PWAR1

Gene Summary

Gene:PWAR1; Prader Willi/Angelman region RNA 1
Aliases: PAR1, PAR-1, D15S227E
Location:15q11.2
Summary:-
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Source:NCBIAccessed: 31 August, 2019

Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 31 August 2019 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

Tag cloud generated 31 August, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (3)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: PWAR1 (cancer-related)

Kuroda N, Yorita K
Clinicopathologic study of 10 cases of gastric adenocarcinoma with hepatoid or enteroblastic differentiation.
Pol J Pathol. 2018; 69(2):128-135 [PubMed] Related Publications
Gastric adenocarcinoma with hepatoid or enteroblastic differentiation (GAHED), known also as AFP-producing carcinoma, is a rare neoplasm. Ten cases with GAHED and 209 cases without GAHED were selected. Clinicopathological features of GAHED were investigated. The disease-free survival (DFS) of the GAHED group was compared with that of the non-GAHED group. Grossly, the tumours consisted of two early types and eight advanced types. Histologically, all tumours were composed of various proportions of tubular, cribriform, papillary, solid, and/or trabecular growth patterns of clear to slightly eosinophilic tumour cells. Hyaline globules were observed in all tumours. AFP and Hep-Par1 were immunoreactive in all tumours. In fluorescence in situ hybridisation of HER2 gene/chromosome 17, the amplification of HER2 gene was observed in two cases that showed positive reaction for HER2 protein. Clinical follow-up was available in nine cases. Regarding the clinical outcome, 3 and 6 patients were alive without disease and alive with disease, respectively. In a statistical analysis, the DFS of the GAHED group was significantly worse than that of the non-GAHED group. GAHED is morphologically characterised by various growth patterns of clear to slightly eosinophilic tumour cells and intracytoplasmic possession of hyaline globules. This tumour may have the potential to behave in an aggressive clinical fashion.

Lin J, Cao Y, Yu L, Lin L
Non-α-fetoprotein-producing adrenal hepatoid adenocarcinoma: A case report and literature review.
Medicine (Baltimore). 2018; 97(39):e12336 [PubMed] Free Access to Full Article Related Publications
RATIONALE: Adrenal hepatoid adenocarcinoma typically secretes alpha-fetoprotein (AFP). Here, we report a case of non-AFP-producing adrenal hepatoid adenocarcinoma. Next-generation sequencing (NGS) was conducted to identify gene mutations.
PATIENT CONCERNS: A 64-year-old man presented with mild back pain and unexplained weight loss for 3 months.
DIAGNOSES: Contrast-enhanced magnetic resonance imaging (MRI) showed a mass (9.9 × 9.7 × 9.1 mm) above the upper pole of the left kidney. The left renal artery and vein were compressed. The tumor was positive for CK8/18, CK19, CK7, hepatocyte marker (Hepatocyte), and Hep Par 1, but negative for AFP. Plasma AFP was 2.75 ng/mL (normal range: 0-7 ng/mL). NGS revealed mutations of the following genes: ATM, CDKN2A, EGFR, STK11, TP53, BIM, and MLH1. A diagnosis of adrenal hepatoid adenocarcinoma was established.
INTERVENTIONS: The treatment included 4 cycles of the mFOLFOX6 regimen (oxaliplatin, leucovorin, and fluorouracil), transcatheter arterial chemoembolization, and apatinib.
OUTCOMES: The patient died 9 months after the diagnosis.
LESSONS: This case highlights the importance of thorough clinical, radiological, and immunohistochemical investigation for suspected adrenal hepatoid adenocarcinoma. Metastasis from other primary tumors should be ruled out. Furthermore, AFP is not necessarily elevated in adrenal hepatoid adenocarcinoma. NGS could be helpful in establishing the diagnosis and selecting treatments.

Olsson L, Lundin-Ström KB, Castor A, et al.
Improved cytogenetic characterization and risk stratification of pediatric acute lymphoblastic leukemia using single nucleotide polymorphism array analysis: A single center experience of 296 cases.
Genes Chromosomes Cancer. 2018; 57(11):604-607 [PubMed] Related Publications
Single nucleotide polymorphism array (SNP-A) analyses are increasingly being introduced in routine genetic diagnostics of acute lymphoblastic leukemia (ALL). Despite this, only few studies that have compared the diagnostic value of SNP-A with conventional chromosome banding have been published. We here report such a comparison of 296 ALL cases, the largest series to date. Only genomic imbalances >5 Mb and microdeletions targeting the BTG1, CDKN2A/B, EBF1, ERG, ETV6, IKZF1, PAX5, and RB1 genes and the pseudoautosomal region 1 (PAR1) were ascertained, in agreement with recent guidelines. Of 36 T-cell ALL cases, the karyotypes of 24 cases (67%) were revised by SNP-A analyses that either revealed additional imbalances >5 Mb or better characterized the changes found by G-banding. Of 260 B-cell precursor (BCP) ALL cases, SNP-A analyses identified additional copy number alterations, including the above-mentioned microdeletions, or better characterized the imbalances found by G-banding in 236 (91%) cases. Furthermore, the cytogenetic subtype classification of 41/260 (16%) BCP ALL cases was revised based on the SNP-A findings. Of the subtype revisions, 12/41 (29%) had clinical implications as regards risk stratifying cytogenetic groups or genotype-specific minimal residual disease stratification. We conclude that SNP-A analyses dramatically improve the cytogenetic characterization of both T-cell and BCP ALL and also provide important information pertinent to risk stratification of BCP ALL.

