Gene Summary

Gene:PRB1; proline rich protein BstNI subfamily 1 (gene/pseudogene)
Aliases: PM, PMF, PMS, PRB1L, PRB1M
Summary:This gene encodes a member of the heterogeneous family of basic, proline-rich, human salivary glycoproteins. The encoded preproprotein undergoes proteolytic processing to generate one or more mature peptides before secretion from the parotid glands. Multiple alleles of this gene exhibiting variations in the length of the tandem repeats have been identified. The reference genome encodes the "Medium" allele. This gene is located in a cluster of closely related salivary proline-rich proteins on chromosome 12. Alternative splicing results in multiple transcript variants encoding different isoforms that may undergo similar proteolytic processing. [provided by RefSeq, Nov 2015]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:basic salivary proline-rich protein 1
Source:NCBIAccessed: 31 August, 2019


What does this gene/protein do?
PRB1 is implicated in:
- biological_process
- extracellular region
- molecular_function
Data from Gene Ontology via CGAP

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.

  • Nuclear Proteins
  • Urinary Tract
  • Viral Core Proteins
  • Cancer DNA
  • Chromosome 12
  • Genes, Retinoblastoma
  • Molecular Sequence Data
  • Phosphoproteins
  • Cell Differentiation
  • Cell Proliferation
  • Neoplastic Cell Transformation
  • Mutation
  • Phosphorylation
  • S Phase
  • Cell Cycle Proteins
  • p53 Protein
  • Retinoblastoma-Like Protein p130
  • Knockout Mice
  • Retinoblastoma
  • Apoptosis
  • Transcription Factors
  • Proteins
  • Base Sequence
  • Squamous Cell Carcinoma of Head and Neck
  • Transcription
  • Cell Cycle
  • Xenograft Models
  • DNA-Binding Proteins
  • tat Gene Products, Human Immunodeficiency Virus
  • Thrombocytosis
  • Cancer Gene Expression Regulation
  • Promoter Regions
  • RB1
  • E2F Transcription Factors
  • Signal Transduction
  • Transfection
  • Point Mutation
  • Tumor Suppressor Gene
  • T-Lymphocytes
Tag cloud generated 31 August, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (1)

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: PRB1 (cancer-related)

Gao R, Yun Y, Cai Z, Sang N
Sci Total Environ. 2019; 678:611-617 [PubMed] Related Publications
Extensive epidemiological studies have revealed that nearly 25% of the premature mortality from lung cancer is attributed to regional haze caused by a high level of fine particulate matter (PM

Duan Y, Luo L, Qiao C, et al.
A novel human anti-AXL monoclonal antibody attenuates tumour cell migration.
Scand J Immunol. 2019; 90(2):e12777 [PubMed] Related Publications
TAM family members (TYRO3, AXL and MERTK) play essential roles in the resolution of inflammation and in infectious diseases and cancer. AXL, a tyrosine kinase receptor, is commonly overexpressed in several solid tumours and numerous hematopoietic malignancies including acute myeloid leukaemia, acute lymphocytic leukaemia, chronic myeloid leukaemia, chronic lymphocytic leukaemia and multiple myeloma. AXL significantly promotes tumour cell migration, invasion and metastasis, as well as angiogenesis. AXL also plays an important role in inflammation and macrophage ontogeny. Recent studies have revealed that AXL contributes to leukaemic phenotypes through activation of oncogenic signalling pathways that lead to increased cell migration and proliferation. To evaluate the mechanisms underlying the role of AXL signalling in tumour metastasis, we screened a phage display library to generate a novel human monoclonal antibody, named DAXL-88, that recognizes both human and murine AXL. The concentrations of DAXL-88 required for 50% maximal binding to human and murine AXL were 0.118 and 0.164 μg/mL, respectively. Furthermore, DAXL-88 bound to human AXL with high affinity (K

