Impact of suppression of tumorigenicity 14 (ST14)/serine protease 14 (Prss14) expression analysis on the prognosis and management of estrogen receptor negative breast cancer

Kim, Sauryang; Yang, Jae Woong; Kim, Chungho; Kim, Moon Gyo

doi:10.18632/oncotarget.9155

Cited by 11 publications

(14 citation statements)

References 76 publications

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“…To investigate the clinical relevance of this finding, a bioinformatics approach was utilized. Previously, we reported that high expression of epithin/PRSS14 in patients with ERnegative breast cancer indicated poor patient survival [12]. Consistently, we found that three out of four ER-negative patient samples showed higher expression of epithin/ PRSS14 in tumor than in normal tissues (Additional file 1: Figure S10).…”

Section: Eicd Induces Changes In Gene Expressionsupporting

confidence: 82%

“…Many studies have shown that epithin/PRSS14 is upregulated in a variety of human epithelial cancers [7] and is tightly linked to higher tumor grades and poorer survival of patients [8][9][10][11]. Recently, we reported from the analysis of public databases of patients with breast cancer that epithin/PRSS14 is a prominent prognosis marker for patients with estrogen receptor (ER)-negative breast cancer [12]. The role of epithin/ PRSS14 in metastasis and survival has been evaluated in multiple animal studies.…”

Section: Introductionmentioning

confidence: 99%

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Intramembrane proteolysis of an extracellular serine protease, epithin/PRSS14, enables its intracellular nuclear function

Cho

Kim

et al. 2020

BMC Biol

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Background: Epithin/PRSS14, a type II transmembrane serine protease, is an emerging target of cancer therapy because of its critical roles in tumor progression and metastasis. In many circumstances, the protease, through its ectodomain shedding, exists as a soluble form and performs its proteolytic functions in extracellular environments increasing cellular invasiveness. The seemingly functional integrity of the soluble form raises the question of why the protease is initially made as a membrane-associated protein. Results: In this report, we show that the epithin/PRSS14 intracellular domain (EICD) can be released from the membrane by the action of signal peptide peptidase-like 2b (SPPL2b) after ectodomain shedding. The EICD preferentially localizes in the nucleus and can enhance migration, invasion, and metastasis of epithelial cancer when heterologously expressed. Unbiased RNA-seq analysis and subsequent antibody arrays showed that EICD could control the gene expression of chemokines involved in cell motility, by increasing their promoter activities. Finally, bioinformatics analysis provided evidence for the clinical significance of the intramembrane proteolysis of epithin/ PRSS14 by revealing that the poor survival of estrogen receptor (ER)-negative breast cancer patients with high epithin/PRSS14 expression is further worsened by high levels of SPPL2b. Conclusions: These results show that ectodomain shedding of epithin/PRSS14 can initiate a unique and synchronized bidirectional signal for cancer metastasis: extracellularly broadening proteolytic modification of the surrounding environment and intracellularly reprogramming the transcriptome for metastatic conversion. Clinically, this study also suggests that the intracellular function of epithin/PRSS14 should be considered for targeting this protease for anti-cancer treatment.

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Section: Eicd Induces Changes In Gene Expressionsupporting

confidence: 82%

Section: Introductionmentioning

confidence: 99%

Intramembrane proteolysis of an extracellular serine protease, epithin/PRSS14, enables its intracellular nuclear function

Cho

Kim

et al. 2020

BMC Biol

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“…In our earlier careful analysis of TCGA breast cancer patients, we showed that Prss14/epithin (ST14) is an excellent prognostic marker for highly metastatic ERbreast cancer (3). In this study, we have shown that expression profiles of PKCB (PKC and ST14 are in reasonably well-correlated (Fig.…”

Section: Implication Of Pkc and Jnk As Prognosis Markers As Well As supporting

confidence: 52%

“…Overexpression of Prss14/epithin is found in various epithelial cancer types (2). Particularly, ER-negative (ER -) breast cancer patients with poor prognosis express higher levels of Prss14/epithin (3). In our earlier report involving pathological examinations, we showed that prognosis of postsurgery esophageal cancer patients with higher Prss14/epithin expression is very poor (4).…”

mentioning

confidence: 92%

A JUN N-terminal kinase inhibitor induces ectodomain shedding of the cancer-associated membrane protease Prss14/epithin via protein kinase CβII