Xiao T, Zhang Q, Zong S, et al.
Protease-activated receptor-1 (PAR1) promotes epithelial-endothelial transition through Twist1 in hepatocellular carcinoma.
J Exp Clin Cancer Res. 2018; 37(1):185 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Tumor cells transfer into endothelial cells by epithelial-endothelial transition (EET), which is characterized by vasculagenic mimicry (VM) in morphology. VM can change tumor microcirculation, progression, and metastasis. However, the molecular mechanisms of endothelial-like transition remain unclear. EET is a subtype of epithelial-mesenchymal transition (EMT). Twist1, a transcriptional regulatory factor of EMT, is an important factor that induces EET in hepatocellular carcinoma(HCC), but the upstream signal of Twist1 is unclear.
METHODS: Expression plasmids, Ca mobilization, and three-dimensional cultures were evaluated. Western blot assay, reporter gene assay, and immunofluorescence staining were conducted. A murine xenograft model was established. Analyses of immunohistochemistry, patient samples, and complementary DNA (cDNA) microarrays were also performed.
RESULTS: This study demonstrated that protease-activated receptor-1 (PAR1) can increase the expression of endothelial markers and enhance VM formation by upregulating Twist1 both in vitro and in vivo through thrombin binding. Thrombin not only activates PAR1 but also promotes PAR1 internalization in a time-dependent manner. Clinical pathological analysis further confirms that PAR1 expression is directly correlated with the endothelial marker expression, VM formation, and metastasis and indicates poor survival rate of patients with tumors.
CONCLUSION: PAR1 promotes EET through Twist1 in HCC.

Borges CS, Ferreira AF, Almeida VH, et al.
Crosstalk between BCR-ABL and protease-activated receptor 1 (PAR1) suggests a novel target in chronic myeloid leukemia.
Exp Hematol. 2018; 66:50-62 [PubMed] Related Publications
Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm characterized by the presence of the Philadelphia chromosome, which generates the oncogene BCR-ABL1. Protease-activated receptor 1 (PAR1) is involved in tumor progression and angiogenesis. We have previously reported that PAR1 expression is elevated in human leukemias that display a more aggressive clinical behavior, including the blast crisis of CML. In this study, we analyzed the crosstalk between the oncoprotein BCR-ABL and PAR1 in CML. Leukemic cell lines transfected with the BCR-ABL1 oncogene showed significantly higher expression levels of PAR1 compared with that of wild-type counterparts. This phenomenon was reversed by treatment with tyrosine kinase inhibitors (TKIs). Conversely, treatment with the PAR1 antagonist SCH79797 inhibited BCR-ABL expression. The PAR1 antagonist induced apoptosis in a dose- and time-dependent manner. Higher vascular endothelial growth factor (VEGF) levels were observed in cells transfected with BCR-ABL1 than in their wild-type counterparts. VEGF expression was strongly inhibited after treatment with either TKIs or the PAR1 antagonist. Finally, we evaluated PAR1 expression in CML patients who were either in the blast or chronic phases and had either received TKI treatment or no treatment. A significant decrease in PAR1 expression was observed in treatment-responsive patients, as opposed to a significant increase in PAR1 expression levels in treatment-resistant patients. Patients classified as high risk according to the Sokal index showed higher PAR1 expression levels. Our results demonstrate the crosstalk between BCR-ABL and PAR1. These data may offer important insight into the development of new therapeutic strategies for CML.

Huang C, Li Y, Guo Y, et al.
MMP1/PAR1/SP/NK1R paracrine loop modulates early perineural invasion of pancreatic cancer cells.
Theranostics. 2018; 8(11):3074-3086 [PubMed] Free Access to Full Article Related Publications
The molecular mechanism of perineural invasion (PNI) is unclear, and insufficient detection during early-stage PNI

Ungefroren H, Gieseler F, Kaufmann R, et al.
Signaling Crosstalk of TGF-β/ALK5 and PAR2/PAR1: A Complex Regulatory Network Controlling Fibrosis and Cancer.
Int J Mol Sci. 2018; 19(6) [PubMed] Free Access to Full Article Related Publications
Both signaling by transforming growth factor-β (TGF-β) and agonists of the G Protein-coupled receptors proteinase-activated receptor-1 (PAR1) and -2 (PAR2) have been linked to tissue fibrosis and cancer. Intriguingly, TGF-β and PAR signaling either converge on the regulation of certain matrix genes overexpressed in these pathologies or display mutual regulation of their signaling components, which is mediated in part through sphingosine kinases and sphingosine-1-phosphate and indicative of an intimate signaling crosstalk between the two pathways. In the first part of this review, we summarize the various regulatory interactions that have been discovered so far according to the organ/tissue in which they were described. In the second part, we highlight the types of signaling crosstalk between TGF-β on the one hand and PAR2/PAR1 on the other hand. Both ligand⁻receptor systems interact at various levels and by several mechanisms including mutual regulation of ligand⁻ligand, ligand⁻receptor, and receptor⁻receptor at the transcriptional, post-transcriptional, and receptor transactivation levels. These mutual interactions between PAR2/PAR1 and TGF-β signaling components eventually result in feed-forward loops/vicious cycles of matrix deposition and malignant traits that exacerbate fibrosis and oncogenesis, respectively. Given the crucial role of PAR2 and PAR1 in controlling TGF-β receptor activation, signaling, TGF-β synthesis and bioactivation, combining PAR inhibitors with TGF-β blocking agents may turn out to be more efficient than targeting TGF-β alone in alleviating unwanted TGF-β-dependent responses but retaining the beneficial ones.