Ma S, Jia S, Ren Y, et al.
ErbB3 Ligand Heregulin1 Is a Major Mitogenic Factor for Uncontrolled Lung Cancer Cell Proliferation.
Neoplasia. 2019; 21(4):343-352 [PubMed] Free Access to Full Article Related Publications
There are seven ligands for the epidermal growth factor receptor (EGFR) ErbB1 and two ligands for ErbB3. EGFR can form a homodimer or a heterodimer with ErbB3. In this study, we investigated whether homodimers or heterodimers, and which ligand, play a major role in cancer development, with the goal of ultimately identifying therapeutic targets. We demonstrated that the ErbB3 ligand heregulin1 is the strongest mitogenic factor for non-small cell lung cancer cells and is more potent in activating EGFRmut-ErbB3 heterodimers than EGFRwt-ErbB3 heterodimers. We discovered that four of the seven EGFR ligands inhibited heregulin1-induced EGFRwt-ErbB3 activation and cell proliferation by promoting dephosphorylation of heregulin1-induced ErbB3 phosphorylation, whereas the other three did not exhibit such inhibition. Importantly, those four EGFR ligands did not inhibit heregulin1-induced EGFRmut-ErbB3 activation and proliferation of cells with EGFR mutants. We demonstrated that ErbB3 was overexpressed in the lung cancer cells but not in the adjacent normal alveoli or stromal tissue. EGFR and heregulin1 were also highly expressed in lung cancer cells. We conclude that the overexpression of heregulin1, ErbB3, and EGFR mutant renders uncontrolled cell proliferation.

Jovanović N, Mitrović T, Cvetković VJ, et al.
The Impact of
Medicina (Kaunas). 2019; 55(2) [PubMed] Free Access to Full Article Related Publications

Cottin L, Riou J, Boyer F, et al.
WT1 gene is overexpressed in myeloproliferative neoplasms, especially in myelofibrosis.
Blood Cells Mol Dis. 2019; 75:35-40 [PubMed] Related Publications
Classical Philadelphia-negative myeloproliferative neoplasms include Polycythemia Vera (PV), Essential Thrombocythemia (ET) and Primary Myelofibrosis (PMF). They are characterized by the presence of driver mutations of JAK2, CALR or MPL genes. Overexpression of WT1 is used as a marker of minimal residual disease in acute myeloid leukemia, especially after allogeneic stem cell transplantation (SCT). We investigated WT1 expression at diagnosis in 152 MPN patients and showed that the WT1 transcript was overexpressed in PMFs and PVs compared to controls. In particular, WT1 transcript levels were higher in PMF than in ET and PV. WT1 transcript levels were significantly increased during myelofibrotic transformation of ET or PV. Using multivariate linear regression, high WT1 transcript levels in PMF were associated with age over 65, splenomegaly and thrombocytopenia. The ROC curve analysis showed that a level of WT1 transcript >10 WT1 copies/10

Varghese E, Samuel SM, Varghese S, et al.
Triptolide Decreases Cell Proliferation and Induces Cell Death in Triple Negative MDA-MB-231 Breast Cancer Cells.
Biomolecules. 2018; 8(4) [PubMed] Free Access to Full Article Related Publications
Triple negative breast cancers (TNBCs) do not respond to conventional estrogen receptor/progesterone receptor/human epidermal growth factor receptor-2 targeted interventions due to the absence of the respective receptor targets. They are aggressive, exhibit early recurrence, metastasize, are more invasive in nature, and develop drug resistance. Some plant-derived substances have been screened and have gained attention as efficient anticancer drugs for TNBCs with few adverse effects. Here, we evaluate triptolide (concentrations in the range of 100 pM to 10 µM), a di-terpene tri-epoxide isolated from thunder god vine for its efficacy as anticancer drug in MDA-MB-231 TNBC cells. Cell proliferation and viability were assessed using 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2