Yoon

Cho

Kim

et al. 2020

Journal of Biological Chemistry

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Serine protease 14 (Prss14)/epithin is a transmembrane serine protease that plays essential roles in tumor progression and metastasis and therefore is a promising target for managing cancer. Prss14/epithin shedding may underlie its activity in cancer and worsen outcomes; accordingly, a detailed understanding of the molecular mechanisms in Prss14/epithin shedding may inform the design of future cancer therapies. On the basis of our previous observation that an activator of PKC, phorbol 12-myristate 13-acetate (PMA), induces Prss14/epithin shedding, here we further investigated the intracellular signaling pathway involved in this process. While using mitogen-activated protein kinase inhibitors to investigate possible effectors of downstream PKC signaling, we unexpectedly found that an inhibitor of c-Jun N-terminal kinase (JNK), SP600125, induces Prss14/epithin shedding even in the absence of PMA. SP600125-induced shedding, like that stimulated by PMA, was mediated by tumor necrosis factor-α–converting enzyme. In contrast, a JNK activator, anisomycin, partially abolished the effects of SP600125 on Prss14/epithin shedding. Moreover, the results from loss-of-function experiments with specific inhibitors, short hairpin RNA–mediated knockdown, and overexpression of dominant-negative PKCβII variants indicated that PKCβII is a major player in JNK inhibition– and PMA-mediated Prss14/epithin shedding. SP600125 increased phosphorylation of PKCβII and tumor necrosis factor-α–converting enzyme and induced their translocation into the plasma membrane. Finally, in vitro cell invasion experiments and bioinformatics analysis of data in The Cancer Genome Atlas breast cancer database revealed that JNK and PKCβII are important for Prss14/epithin-mediated cancer progression. These results provide important information regarding strategies against tumor metastasis.

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“…Serine protease 14 (PRSS14), also called epithin ( 14 ), matriptase ( 15 ), or membrane-type serine protease 1 ( 16 ), is a typical membrane-type serine protease that is overexpressed in multiple cancer cell lines and breast cancer tissues ( 17 18 ). Its role in breast cancer progression has been demonstrated in several conventional pathologic studies ( 19 20 21 ). When Prss14 hypomorphic mice, which express a minimal amount of Prss14, were crossed into spontaneous breast cancer transgenic mice, mouse mammary tumor virus (MMTV)-polyoma middle tumor-antigen (PyMT), tumor growth was significantly reduced ( 22 ).…”

Section: Introductionmentioning

confidence: 98%

Critical Adjuvant Influences on Preventive Anti-Metastasis Vaccine Using a Structural Epitope Derived from Membrane Type Protease PRSS14

et al. 2020

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We tested how adjuvants effect in a cancer vaccine model using an epitope derived from an autoactivation loop of membrane-type protease serine protease 14 (PRSS14; loop metavaccine) in mouse mammary tumor virus (MMTV)-polyoma middle tumor-antigen (PyMT) system and in 2 other orthotopic mouse systems. Earlier, we reported that loop metavaccine effectively prevented progression and metastasis regardless of adjuvant types and T H types of hosts in tail-vein injection systems. However, the loop metavaccine with Freund's complete adjuvant (CFA) reduced cancer progression and metastasis while that with alum, to our surprise, were adversely affected in 3 tumor bearing mouse models. The amounts of loop peptide specific antibodies inversely correlated with tumor burden and metastasis, meanwhile both T H 1 and T H 2 isotypes were present regardless of host type and adjuvant. Tumor infiltrating myeloid cells such as eosinophil, monocyte, and neutrophil were asymmetrically distributed among 2 adjuvant groups with loop metavaccine. Systemic expression profiling using the lymph nodes of the differentially immunized MMTV-PyMT mouse revealed that adjuvant types, as well as loop metavaccine can change the immune signatures. Specifically, loop metavaccine itself induces T H 2 and T H 17 responses but reduces T H 1 and T reg responses regardless of adjuvant type, whereas CFA but not alum increased follicular T H response. Among the myeloid signatures, eosinophil was most distinct between CFA and alum. Survival analysis of breast cancer patients showed that eosinophil chemokines can be useful prognostic factors in PRSS14 positive patients. Based on these observations, we concluded that multiple immune parameters are to be considered when applying a vaccine strategy to cancer patients.

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Impact of suppression of tumorigenicity 14 (ST14)/serine protease 14 (Prss14) expression analysis on the prognosis and management of estrogen receptor negative breast cancer

Cited by 11 publications

References 76 publications

Intramembrane proteolysis of an extracellular serine protease, epithin/PRSS14, enables its intracellular nuclear function

Intramembrane proteolysis of an extracellular serine protease, epithin/PRSS14, enables its intracellular nuclear function

A JUN N-terminal kinase inhibitor induces ectodomain shedding of the cancer-associated membrane protease Prss14/epithin via protein kinase CβII

Critical Adjuvant Influences on Preventive Anti-Metastasis Vaccine Using a Structural Epitope Derived from Membrane Type Protease PRSS14

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