Stanulla M, Dagdan E, Zaliova M, et al.
IKZF1
J Clin Oncol. 2018; 36(12):1240-1249 [PubMed] Related Publications
Purpose Somatic deletions that affect the lymphoid transcription factor-coding gene IKZF1 have previously been reported as independently associated with a poor prognosis in pediatric B-cell precursor (BCP) acute lymphoblastic leukemia (ALL). We have now refined the prognostic strength of IKZF1 deletions by analyzing the effect of co-occurring deletions. Patients and Methods The analysis involved 991 patients with BCP ALL treated in the Associazione Italiana Ematologia ed Oncologia Pediatrica-Berlin-Frankfurt-Muenster (AIEOP-BFM) ALL 2000 trial with complete information for copy number alterations of IKZF1, PAX5, ETV6, RB1, BTG1, EBF1, CDKN2A, CDKN2B, Xp22.33/Yp11.31 (PAR1 region; CRLF2, CSF2RA, and IL3RA), and ERG; replication of findings involved 417 patients from the same trial. Results IKZF1 deletions that co-occurred with deletions in CDKN2A, CDKN2B, PAX5, or PAR1 in the absence of ERG deletion conferred the worst outcome and, consequently, were grouped as IKZF1

Wang Q, Yang H, Zhuo Q, et al.
Knockdown of EPCR inhibits the proliferation and migration of human gastric cancer cells via the ERK1/2 pathway in a PAR-1-dependent manner.
Oncol Rep. 2018; 39(4):1843-1852 [PubMed] Related Publications
Endothelial protein C receptor (EPCR) has been implicated in the carcinogenesis of diverse tumor types. This tumor-promoting effect of EPCR is associated with the upregulation of activated protein C and the activation of protease-activated receptor 1 (PAR-1). However, the exact role of EPCR in gastric cancer (GC) and the mechanisms underlying the regulation of EPCR remain elusive. In the present study, we investigated the effects of EPCR on human GC cells, as well as the underlying mechanisms. An siRNA inference system was used to knock down the expression of EPCR in GC cells, and CCK-8, colony formation and Transwell assays were performed to determine the effects of EPCR knockdown on the proliferation and migration of the tumor cells. Additionally, cell cycle distribution and apoptosis were assessed by flow cytometry, and activated PAR-1 levels were determined by cell ELISA. The results indicated that the proliferation, clonogenicity and migration were significantly reduced and that the cell cycle was arrested in the Gap 1 phase by EPCR knockdown in SGC7901 and AGS cells. Meanwhile, apoptosis was promoted by EPCR knockdown in the two cell lines. The activation of PAR-1 on the cell surface of SGC7901 and AGS cells was significantly reduced after the knockdown of EPCR. By contrast, blockade of PAR-1 reduced the proliferation and migration of gastric cells in vitro. Additionally, after the knockdown of EPCR or treatment with PAR-1 antibody, the expression of pERK1/2 was significantly downregulated in the SGC7901 and AGS cells, while the expression levels of p-AKT (S473) and p-AKT (T308) were unchanged. The findings of the present study demonstrated that EPCR exerts pro-carcinogenic effects in GC cells in a PAR-1-dependent manner via the ERK1/2-MAPK pathway. Thus, EPCR may be a potential molecular diagnostic or therapeutic target for GC.

Volejnikova J, Zapletalova J, Jarosova M, et al.
Acute lymphoblastic leukemia in a child with Leri-Weill syndrome and complete SHOX gene deletion: A Case Report.
Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub. 2018; 162(1):65-70 [PubMed] Related Publications
BACKGROUND: Leri-Weill syndrome (LWS) ranks among conditions with short stature homeobox gene (SHOX) haploinsufficiency. Data on possible association of SHOX aberrations with malignant diseases are scarce.
METHODS AND RESULTS: We report a unique case of an 8-year-old girl who was successfully treated for acute lymphoblastic leukemia (pre-B ALL, intermediate risk) and was subsequently diagnosed with LWS due to characteristic clinical appearance (short disproportionate stature, Madelung deformity of the wrist) and molecular genetic examination (complete deletion of SHOX). An identical SHOX deletion was identified also in the patient's mother. Leukemic cells of the patient were retrospectively examined by array comparative genomic hybridization (aCGH), which revealed five regions of deletions at chromosome X, including the SHOX gene locus.
CONCLUSION: Growth retardation in children with hemato-oncologic malignancies cannot always be attributed to cytotoxic treatment and should be carefully evaluated, especially with regards to growth hormone therapy.

Singh M, Bhatia P, Trehan A, et al.
High frequency of intermediate and poor risk copy number abnormalities in pediatric cohort of B-ALL correlate with high MRD post induction.
Leuk Res. 2018; 66:79-84 [PubMed] Related Publications
Copy number abnormalities (CNAs) and recurrent fusion transcripts are important genetic events which define and prognosticate B-Cell Acute Lymphoblastic Leukemia (B-ALL). We evaluated CNAs and fusion transcripts in 67 pediatric B-ALL cases and correlated the data with standard risk factors and early treatment outcome parameters. Common fusion transcripts ETV6-RUNX1, E2A-PBX, BCR-ABL1 and MLL-AF4 were examined by RT-PCR and noted in 15%, 15%, 13% and 1.4% of all cases respectively. CNAs in IKZF1, PAX5, EBF1, BTG1, RB1, CDKN2A/B and genes from PAR1 region viz., CSF2RA, IL3RA,P2RY8, SHOX region and CRLF2 were analyzed by multiplex ligation dependent probe amplification assay and were detected in 70% (47/67) of cases, with predominantly deletions in CDKN2A/B (36%), PAX5 (18%) and IKZF1 (16%). A statistically significant association of intermediate/poor risk CNAs was noted with high WBC count (p = 0.001), NCI group (p = 0.02) and minimal residual disease at Day35 (p < 0.0001). IKZF1 and CDKN2A/B deletion revealed poor EFS of 56% at 24 months as compared to EFS of 80% in rest of the cases (p = 0.05) suggesting their potential role in early risk stratification.

Cavalcante GC, Amador MA, Ribeiro Dos Santos AM, et al.
Analysis of 12 variants in the development of gastric and colorectal cancers.
World J Gastroenterol. 2017; 23(48):8533-8543 [PubMed] Free Access to Full Article Related Publications
AIM: To evaluate the relation between 12 polymorphisms and the development of gastric cancer (GC) and colorectal cancer (CRC).
METHODS: In this study, we included 125 individuals with GC diagnosis, 66 individuals with CRC diagnosis and 475 cancer-free individuals. All participants resided in the North region of Brazil and authorized the use of their samples. The 12 polymorphisms (in
RESULTS: After statistical analyses with the control of confounding factors, such as genetic ancestry, three markers (rs79071878 in
CONCLUSION: These findings are important for the comprehension of gastric and CRC development, particularly in highly admixed populations, such as the Brazilian population.

