PACE4 is an important driver of ZR-75-1 estrogen receptor-positive breast cancer proliferation and tumor progression

Panet, François; Couture, Frédéric; Kwiatkowska, Anna; Desjardins, Roxane; Guérin, Brigitte; Day, Robert

doi:10.1016/j.ejcb.2017.03.006

Cited by 15 publications

(17 citation statements)

References 33 publications

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“…The central role of PACE4 in the sustained growth capabilities of prostate cancer cells has been demonstrated by the induction of proliferation arrest using either a PACE4 inhibitor or PACE4-specific gene-silencing tools [ 21 ]. Similar results have been obtained for breast cancer [ 12 ]. In recent work, Couture et al characterized a novel PACE4 isoform, PACE4-altCT, that is generated by an alternative splicing mechanism, and is oncogenic in prostate cancer cells [ 13 ].…”

Section: Discussionsupporting

confidence: 89%

“…A growing number of publications highlight the role of this protease in carcinogenesis and tumor progression [ 7 – 9 ]. PACE4 plays a role in the oncogenesis of prostate, ovary, and breast cancer [ 10 – 12 ]. More recently, two PACE4 isoforms have been described by Couture et al: a full-length isoform, PACE4-FL, and its alternative isoform, PACE4-altCT, which is different from its parent isoform in term of autocatalytic processing and cellular trafficking, as it remains inside the secretory pathway without being secreted.…”

Section: Introductionmentioning

confidence: 99%

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Evaluation of PACE4 isoforms as biomarkers in thyroid cancer

Fradet

Temmar

Couture

et al. 2018

J of Otolaryngol - Head & Neck Surg

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BackgroundTo date, no single molecular marker has been demonstrated as clinically useful in differentiating malignant from benign thyroid nodules when a fine needle aspiration falls in the “unknown significance” categories of the Bethesda Classification. PACE4, a member of the proprotein convertase family of enzymes, has been shown to play a major role in the pathogenesis of prostate cancer, through the formation of an oncogenic isoform named PACE4-altCT. PACE4 isoforms have also been suggested to play a role in other cancers, including thyroid cancer, but have never been investigated in a detailed manner. Our objective is to compare the histochemical distribution of the two major PACE4 isoforms in benign and malignant thyroid nodules, in order to determine their potential usefulness as discriminatory biomarkers.MethodsThyroid tissues of patients who underwent thyroidectomy were classified according to final pathology. Corresponding tissue sections were immunostained, using two previously validated antibodies raised against the C-terminal end of the two PACE4 isoforms, namely the full-length PACE4 protein (PACE4-FL) and its alternative isoform (PACE4-altCT). Nodules were compared with adjacent normal parenchyma and immunostaining was rated as “low” or “high” by a head and neck pathologist.ResultsNon-lesional thyroid parenchyma did not express PACE4-FL (p = 0.002). As a group, malignant (n = 17) nodules expressed PACE4-FL significantly more than benign (n = 24) nodules (percentage of high immunostaining: 52.9% vs 4.2%; p = 0.001). Reciprocally, there was a statistically lower expression of PACE4-altCT in malignant nodules than in adjacent non-lesional parenchyma (p = 0.014). The specificity of a high PACE4-FL immunostaining in determining malignancy was 95.8% (95% CI, 78.9% to 99.9%).ConclusionThis study supports the previously described relationship between PACE4-FL and PACE4-altCT through alternative splicing. It also suggests that PACE4-FL is a promising biomarker for thyroid malignancy. Its high specific expression for malignancy could make it an interesting “rule in” test for thyroid cancer. Further prospective, quantitative studies are currently being designed to address how measurements of PACE4 isoforms could be used in a clinical setting.Trial registrationThis study does not report the results of a health care intervention on human participants. It was nonetheless registered on ClinicalTrials.gov under reference number NCT03160482.Electronic supplementary materialThe online version of this article (10.1186/s40463-018-0311-x) contains supplementary material, which is available to authorized users.

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Section: Discussionsupporting

confidence: 89%

Section: Introductionmentioning

confidence: 99%

Evaluation of PACE4 isoforms as biomarkers in thyroid cancer

Fradet

Temmar

Couture

et al. 2018

J of Otolaryngol - Head & Neck Surg

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“…37,38 TGFB1 is primarily secreted by endometrial cells, platelets, and In addition to TGFB1, it has been previously reported that FURIN is one of the target genes regulated by HIF-1A transactivation, and PACE4 which belongs to the PC family, which FURIN is a part off was regulated by estrogen. 56 The ectopic endometriotic lesions contain higher levels of 17B-estradiol and HIF-1A. 57,58 Whether there are other mechanisms for regulation of FURIN or whether the regulation of FURIN by baicalein is completely dependent on TGFB1 is not clear and requires further study.…”