Bahnassy AA, Helal TE, El-Ghazawy IM, et al.
The role of E-cadherin and Runx3 in Helicobacter Pylori - Associated gastric carcinoma is achieved through regulating P21waf and P27 expression.
Cancer Genet. 2018; 228-229:64-72 [PubMed] Related Publications
BACKGROUND: We assessed the role of E-cadherin (CDH1), runt-related transcription factor 3, p21waf and p27 promoter methylation (PM) and protein expression in Helicobacter pylori (HP)-associated gastric carcinomas (GCs) and adjacent non-neoplastic tissues (ANNTs).
PATIENTS AND METHODS: 192 cases were assessed for PM and protein expression of CDH1, RUNX3, p21waf and p27 by methylation-specific PCR (MSP) and immunohistochemistry. The CagA gene was also assessed.
RESULTS: In GCs, 66 (34.4%) and 84 (43.8%) cases showed CDH1-PM and reduced expression. It is significantly affected in GCs rather than in non-neoplastic groups (p < 0.001). In ANNTs, 108 (56.3%) cases showed CDH1-PM and all cases revealed preserved protein expression. RUNX3-PM was detected in 78 GCs (40.6%) and 69 ANNTs (35.9%), whereas reduced protein expression was detected in 99 (51.65%) GC compared to ANNTs 90 (46.9%). p21WAF and p27 showed PM in (48.4% and 45.3%) GCs and ANNTs; respectively. p21waf protein was reduced in 90 (46.9%) cases and 91 ANNTs (47.4%). p27 was reduced in 86 (44.8%) cases and 87 ANNTs (45.3%). CDH1 aberrations correlated with HP in tumors and ANNTs and with diffuse/intestinal tumors (p = 0.014, p = 0.014 and p = 0.02). RUNX3 aberrations associated with HP (p = 0.04), high grade (p = 0.04), and advanced stage (p = 032). Tumor grade associated with RUNX3-PM, CDH, p21 and p27 protein (p < 0.05 for all). Tumor stage associated significantly with PM and reduced protein expression of all markers. Positive lymph nodes associated significantly with p27PM (p < 0.001).
CONCLUSIONS: HP plays an important role in the development and progression of GC through silencing of CDH1, RUNX3, p21WAF and p27 expression.

Brooks JD, Comen EA, Reiner AS, et al.
CYP2D6 phenotype, tamoxifen, and risk of contralateral breast cancer in the WECARE Study.
Breast Cancer Res. 2018; 20(1):149 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Tamoxifen treatment greatly reduces a woman's risk of developing a second primary breast cancer. There is, however, substantial variability in treatment response, some of which may be attributed to germline genetic variation. CYP2D6 is a key enzyme in the metabolism of tamoxifen to its active metabolites, and variants in this gene have been associated with reduced tamoxifen metabolism. The impact of variation on risk of contralateral breast cancer (CBC) is unknown.
METHODS: Germline DNA from 1514 CBC cases and 2203 unilateral breast cancer controls was genotyped for seven single nucleotide polymorphisms, one three-nucleotide insertion-deletion, and a full gene deletion. Each variant has an expected impact on enzyme activity, which in combination allows for the classification of women as extensive, intermediate, and poor metabolizers (EM, IM, and PM respectively). Each woman was assigned one of six possible diplotypes and a corresponding CYP2D6 activity score (AS): EM/EM (AS = 2), EM/IM (AS = 1.5), EM/PM (AS = 1), IM/IM (AS = 0.75), IM/PM (AS = 0.5), and PM/PM (AS = 0). We also collapsed categories of the AS to generate an overall phenotype (EM, AS ≥ 1; IM, AS = 0.5-0.75; PM, AS = 0). Rate ratios (RRs) and 95% confidence intervals (CIs) for the association between tamoxifen treatment and risk of CBC in our study population were estimated using conditional logistic regression, stratified by AS.
RESULTS: Among women with AS ≥ 1 (i.e., EM), tamoxifen treatment was associated with a 20-55% reduced RR of CBC (AS = 2, RR = - 0.81, 95% CI 0.62-1.06; AS = 1.5, RR = 0.45, 95% CI 0.30-0.68; and AS = 1, RR = 0.55, 95% CI 0.40-0.74). Among women with no EM alleles and at least one PM allele (i.e., IM and PM), tamoxifen did not appear to impact the RR of CBC in this population (AS = 0.5, RR = 1.08, 95% CI 0.59-1.96; and AS = 0, RR = 1.17, 95% CI 0.58-2.35) (p for homogeneity = - 0.02).
CONCLUSION: This study suggests that the CYP2D6 phenotype may contribute to some of the observed variability in the impact of tamoxifen treatment for a first breast cancer on risk of developing CBC.