Arakaki AKS, Pan WA, Lin H, Trejo J
The α-arrestin ARRDC3 suppresses breast carcinoma invasion by regulating G protein-coupled receptor lysosomal sorting and signaling.
J Biol Chem. 2018; 293(9):3350-3362 [PubMed] Free Access to Full Article Related Publications
Aberrant G protein-coupled receptor (GPCR) expression and activation has been linked to tumor initiation, progression, invasion, and metastasis. However, compared with other cancer drivers, the exploitation of GPCRs as potential therapeutic targets has been largely ignored, despite the fact that GPCRs are highly druggable. Therefore, to advance the potential status of GPCRs as therapeutic targets, it is important to understand how GPCRs function together with other cancer drivers during tumor progression. We now report that the α-arrestin domain-containing protein-3 (ARRDC3) acts as a tumor suppressor in part by controlling signaling and trafficking of the GPCR, protease-activated receptor-1 (PAR1). In a series of highly invasive basal-like breast carcinomas, we found that expression of ARRDC3 is suppressed whereas PAR1 is aberrantly overexpressed because of defective lysosomal sorting that results in persistent signaling. Using a lentiviral doxycycline-inducible system, we demonstrate that re-expression of ARRDC3 in invasive breast carcinoma is sufficient to restore normal PAR1 trafficking through the ALG-interacting protein X (ALIX)-dependent lysosomal degradative pathway. We also show that ARRDC3 re-expression attenuates PAR1-stimulated persistent signaling of c-Jun N-terminal kinase (JNK) in invasive breast cancer. Remarkably, restoration of ARRDC3 expression significantly reduced activated PAR1-induced breast carcinoma invasion, which was also dependent on JNK signaling. These findings are the first to identify a critical link between the tumor suppressor ARRDC3 and regulation of GPCR trafficking and signaling in breast cancer.

You S, Li W, Guan Y
Tunicamycin inhibits colon carcinoma growth and aggressiveness via modulation of the ERK-JNK-mediated AKT/mTOR signaling pathway.
Mol Med Rep. 2018; 17(3):4203-4212 [PubMed] Free Access to Full Article Related Publications
Epidemiology and evidence have demonstrated that colon carcinoma is one of the most common gastrointestinal tumors in the clinic. Reports have suggested that Tunicamycin significantly inhibits aggressiveness of colon carcinoma cells by promotion of apoptosis. In the present study, the inhibitory effect of tunicamycin on colon cancer cells and the potential underlying molecular mechanism was investigated. Western blotting, immunohistochemistry, apoptotic assays and immunofluorescence were used to analyze the therapeutic effects of tunicamycin on apoptosis, growth, aggressiveness and cell cycle of colon tumor cells, by downregulation of fibronectin, vimentin and E‑cadherin expression levels. In vitro experiments demonstrated that tunicamycin significantly inhibited growth, migration and invasion of colon carcinoma cells. In addition, tunicamycin administration promoted apoptosis of colon carcinoma cells via upregulation of apoptotic protease activating factor 1 and cytochrome c expression levels, which are proteins that have a role in mitochondrial apoptosis signaling. Cell cycle assays revealed that tunicamycin suppressed proliferation and arrested S phase entry of colon carcinoma cells. Mechanistic analysis demonstrated that tunicamycin reduced expression and phosphorylation levels of extracellular signal‑regulated kinase (ERK), c‑JUN N‑terminal kinase (JNK) and protein kinase B (AKT), and inhibited mammalian target of rapamycin (mTOR) expression levels in colon carcinoma cells. Endogenous overexpression of ERK inhibited tunicamycin‑mediated downregulation of JNK, AKT and mTOR expression, which further blocked tunicamycin‑mediated inhibition of growth and aggressiveness of colon carcinoma. In vivo assays revealed that tunicamycin treatment significantly inhibited tumor growth and promoted apoptosis, which led to long‑term survival of tumor‑bearing mice compared with the control group. In conclusion, these results suggested that tunicamycin may inhibit growth and aggressiveness of colon cancer via the ERK‑JNK‑mediated AKT/mTOR signaling pathway, and suggested that tunicamycin may be a potential anti‑cancer agent for colon carcinoma therapy.

Kaneko N, Kawano S, Yasuda K, et al.
Differential roles of kallikrein-related peptidase 6 in malignant transformation and ΔNp63β-mediated epithelial-mesenchymal transition of oral squamous cell carcinoma.
Oral Oncol. 2017; 75:148-157 [PubMed] Related Publications
We previously reported that epithelial-to-mesenchymal transition (EMT) was mediated by ΔNp63β in oral squamous cell carcinoma (OSCC). In this study, DNA microarray analyses were performed using ΔNp63β-overexpressing OSCC cells to identify genes associated with ΔNp63β-mediated EMT. Thereby, we focused on kallikrein-related peptidase (KLK) 6, most up-regulated following ΔNp63β-overexpression, that activates protease-activated receptors (PARs). In RT-PCR analyses, ΔNp63 was positively associated with KLK6 and PAR2 and negatively with PAR1 in OSCC cells. By ΔNp63 knockdown, KLK6 and PAR2 expression was decreased and PAR1 was increased. Furthermore, KLK6 knockdown led to enhancing migration and invasion, and inhibiting proliferation, suggesting EMT-phenotypes. Although, in the KLK6 or PAR2 knockdown cells, phosphorylation of ERK was reduced, it was restored in the KLK6 knockdown OSCC cells treated with recombinant KLK6 proteins. Immunohistochemistry showed ΔNp63, KLK6, and PAR2 were more strongly expressed in the epithelial dysplasia and central region of OSCC than normal oral epithelium, whereas PAR1 expression was undetectable. Interestingly, at the invasive front of OSCC, ΔNp63, KLK6, and PAR2 were reduced, but PAR1 was elevated. In addition, the OSCC patients with decreasing KLK6 expression at the invasive front had more unfavourable prognosis. These results suggested differential roles of KLK6 in malignant transformation and EMT; high ΔNp63β expression up-regulates KLK6-PAR2 and down-regulates PAR1, inducing malignant transformation in oral epithelium with stimulating proliferation through ERK signal activation. Moreover, KLK6-PAR2 expression is down-regulated and PAR1 is up-regulated when ΔNp63β expression is decreased, leading to EMT with enhancing migration and invasion through ERK signal reduction at the invasive front.