Section: Discussionmentioning

confidence: 99%

Baicalein inhibits FURIN‐MT1‐MMP‐mediated invasion of ectopic endometrial stromal cells in endometriosis possibly by reducing the secretion of TGFB1

Yang

et al. 2020

American J Rep Immunol

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Problem: Endometriosis (EMs) is characterized by the presence of endometrial stroma and glands outside the uterus. Our previous study showed that baicalein inhibited proliferation and induced apoptosis in EMs. However, the effects of baicalein on the invasiveness of ectopic endometrial stromal cells (EcESCs) remain unclear. The aim of this study was to assess the potential anti-invasive effect of baicalein and determine the underlying mechanism. Methods: The invasive and migratory properties of EcESCs were assessed in vitro using Transwell and wound healing assays. The expression of functional markers of EcESCs, including matrix metalloproteases (MMPs), FURIN, and TGFB1, was analyzed using WB and ELISA. Additionally, a mouse model of EMs was treated with baicalein (10 mg/kg/d and 35 mg/kg/d) for 4 weeks. The weight and number of ectopic lesions were determined, and the expression of markers was assessed using immunohistochemistry. Results: Baicalein inhibited the invasion of EcESCs and the expression of certain invasion-related proteins, including MMP9, MMP2, and MT1-MMP. Exposure to baicalein reduced the extracellular levels of TGFB1 in EcESCs and the reduced expression of TGFB1, resulting in decreased expression of FURIN in EcESCs, which serves a pivotal role in the transformation of pro-MT1-MMP to activated MT1-MMP. In the mouse model of EMs, intraperitoneal injection of baicalein inhibited the growth of ectopic lesions and reduced MT1-MMP, FURIN, and TGFB1 expression. Conclusions: Baicalein reduced the invasion of EMs, potentially by restricting the FURIN-MT1-MMP-mediated cell invasion of EcESCs maybe through reduction of the autocrine of TGFB1.

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“… 22 Additionally, in lung carcinoma, our previous study exhibited that overexpression of PACE4 is indicative of poor clinical outcome. 23 Mechanistically, Panet et al 24 showed that PCAE4 was the key driver of ZR-75-1 estrogen receptor-positive breast proliferation and tumor progression. PACE4 can modulate apoptosis in human prostate cancer cells via endoplasmic reticulum stress and mitochondrial signaling pathways.…”

Section: Discussionmentioning

confidence: 99%

<p>PACE4 Expression is a Novel Independent Prognostic Factor in Nasopharyngeal Carcinoma</p>

Lin

Long

Tan

et al. 2020

CMAR

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Background Paired basic amino acid-cleaving enzyme 4 (PACE4) belongs to the family of proprotein convertase and is essential for tumor progression, whereas its role in cancer remains controversial and little is known about its role in nasopharyngeal carcinoma (NPC). The aim of this study was to examine if the expression of PACE4 is a prognostic biomarker for patients with NPC. Methods Immunofluorescence (IF) and immunohistochemistry (IHC) were used to analyze PACE4 expression in NPC cell line CNE1 and 172 clinicopathologically characterized NPC tissues. The data were analyzed by Chi-square test, Kaplan–Meier plots, and Cox proportional hazards regression model. Results IF and IHC staining results showed that PACE4 was mainly located in the cytoplasm of NPC cell line (CNE1) and NPC tissues. Expression of PACE4 was observed in 46/172 (26.7%) of NPC tissues. Further analysis showed that expression of PACE4 was positively associated with late N stage, distant metastasis, and late clinical stage ( P <0.05). High expression of PACE4 predicted shorter 5-year overall survival of patients with NPC, especially for the patients in advanced stage (32.7% vs 77.3%, P <0.001). Furthermore, multivariate analysis showed that PACE4 expression may serve as a potential prognostic factor for NPC. Conclusion Our results suggest that PACE4 may play a crucial role in tumor progression and may serve as a valuable prognostic biomarker for patients with NPC.

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PACE4 is an important driver of ZR-75-1 estrogen receptor-positive breast cancer proliferation and tumor progression

Cited by 15 publications

References 33 publications

Evaluation of PACE4 isoforms as biomarkers in thyroid cancer

Evaluation of PACE4 isoforms as biomarkers in thyroid cancer

Baicalein inhibits FURIN‐MT1‐MMP‐mediated invasion of ectopic endometrial stromal cells in endometriosis possibly by reducing the secretion of TGFB1

<p>PACE4 Expression is a Novel Independent Prognostic Factor in Nasopharyngeal Carcinoma</p>

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