Li P, Wei M, Zhang F, et al.
Novel Fluorescence Switch for MicroRNA Imaging in Living Cells Based on DNAzyme Amplification Strategy.
ACS Appl Mater Interfaces. 2018; 10(50):43405-43410 [PubMed] Related Publications
MicroRNAs (miRNAs) play important roles in the regulation of target gene expression and cell development. Therefore, developing of accurate and visual detection methods for miRNAs is important for early diagnosis of cancer. In this study, we established a visual detection method for miRNA 155 based on DNAzyme amplification strategy in living cells. MnO

Wang M, Tang Y, Chen Y, et al.
Catalytic hairpin assembly-programmed formation of clickable nucleic acids for electrochemical detection of liver cancer related short gene.
Anal Chim Acta. 2019; 1045:77-84 [PubMed] Related Publications
DNA amplification usually takes place in an aqueous system to facilitate a highly efficient reaction. Therefore, it is a challenge to connect the DNA amplification with popular dry chemical methods, whose signal outputs usually come from a solid-liquid interface. Here, by linking catalytic hairpin assembly (CHA) with electrochemical biosensors through clickable nucleic acids, we develop a facile method for the detection of liver cancer related short gene MXR7. On one hand, the method maintains the advantages of CHA especially its high efficiency by performing the whole process of CHA in aqueous phase. On the other hand, the method realizes electrochemical detection of MXR7 by transferring a clickable double-helix production of MXR7-triggerd CHA to a dibenzocyclooctyne-functionalized electrode quickly through copper-free click chemistry. In comparison with traditional biotin-streptavidin or hybridization-assisted conjugation, the click chemistry allows quick response in a quarter of an hour, shortening the detection time greatly. In addition, owing to the lower steric hindrance as compared with streptavidin, the signal intensity is strong, making a sensitive detection possible. The detection limit reaches 125 fM, better than previous electrochemical methods. Results also reveal that CHA in solution has much better efficiency than that on interface, allowing two orders of magnitude improvement in detection limit (125 fM vs. 50 pM) with a shorter detection time (135 min vs. 165 min). This work also provides a novel concept to connect aqueous amplification system with interfacial detection method for other bio-analysis.

Zhao Q, Hong B, Liu T, et al.
VEGI174 protein and its functional domain peptides exert antitumour effects on renal cell carcinoma.
Int J Oncol. 2019; 54(1):390-398 [PubMed] Related Publications
Vascular endothelial growth inhibitor (VEGI) has been identified as an anti‑angiogenic cytokine. However, the effects of VEGI174 protein, and its functional domain peptides V7 and V8, on renal cell carcinoma (RCC) remain unknown. In the present study, the protein and peptides were biosynthesised as experimental agents. The A498 and 786‑O RCC cell lines, and an established mouse xenograft model, were separately treated with VEGI174, V7 or V8. Cellular functions, including proliferation, migration and invasion, were subsequently detected. Cell migration and invasion were monitored using the xCELLigence system. Furthermore, tumour growth and mouse behaviours, including mobility, appetite and body weight, were assessed. The results demonstrated that VEGI174, V7 and V8 inhibited the proliferation, migration and invasion of A498 and 786‑O cell lines when administered at concentrations of 1 and 100 pM, 10 nM and 1 µM. The inhibitory effects exhibited dose‑ and time‑dependent antitumour activity. Furthermore, VEGI174, V7 and V8 inhibited tumour growth in A498 and 786‑O xenograft mice. In the A498 xenografts, the tumour growth inhibition (TGI) rates in the VEGI174‑, V7‑ and V8‑treated groups were 71, 20 and 31%, respectively. In the 786‑O xenografts, the TGI rates in the VEGI174‑, V7‑ and V8‑treated groups were 34, 26 and 31%, respectively. There was no significant loss in body weight and no cases of mortality were observed for all treated mice. In conclusion, VEGI174, V7 and V8 exhibited potential antitumour effects and were well tolerated in vivo. V7 and V8, as functional domain peptides of the VEGI174 protein, may be studied for the future treatment of RCC.

Farago AF, Drapkin BJ, Lopez-Vilarino de Ramos JA, et al.
ATLANTIS: a Phase III study of lurbinectedin/doxorubicin versus topotecan or cyclophosphamide/doxorubicin/vincristine in patients with small-cell lung cancer who have failed one prior platinum-containing line.
Future Oncol. 2019; 15(3):231-239 [PubMed] Article available free on PMC after 01/01/2020 Related Publications
Lurbinectedin is an inhibitor of active transcription of protein-coding genes, causing DNA-break accumulation, apoptosis and modulation of the tumor microenvironment. Early-phase clinical trials indicate promising activity of lurbinectedin in small-cell lung cancer. Here, we describe the rationale and design of ATLANTIS (NCT02566993), an open-label, randomized, multicenter Phase III study to compare the efficacy of lurbinectedin and doxorubicin combination with standard-of-care chemotherapy, investigator's choice of cyclophosphamide/doxorubicin/vincristine or topotecan, in patients with small-cell lung cancer that has progressed following one line of platinum-based chemotherapy. Patients are randomized in a 1:1 ratio. The primary end point is overall survival and key secondary end points include progression-free survival, best tumor response and duration of response, each assessed by independent review committee.

