate cell proliferation and metastasis in BC, and SPOCK1/SIX1 might be promising clinical therapeutic targets to prevent BC progression. IMPORTANCE:The incidence of BC is alarmingly high and many patients initially diagnosed without detectable metastases will eventually develop metastatic lesions. The occurrence of metastasis is responsible for the death of many patients, which also represents a big challenge for researchers to improve the survival rates of BC patients.Hence the scientific community pays more attention on cancer targeted therapy. This research is significant for identifying the underlying mechanisms and capabilities of SPOCK1-induced BC activities, which will greatly apply novel targets and new treatment strategies for clinicians, leading to broader biomedical impacts. KEYWORDS: SPOCK1; SIX1; EMT; Breast cancer; AKT/mTOR signaling pathwayBreast cancer (BC), the most frequently diagnosed lethal gynecologic malignancy in women worldwide (1), which is an increasing concern because of its rising incidence. Despite major advances in BC therapy, the prognosis for most patients would be significantly worse once spread metastasized occurs (2). Metastasis is the mainspring for most patient death and represents the fundamental challenge of the clinical treatment for the patients with BC. The initiation and metastasis of BC are intricate processes, which triggered by multiple genes and intracellular signal transduction cross-talks. Thus, looking for valid molecular hallmarks and understanding the mechanisms of BC initiation and metastasis process are urged to put on the agenda. Sparc/osteonectin, cwcv and kazal-like domains proteoglycan 1 (SPOCK1), is also known as TIC1; SPOCK; TESTICAN, belongs to multidomain testicular proteoglycan family (3). This protein family includes SPARC, TESTICAN-2, and TESTICAN-3, which are associated with ...

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EPCR promotes breast cancer progression by altering SPOCK1/testican 1-mediated 3D growth

Cited by 22 publications

References 38 publications

NR2C2-uORF targeting UCA1-miR-627-5p-NR2C2 feedback loop to regulate the malignant behaviors of glioma cells

NR2C2-uORF targeting UCA1-miR-627-5p-NR2C2 feedback loop to regulate the malignant behaviors of glioma cells

The Matrix Revolution: Matricellular Proteins and Restructuring of the Cancer Microenvironment

SPOCK1 promotes breast cancer progression via interacting with SIX1 and activating AKT/mTOR signaling pathway

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