Lopez MV, Cafferata EG, Viale DL, Podhajcer OL
Synthetic Tumor-Specific Promoters for Transcriptional Regulation of Viral Replication.
Methods Mol Biol. 2017; 1651:113-130 [PubMed] Related Publications
Here we describe a collection of methods that have been adapted to isolate and modify tumor-specific promoters (TSPs ) to drive viral replication for cancer therapy and other uses. We will describe as examples the secreted protein acidic and rich in cysteine (SPARC ) and the protease-activated receptor-1 (PAR-1) promoter. We outline strategies to select appropriate TSPs using bioinformatics resources and the methods utilized in their subsequent cloning, assessment of transcriptional activity, and their use in conditionally replicative oncolytic adenoviruses .

Ribera J, Zamora L, Morgades M, et al.
Copy number profiling of adult relapsed B-cell precursor acute lymphoblastic leukemia reveals potential leukemia progression mechanisms.
Genes Chromosomes Cancer. 2017; 56(11):810-820 [PubMed] Related Publications
The outcome of relapsed adult acute lymphoblastic leukemia (ALL) remains dismal despite new therapeutic approaches. Previous studies analyzing relapse samples have shown a high degree of heterogeneity regarding gene alterations without an evident relapse signature. Bone marrow or peripheral blood samples from 31 adult B-cell precursor ALL patients at first relapse, and 21 paired diagnostic samples were analyzed by multiplex ligation probe-dependent amplification (MLPA). Nineteen paired diagnostic and relapse samples of these 21 patients were also analyzed by SNP arrays. A trend to acquire homozygous CDKN2A/B deletions and a significant increase in the number of copy number alterations (CNA) was observed from diagnosis to first relapse. Evolution from an ancestral clone was the main pattern of clonal evolution. Relapse samples were extremely heterogeneous regarding CNA frequencies. However, CDKN2A/B, PAX5, ETV6, ATM, IKZF1, VPREB1, and TP53 deletions and duplications of 1q, 8q, 17q, 21, X/Y PAR1, and Xp were frequently detected at relapse. Duplications of genes involved in cell proliferation, drug resistance and stem cell homeostasis regulation, as well as deletions of KDM6A and STAG2 genes emerged as specific alterations at relapse. Genomics of relapsed adult B-cell precursor ALL is highly heterogeneous, although some recurrent lesions involved in essential pathways deregulation were frequently observed. Selective and simultaneous targeting of these deregulated pathways may improve the results of current salvage therapies.

Wang T, Jiao J, Zhang H, et al.
TGF-β induced PAR-1 expression promotes tumor progression and osteoclast differentiation in giant cell tumor of bone.
Int J Cancer. 2017; 141(8):1630-1642 [PubMed] Related Publications
Although protease activated receptor-1 (PAR-1) has been confirmed as an oncogene in many cancers, the role of PAR-1 in giant cell tumor (GCT) of bone has been rarely reported. The mechanism of PAR-1 in tumor-induced osteoclastogenesis still remains unclear. In the present study, we detected that PAR-1 was significantly upregulated in GCT of bone compared to normal tissues, while TGF-β was also overexpressed in GCT tissues and could promote the expression of PAR-1 in a dose and time dependent manner. Using the luciferase reporter assay, we found that two downstreams of TGF-β, Smad3 and Smad4, could activate the promoter of PAR-1, which might explain the mechanism of TGF-β induced PAR-1 expression. Meanwhile, PAR-1 was also overexpressed in microvesicles from stromal cells of GCT (GCTSCs), and might be transported from GCTSCs to monocytes through microvesicles. In addition, knockout of PAR-1 by TALENs in GCTSCs inhibited tumor growth, angiogenesis and osteoclastogenesis in GCT in vitro. Using the chick CAM models, we further showed that inhibition of PAR-1 suppressed tumor growth and giant cell formation in vivo. Using microarray assay, we detected a number of genes involved in osteoclastogenesis as the possible downstreams of PAR-1, which may partly explain the mechanism of PAR-1 in GCT. In brief, for the first time, these results reveal an upstream regulatory role of TGF-β in PAR-1 expression, and PAR-1 expression promotes tumor growth, angiogenesis and osteoclast differentiation in GCT of bone. Hence, PAR-1 represents a novel potential therapeutic target for GCT of bone.