Wei N, Li J, Fang C, et al.
Targeting colon cancer with the novel STAT3 inhibitor bruceantinol.
Oncogene. 2019; 38(10):1676-1687 [PubMed] Related Publications
STAT3, a transcriptional mediator of oncogenic signaling, is constitutively active in ~70% of human cancers. The development of STAT3 inhibitors remains an active area of research as no inhibitors have yet to be approved for the treatment of human cancer. Herein, we revealed that bruceantinol (BOL) is a novel STAT3 inhibitor demonstrating potent antitumor activity in in vitro and in vivo human colorectal cancer (CRC) models. BOL strongly inhibited STAT3 DNA-binding ability (IC

Herrmann M, Krupka C, Deiser K, et al.
Bifunctional PD-1 × αCD3 × αCD33 fusion protein reverses adaptive immune escape in acute myeloid leukemia.
Blood. 2018; 132(23):2484-2494 [PubMed] Related Publications
The CD33-targeting bispecific T-cell engager (BiTE) AMG 330 proved to be highly efficient in mediating cytolysis of acute myeloid leukemia (AML) cells in vitro and in mouse models. Yet, T-cell activation is correlated with upregulation of programmed cell death-ligand 1 (PD-L1) and other inhibitory checkpoints on AML cells that confer adaptive immune resistance. PD-1 and PD-L1 blocking agents may counteract T-cell dysfunction, however, at the expense of broadly distributed immune-related adverse events (irAEs). We developed a bifunctional checkpoint inhibitory T cell-engaging (CiTE) antibody that combines T-cell redirection to CD33 on AML cells with locally restricted immune checkpoint blockade. This is accomplished by fusing the extracellular domain of PD-1 (PD-1

Kim H, Moon JY, Burapan S, et al.
Induction of ER Stress-Mediated Apoptosis by the Major Component 5,7,4'-Trimethoxyflavone Isolated from Kaempferia parviflora Tea Infusion.
Nutr Cancer. 2018 Aug-Sep; 70(6):984-996 [PubMed] Related Publications
Kaempferia parviflora (KP) is a famous medicinal plant from Thailand, and is a rich source of various kinds of methoxyflavones (MFs). Many kinds of food products such as tea, capsule, and liquor are manufactured from the rhizomes of KP. In this study, KP infusions were prepared with different brewing conditions, and the amounts of three major methoxylflavones, 5,7-dimethoxyflavone (DMF), 5,7,4'-trimethoxyflavone (TMF), and 3,5,7,3',4'-pentamethoxyflavone (PMF), were analyzed. The antiproliferative activities of DMF, TMF, and PMF isolated from the brewed tea samples were evaluated. TMF was discovered to be significantly effective at inhibiting proliferation of SNU-16 human gastric cancer cells in a concentration dependent manner. TMF induced apoptosis, as evidenced by increments of sub-G1 phase, DNA fragmentation, annexin-V/PI staining, the Bax/Bcl-xL ratio, proteolytic activation of caspase-3,-7,-8, and degradation of poly (ADP-ribose) polymerase (PARP) protein. Furthermore, it was found that TMF induced apoptosis via ER stress, verified by an increase in the level of C/EBP homologous protein (CHOP), glucose regulated protein 78 (GRP78), inositol-requiring enzyme 1 α (IRE1α), activating transcription factor-4 (ATF-4), and the splice isoform of X-box-binding protein-1 (XBP-1) mRNA.