Patkar N, Subramanian PG, Tembhare P, et al.
An integrated genomic profile that includes copy number alterations is highly predictive of minimal residual disease status in childhood precursor B-lineage acute lymphoblastic leukemia.
Indian J Pathol Microbiol. 2017 Apr-Jun; 60(2):209-213 [PubMed] Related Publications
INTRODUCTION: Copy number alterations (CNA) have been described in childhood precursor B-lineage acute lymphoblastic leukemia (B-ALL) which in conjunction with chromosomal abnormalities drive leukemogenesis. There is no consensus on the clinical incorporation of CNA in B-ALL. An integrated genomic classification (IGC) has been proposed which includes CNA and cytogenetics.
METHODS: We correlated this IGC with immunophenotypic minimal residual disease (MRD) as well as other standard criteria for 245 patients of B-ALL such as National Cancer Institute (NCI) risk, D+8 prednisolone response, cytogenetics, and ploidy status.
RESULTS: MRD was detectable in 81 patients (33.1%). The most common abnormalities were seen in CDKN2A/B (25.7%) followed by PAX5(20%), ETV6(16.7%), IKZF1(15.5%), Rb1(5.3%), BTG (3.3%), EBF1(2.0%), and PAR1(0.8%). On integrating CNA into the IGC, 170 patients (69.4%) were classified into good genomic risk (GEN-GR) whereas 75 (30.6%) belonged to the poor genomic risk (GEN-PR) category. The IGC showed a significant correlation with MRD and NCI risk. The presence of CNA predicted MRD clearance in intermediate cytogenetics group.
CONCLUSION: These data seem to indicate that in addition to cytogenetics, CNA should be incorporated into routine clinical testing and risk algorithms for B-ALL. The IGC is of prognostic relevance and offers an additional avenue for prognostication and risk-adapted therapy.

Kryza T, Silva LM, Bock N, et al.
Kallikrein-related peptidase 4 induces cancer-associated fibroblast features in prostate-derived stromal cells.
Mol Oncol. 2017; 11(10):1307-1329 [PubMed] Free Access to Full Article Related Publications
The reciprocal communication between cancer cells and their microenvironment is critical in cancer progression. Although involvement of cancer-associated fibroblasts (CAF) in cancer progression is long established, the molecular mechanisms leading to differentiation of CAFs from normal fibroblasts are poorly understood. Here, we report that kallikrein-related peptidase-4 (KLK4) promotes CAF differentiation. KLK4 is highly expressed in prostate epithelial cells of premalignant (prostatic intraepithelial neoplasia) and malignant lesions compared to normal prostate epithelia, especially at the peristromal interface. KLK4 induced CAF-like features in the prostate-derived WPMY1 normal stromal cell line, including increased expression of alpha-smooth muscle actin, ESR1 and SFRP1. KLK4 activated protease-activated receptor-1 in WPMY1 cells increasing expression of several factors (FGF1, TAGLN, LOX, IL8, VEGFA) involved in prostate cancer progression. In addition, KLK4 induced WPMY1 cell proliferation and secretome changes, which in turn stimulated HUVEC cell proliferation that could be blocked by a VEGFA antibody. Importantly, the genes dysregulated by KLK4 treatment of WPMY1 cells were also differentially expressed between patient-derived CAFs compared to matched nonmalignant fibroblasts and were further increased by KLK4 treatment. Taken together, we propose that epithelial-derived KLK4 promotes tumour progression by actively promoting CAF differentiation in the prostate stromal microenvironment.

Hatakeyama M
Structure and function of Helicobacter pylori CagA, the first-identified bacterial protein involved in human cancer.
Proc Jpn Acad Ser B Phys Biol Sci. 2017; 93(4):196-219 [PubMed] Free Access to Full Article Related Publications
Chronic infection with Helicobacter pylori cagA-positive strains is the strongest risk factor of gastric cancer. The cagA gene-encoded CagA protein is delivered into gastric epithelial cells via bacterial type IV secretion, where it undergoes tyrosine phosphorylation at the Glu-Pro-Ile-Tyr-Ala (EPIYA) motifs. Delivered CagA then acts as a non-physiological scaffold/hub protein by interacting with multiple host signaling molecules, most notably the pro-oncogenic phosphatase SHP2 and the polarity-regulating kinase PAR1/MARK, in both tyrosine phosphorylation-dependent and -independent manners. CagA-mediated manipulation of intracellular signaling promotes neoplastic transformation of gastric epithelial cells. Transgenic expression of CagA in experimental animals has confirmed the oncogenic potential of the bacterial protein. Structural polymorphism of CagA influences its scaffold function, which may underlie the geographic difference in the incidence of gastric cancer. Since CagA is no longer required for the maintenance of established gastric cancer cells, studying the role of CagA during neoplastic transformation will provide an excellent opportunity to understand molecular processes underlying "Hit-and-Run" carcinogenesis.

Bhandari P, Ahmad F, Das BR
Molecular profiling of gene copy number abnormalities in key regulatory genes in high-risk B-lineage acute lymphoblastic leukemia: frequency and their association with clinicopathological findings in Indian patients.
Med Oncol. 2017; 34(5):92 [PubMed] Related Publications
Genes related to key cellular pathways are frequently altered in B cell ALL and are associated with poor survival especially in high-risk (HR) subgroups. We examined gene copy number abnormalities (CNA) in 101 Indian HR B cell ALL patients and their correlation with clinicopathological features by multiplex ligation-dependent probe amplification. Overall, CNA were detected in 59 (59%) cases, with 26, 10 and 23% of cases harboring 1, 2 or +3 CNA. CNA were more prevalent in BCR-ABL1 (60%), pediatric (64%) and high WCC (WBC count) (63%) patients. Frequent genes deletions included CDNK2A/B (26%), IKZF1 (25%), PAX5 (14%), JAK2 (7%), BTG1 (6%), RB1 (5%), EBF1 (4%), ETV6 (4%), while PAR1 region genes were predominantly duplicated (20%). EBF1 deletions selectively associated with adults, IKZF1 deletions occurred frequently in high WCC and BCR-ABL1 cases, while PAR1 region gains significantly associated with MLL-AF4 cases. IKZF1 haploinsufficiency group was predominant, especially in adults (65%), high WCC (60%) patients and BCR-ABL1-negative (78%) patients. Most cases harbored multiple concurrent CNA, with IKZF1 concomitantly occurring with CDNK2A/B, PAX5 and BTG1, while JAK2 occurred with CDNK2A/B and PAX5. Mutually exclusive CNA included ETV6 and IKZF1/RB1, and EBF1 and JAK2. Our results corroborate with global reports, aggregating molecular markers in Indian HR B-ALL cases. Integration of CNA data from rapid methods like MLPA, onto background of existing gold-standard methods detecting significant chromosomal abnormalities, provides a comprehensive genetic profile in B-ALL.

Pang L, Li JF, Su L, et al.
ALEX1, a novel tumor suppressor gene, inhibits gastric cancer metastasis via the PAR-1/Rho GTPase signaling pathway.
J Gastroenterol. 2018; 53(1):71-83 [PubMed] Related Publications
BACKGROUND: The ALEX is a novel member of the armadillo family and ALEX1 was reported to be reduced or even lost in multiple solid tumors. However, its expression profile and oncogenic role in gastric cancer (GC) remains largely unknown.
METHODS: ALEX1 expression was detected in 161 GC samples by immunohistochemistry staining. NCI-N87 cells transfected by ALEX1 lentivirus vectors and MKN28 cells transfected by ALEX1 shRNA were used for biological function investigation. Western blot was applied to explore the molecular mechanism and pull-down assays were applied to measure the activity of Rho GTPases. In vivo tumorigenicity, peritoneal and lung metastasis experiments were performed by tumor cell engraftment into nude mice. Bisulfite genomic sequencing and methylation-specific PCR were applied to check the methylation status of the ALEX1 gene.
RESULTS: The expression rate of ALEX1 was significantly reduced in gastric tumor samples compared to non-tumor samples (43.5 vs. 90.2%), and its expression was closely related to the tumor differentiation, TNM staging, and lymph nodes metastasis. ALEX1 overexpression in NCI-N87 cells significantly inhibited cell proliferation, migration, and invasion in vitro, and disrupted the structure of the cytoskeleton. ALEX1 overexpression attenuated xenografts growth, peritoneal, and lung metastasis in nude mice. Mechanistically, the overexpression of ALEX1 inhibits thrombin-induced metastasis and Rho GTPases activation. Bisulfite genomic sequencing and methylation-specific PCR revealed that the promoter of ALEX1 is highly methylated in GC cells and tissues.
CONCLUSIONS: ALEX1 expression is reduced in GC and is involved in diverse cellular functions. ALEX1 inhibits metastasis through the PAR-1/Rho GTPase signaling pathway.

Baker E, Jacobs C, Martinie J, et al.
Mixed Hepatocellular Carcinoma, Neuroendocrine Carcinoma of the Liver.
Am Surg. 2016; 82(11):1121-1125 [PubMed] Related Publications
We present the case of a 76-year-old male found to have a large tumor involving the left lateral lobe of the liver, presumed to be hepatocellular carcinoma (HCC). After resection, pathologic features demonstrated both high-grade HCC and high-grade neuroendocrine carcinoma (NEC). Areas of NEC stained strongly for synaptophysin, which was not present in HCC component. The HCC component stained strongly for Hep-Par 1, which was not present in the NEC component. The patient underwent genetic analysis for biomarkers common to both tumor cell types. Both tumor components contained gene mutations in CTNNB1 gene (S33F located in exon 3). They also shared mutations in PD-1, PGP, and SMO. Mixed HCC/NEC tumors have been rarely reported in the literature with generally poor outcomes. This patient has been referred for adjuvant platinum-based chemotherapy; genetic biomarker analysis may provide some insight to guide targeted chemotherapy.

de Smith AJ, Kaur M, Gonseth S, et al.
Correlates of Prenatal and Early-Life Tobacco Smoke Exposure and Frequency of Common Gene Deletions in Childhood Acute Lymphoblastic Leukemia.
Cancer Res. 2017; 77(7):1674-1683 [PubMed] Free Access to Full Article Related Publications
Tobacco smoke exposure has been associated with risk of childhood acute lymphoblastic leukemia (ALL). Understanding the relationship between tobacco exposures and specific mutations may yield etiologic insights. We carried out a case-only analysis to explore whether prenatal and early-life tobacco smoke exposure influences the formation of leukemogenic genomic deletions. Somatic copy number of 8 genes frequently deleted in ALL (

Shah SS, Chandan VS
Hepatocyte Antigen Expression in Barrett Esophagus and Associated Neoplasia.
Appl Immunohistochem Mol Morphol. 2018; 26(8):557-561 [PubMed] Related Publications
Hepatocyte antigen or hepatocyte paraffin 1 (Hep Par 1) is widely used as a diagnostic immunomarker for hepatocellular carcinoma. It has also been identified as a rate-limiting enzyme of the urea cycle, carbamoyl phosphate synthetase 1. Hep Par 1 has been detected in non-neoplastic small intestinal epithelium, but its expression in Barrett esophagus and its related neoplasia has not been well investigated. We immunohistochemically evaluated expression of Hep Par 1 on 75 cases of Barrett esophagus (25 cases without dysplasia, 16 cases with low-grade dysplasia, 25 cases with high-grade dysplasia, and 9 cases with intramucosal adenocarcinoma) on endoscopic biopsies and endoscopic mucosal resections. All 25 cases without dysplasia (100%) showed granular cytoplasmic Hep Par 1 staining (24 diffuse and 1 focal). Of the 16 cases with low-grade dysplasia, 12 (75%) were positive (5 diffuse and 7 focal), whereas 4 (25%) were negative (P=0.018). Of the 25 cases with high-grade dysplasia, 9 (36%) showed focal positivity, whereas 16 (64%) were negative (P=0.0001). Similarly of the 9 cases of intramucosal adenocarcinomas 3 (33%) were focally positive, whereas 6 (67%) were negative (P=0.0001). Hep Par 1 is diffusely expressed in non-neoplastic Barrett esophagus while it is frequently lost in related dysplasia and adenocarcinoma, suggesting decreased level of HepPar1 may represent an early event in Barrett-related tumor genesis. This warrants additional investigation to look for the possible role of carbamoyl phosphate synthetase 1 in the pathogenesis of Barrett-related neoplasia.