Hua W, Zhao Y, Jin X, et al.
METTL3 promotes ovarian carcinoma growth and invasion through the regulation of AXL translation and epithelial to mesenchymal transition.
Gynecol Oncol. 2018; 151(2):356-365 [PubMed] Related Publications
OBJECTIVE: As the most prevalent internal modification in mammalian messenger RNA, N
METHODS: METTL3 expression was assessed by immunohistochemistry in 162 ovarian carcinoma patients. Stable cell lines with METTL3 gene overexpression or knockdown were established to investigate the function of METTL3 in ovarian cancer in vitro and in vivo.
RESULTS: METTL3 was frequently upregulated in ovarian carcinoma and that a high level of METTL3 was significantly associated with tumor grade (P = 0.001), pT status (P = 0.002), pN/pM status (P < 0.001), FIGO stage (P < 0.001), and overall survival rate (P < 0.001). Stable overexpression of METTL3 in the OVCAR3 and COV504 cell lines significantly increased cellular proliferation, focus formation, motility, invasion, and tumor formation in nude mice. Silencing METTL3 expression in the SKOV3 and HO-8910 cell lines with short hairpin RNA effectively inhibited its oncogenic function. Further study found that METTL3 promoted epithelial-mesenchymal transition (EMT) by upregulating the receptor tyrosine kinase AXL.
CONCLUSION: Our findings suggest that METTL3 plays very important oncogenic roles in ovarian carcinoma development and/or aggressiveness by stimulating AXL translation and EMT and that METTL3 may serve as a novel prognostic and/or therapeutic target of interest in ovarian cancer.

Yamauchi H, Okawa M, Yokoyama S, et al.
High rate of occult cancer found in prophylactic mastectomy specimens despite thorough presurgical assessment with MRI and ultrasound: findings from the Hereditary Breast and Ovarian Cancer Registration 2016 in Japan.
Breast Cancer Res Treat. 2018; 172(3):679-687 [PubMed] Article available free on PMC after 01/01/2020 Related Publications
PURPOSE: Prophylactic surgery is a preemptive strategy for hereditary breast and ovarian cancer (HBOC). Prophylactic mastectomy (PM) reduces breast cancer risk by > 90%. The aim of our study is to analyze the information of the Japanese pedigrees and to utilize the results for clinical practice.
METHODS: We statistically analyzed records of HBOC registrees who had undergone BRCA1/2 genetic testing at seven medical institutions up until 2016. In the cases of PM, we examined breasts with the use of mammography (MMG), ultrasound (US), and magnetic resonance imaging (MRI) before surgery. After PM, the specimens were divided about 1 cm serially and examined in their entirety.
RESULTS: Of 1527 registrees who underwent BRCA testing, 1125 (73.7%) were negative for BRCA1/2 mutation, 297 (19.5%) were positive for BRCA1/2 mutation (BRCA1/2
CONCLUSIONS: Our report showed a relatively higher incidence rate of occult cancer at 11.3% in PM specimens despite thorough pre-operative radiological evaluations, which included a breast MRI. Considering the occult cancer rates and the various pathological methods of our study and published studies, we propose the necessity of a histopathological protocol.

Xu PY, Kankala RK, Pan YJ, et al.
Overcoming multidrug resistance through inhalable siRNA nanoparticles-decorated porous microparticles based on supercritical fluid technology.
Int J Nanomedicine. 2018; 13:4685-4698 [PubMed] Article available free on PMC after 01/01/2020 Related Publications
Background: In recent times, the co-delivery therapeutics have garnered enormous interest from researchers in the treatment of cancers with multidrug resistance (MDR) due to their efficient delivery of multiple agents, which result in synergistic effects and capable of overcoming all the obstacles of MDR in cancer. However, an efficient delivery platform is required for the conveyance of diverse agents that can successfully devastate MDR in cancer.
Methods: Initially, short-interfering RNA-loaded chitosan (siRNA-CS) nanoparticles were synthesized using the ionic gelation method. Further, the siRNA-CS nanoparticles and doxorubicin hydrochloride (DOX) were co-loaded in poly-L-lactide porous microparticles (PLLA PMs) (nano-embedded porous microparticles, [NEPMs]) by the supercritical anti-solvent (SAS) process.
Results and discussion: The NEPM formulation exhibited an excellent aerodynamic performance and sustained release of DOX, which displayed higher anticancer efficacy in drug-resistant cells (human small cell lung cancer, H69AR cell line) than those treated with either free DOX and DOX-PLLA PMs due to the siRNA from CS nanoparticles silenced the MDR gene to DOX therapy.
Conclusion: This eco-friendly process provides a convenient way to fabricate such innovative NEPMs co-loaded with a chemotherapeutic agent and a gene, which can devastate MDR in cancer through the co-delivery system.

Andreasen S, Bishop JA, Hellquist H, et al.
Biphenotypic sinonasal sarcoma: demographics, clinicopathological characteristics, molecular features, and prognosis of a recently described entity.
Virchows Arch. 2018; 473(5):615-626 [PubMed] Related Publications
Biphenotypic sinonasal sarcoma (BSNS) is a recently recognized type of sarcoma arising exclusively in the sinonasal tract displaying unique clinical course, histopathology, and genetics. Due to its rarity, only case series and case reports are available. In order to provide an overview of the current understanding of this disease, we present a comprehensive review of the literature and present three previously unreported cases of BSNS. A total of 55 genetically characterized and 41 cases without molecular data were identified in the literature. Two-thirds of patients were female and the peak incidence was in the fifth decade. Fatal outcome was rare (two cases with intracranial extension) and local recurrence occurred in 31.6%, all occurring within 5 years after initial treatment. Histologically, BSNS is highly cellular in the majority of cases and composed of fascicles of spindle cells, with entrapped hyperplastic surface epithelium being a frequent finding. The immunohistochemical profile is characteristic due to the biphasic nature of this lesion, with shared features of both myogenic and neural origin. Rhabdomyoblastic differentiation is apparent in a subset of cases. The most common genetic event is the PAX3-MAML3 fusion (58.6%) but isolated PAX3 rearrangement (19.2%), absence of rearrangements (9.1%), PAX3-FOXO1 (8.1%), PAX3-NCOA1 (4%), and isolated MAML3 rearrangement (2%) have also been reported. In conclusion, the recognition of BSNS is crucial due to its relatively indolent clinical course. A selected immunohistochemical panel and/or molecular confirmation can be used to aid in appropriate diagnosis and consequently in prognostication and to avoid overtreatment with chemotherapy regimens used in its mimics.

Andreasen S, Tan Q, Agander TK, et al.
MicroRNA dysregulation in adenoid cystic carcinoma of the salivary gland in relation to prognosis and gene fusion status: a cohort study.
Virchows Arch. 2018; 473(3):329-340 [PubMed] Related Publications
Adenoid cystic carcinoma (ACC) is among the most frequent malignancies of the salivary gland, and is notorious for its prolonged clinical course characterized by frequent recurrences often years after initial treatment. No molecular marker has been shown to have independent prognostic value in ACC, including characteristic gene fusions involving MYB, MYBL1, and NFIB. MicroRNA has been shown to be associated with clinical outcome in numerous malignancies, including one study of ACC, warranting further validation of this class of markers in this disease. Here, we investigate the prognostic value of microRNA in two ACC cohorts: a training cohort (n = 64) and a validation cohort (n = 120) with microarray and qPCR. In the training cohort, multivariate analysis of microarray data found high expression of hsa-miR-6835-3p to be associated with reduced recurrence-free survival (RFS) (p = 0.016). Measuring the highest ranking microRNAs identified in survival analysis in the same cohort, qPCR identified high expression of hsa-miR-4676 to be associated with reduced overall survival (OS) and high expression of hsa-mir-1180 to be associated with improved RFS. This was not confirmed in the validation cohort, in which qPCR identified high expression of hsa-mir-21, hsa-mir-181a-2, and hsa-mir-152 to be associated with reduced OS and high expression of hsa-miR-374c to be associated with improved RFS. Interestingly, two distinct subsets of ACC separated in microRNA expression irrespective of gene fusion status, but without significant difference in outcome. Collectively, qPCR identified several microRNAs associated with OS and RFS, and different subsets of ACC separated according to microRNA expression, suggestive of ACC being a heterogeneous group of malignancies in its microRNA profile.

Szurián K, Csala I, Marosvári D, et al.
EZH2 is upregulated in the proliferation centers of CLL/SLL lymph nodes.
Exp Mol Pathol. 2018; 105(2):161-165 [PubMed] Related Publications
Lymph node involvement of chronic lymphocytic leukaemia/small lymphocytic lymphoma (CLL/SLL) is characterised by the diffuse infiltration of small neoplastic lymphocytes, which is accompanied by the presence of proliferation centres (PCs) comprising prolymphocytes and paraimmunoblasts. There is increasing evidence of accumulation of various molecular alterations in the tumour cells of PCs, which may explain why extended PCs are related to a less favourable prognosis. To further characterize PCs, we compared the expression level of EZH2 protein, the overexpression of which has recently been recognized as poor prognostic factor in CLL/SLL, in the PCs and the intervening small cell areas in lymph nodes of 15 patients with CLL/SLL. We also investigated the mutational profile of EZH2 and the expression of its upstream regulators c-Myc, E2F1, pRB and miR-26a. Our results showed a significantly increased expression of EZH2 in the PCs. No EZH2 mutations were detected, however, overexpression of c-Myc, E2F1 and pRb proteins as well as reduced expression of the tumor suppressor miR-26a were demonstrated in the PCs. In summary our findings indicate that EZH2 pathway is significantly upregulated in the PCs of CLL/SLL lymph nodes, providing further evidence for the distinguished biological features of the PCs.