Lin C, Majoor CJ, Roelofs JJ, et al.
Potential importance of protease activated receptor (PAR)-1 expression in the tumor stroma of non-small-cell lung cancer.
BMC Cancer. 2017; 17(1):113 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Protease activated receptor (PAR)-1 expression is increased in a variety of tumor cells. In preclinical models, tumor cell PAR-1 appeared to be involved in the regulation of lung tumor growth and metastasis; however the role of PAR-1 in the lung tumor microenvironment, which is emerging as a key compartment in driving cancer progression, remained to be explored.
METHODS: In the present study, PAR-1 gene expression was determined in lung tissue from patients with non-small-cell lung cancer (NSCLC) using a combination of publicly available RNA microarray datasets and in house-made tissue microarrays including tumor biopsies of 94 patients with NSCLC (40 cases of adenocarcinoma, 42 cases of squamous cell carcinoma and 12 cases of other type of NSCLC at different stages).
RESULTS: PAR-1 gene expression strongly correlated with tumor stromal markers (i.e. macrophage, endothelial cells and (myo) fibroblast markers) but not with epithelial cell markers. Immunohistochemical analysis confirmed the presence of PAR-1 in the tumor stroma and showed that PAR-1 expression was significantly upregulated in malignant tissue compared with normal lung tissue. The overexpression of PAR-1 in tumor stroma of NSCLC appeared to be independent from tumor type, tumor stage, histopathological differentiation status, disease progression and patient survival.
CONCLUSION: Overall, our data provide evidence that PAR-1 in NSCLC is mainly expressed on cells that constitute the pulmonary tumor microenvironment, including vascular endothelial cells, macrophages and stromal fibroblasts.

Shirai Y, Uwagawa T, Shiba H, et al.
Recombinant thrombomodulin suppresses tumor growth of pancreatic cancer by blocking thrombin-induced PAR1 and NF-κB activation.
Surgery. 2017; 161(6):1675-1682 [PubMed] Related Publications
BACKGROUND: Thrombomodulin, an anticoagulant that inhibits thrombin-induced growth factor promotion, also has an anti-inflammatory effect. Furthermore, thrombomodulin inhibits nuclear factor-kappa B activation, which plays a crucial role in cancer progression. We assessed the antitumor activity of recombinant thrombomodulin for pancreatic cancer.
METHODS: A xenograft orthotopic model was established in mice by implantation of human pancreatic cancer cells. The animals were treated with intraperitoneal injection of recombinant thrombomodulin 5 times a week for 4 weeks. Nuclear factor-kappa B activation was evaluated by measuring nuclear localization of the p65. Efficacy of recombinant thrombomodulin on the signal transduction of nuclear factor-kappa B was measured in vitro under preconditioning with thrombin or epidermal growth factor.
RESULTS: Tumor growth was suppressed by recombinant thrombomodulin (P < .05). Recombinant thrombomodulin inhibited the expression of IκB kinase β (P < .05) and pIκBα (P < .01), as well as the activation of nuclear factor-kappa B NF-κB (P < .001). Furthermore, recombinant thrombomodulin inhibited thrombin-induced protease activate receptor 1 and nuclear factor-kappa B activation in vitro (P < .05). The number of Ki67-positive cells was decreased by recombinant thrombomodulin (P < .01). Recombinant thrombomodulin also suppressed body weight loss associated with pancreatic cancer (P < .05). No obvious adverse effects were observed.
CONCLUSION: Recombinant thrombomodulin significantly suppressed tumor growth against human pancreatic cancer by blocking thrombin-induced nuclear factor-kappa B activation without adverse effects.

Goyama S, Shrestha M, Schibler J, et al.
Protease-activated receptor-1 inhibits proliferation but enhances leukemia stem cell activity in acute myeloid leukemia.
Oncogene. 2017; 36(18):2589-2598 [PubMed] Free Access to Full Article Related Publications
Eradication of leukemia stem cells (LSCs) is the ultimate goal of treating acute myeloid leukemia (AML). We recently showed that the combined loss of Runx1/Cbfb inhibited the development of MLL-AF9-induced AML. However, c-Kit

Vianello F, Sambado L, Goss A, et al.
Dabigatran antagonizes growth, cell-cycle progression, migration, and endothelial tube formation induced by thrombin in breast and glioblastoma cell lines.
Cancer Med. 2016; 5(10):2886-2898 [PubMed] Free Access to Full Article Related Publications
Thrombin activates its G-coupled seven transmembrane protease-activated receptor (PAR-1) by cleaving the receptor's N-terminal end. In several human cancers, PAR1 expression and activation correlates with tumor progression and metastatization. This provides compelling evidence for the effectiveness of an appropriate antithrombin agent for the adjuvant treatment of patients with cancer. Dabigatran is a selective direct thrombin inhibitor that reversibly binds to thrombin. In this study, we aimed to explore if dabigatran may affect mechanisms favoring tumor growth by interfering with thrombin-induced PAR-1 activation. We confirmed that exposure of tumor cells to thrombin significantly increased cell proliferation and this was coupled with downregulation of p27 and concomitant induction of cyclin D1. Dabigatran was consistently effective in antagonizing thrombin-induced proliferation as well as it restored the baseline pattern of cell cycle protein expression. Thrombin significantly upregulated the expression of proangiogenetic proteins like Twist and GRO-α in human umbilical vascular endothelial cells (HUVEC) cells and their expression was significantly brought down to control levels when dabigatran was added to culture. We also found that the chemoattractant effect of thrombin on tumor cells was lost in the presence of dabigatran, and that the thrombin antagonist was effective in dampening vascular tube formation induced by thrombin. Our data support a role of thrombin in inducing the proliferation, migration, and proangiogenetic effects of tumor cells in vitro. Dabigatran has activity in antagonizing all these effects, thereby impairing tumor growth and progression. In vivo models may help to understand the relevance of this pathway.

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