De Roeck L, Michaux L, Debackere K, et al.
Coexisting driver mutations in MPN: clinical and molecular characteristics of a series of 11 patients.
Hematology. 2018; 23(10):785-792 [PubMed] Related Publications
OBJECTIVES: CML, PV, ET and PMF are so called classical MPN with distinct clinical phenotypes. The discovery of the BCR-ABL1 translocation and mutations in driver genes JAK2, MPL and CALR has provided novel insights in their pathogenesis. While these mutations are thought to be mutually exclusive, rare cases of MPN with coexisting driver mutations have been reported. However, little is known about the clinical, biological and molecular characteristics of these patients and the interaction of the neoplastic clones.
METHODS: We retrospectively studied 11 MPN patients with coexisting driver mutations (JAK2 V617F + BCR-ABL1: n = 8; CALR type 2 + BCR-ABL1: n = 1; JAK2 V617F + MPL W515: n = 1; JAK2 V617F + CALR type 1: n = 1). To assess possible associated molecular aberrations, we analysed DNA of six patients using NGS.
RESULTS: In four CML patients, decreasing BCR-ABL1 transcript levels with increasing JAK2 V617F allele burden under TKI were observed. This strongly suggests that the coexistence of driver mutations originates from two different clones growing independently. Additional somatic mutations were detected in 5 out of 6 (83%) patients affecting 4 different genes, confirming the heterogeneity of this study cohort. Suboptimal response to TKI was observed with a higher frequency (4/8 patients) than reported in conventional series of CML and the overall tolerance of treatment with hydroxyurea and/or imatinib in our series was poor.
CONCLUSION: Given the emergence of NGS in clinical practice, more similar cases will be identified in the coming years. The optimal treatment strategy for this rare group of patients is uncertain and toxicity of combination treatment may have to be considered.

Comenge J, Sharkey J, Fragueiro O, et al.
Multimodal cell tracking from systemic administration to tumour growth by combining gold nanorods and reporter genes.
Elife. 2018; 7 [PubMed] Article available free on PMC after 01/01/2020 Related Publications
Understanding the fate of exogenous cells after implantation is important for clinical applications. Preclinical studies allow imaging of cell location and survival. Labelling with nanoparticles enables high sensitivity detection, but cell division and cell death cause signal dilution and false positives. By contrast, genetic reporter signals are amplified by cell division. Here, we characterise lentivirus-based bi-cistronic reporter gene vectors and silica-coated gold nanorods (GNRs) as synergistic tools for cell labelling and tracking. Co-expression of the bioluminescence reporter luciferase and the optoacoustic reporter near-infrared fluorescent protein iRFP720 enabled cell tracking over time in mice. Multispectral optoacoustic tomography (MSOT) showed immediate biodistribution of GNR-labelled cells after intracardiac injection and successive clearance of GNRs (day 1-15) with high resolution, while optoacoustic iRFP720 detection indicated tumour growth (day 10-40). This multimodal cell tracking approach could be applied widely for cancer and regenerative medicine research to monitor short- and long-term biodistribution, tumour formation and metastasis.

Wang Z, Gao S, Li T, et al.
Exploring the microRNA profiles as potential diagnostic probes for oligo- and polymetastatic prognosis of lung metastasis(es) patients.
Medicine (Baltimore). 2018; 97(23):e10958 [PubMed] Article available free on PMC after 01/01/2020 Related Publications
Presuming the stage of metastatic lung cancer is divided by its location, an intermediate state of ≤5 cumulative metastasis is defined as oligometastases (OM) and a widespread state of >5 cumulative metastasis as polymetastases (PM). According to the phenotypes, the different metastatic cancer patients can be treated with different methods: the OM patients can be treated by a metastasis-directed local therapy method, whereas the PM patients are not recommended to take such a treatment. It is also believed that the patients at the initial OM stage may progress to the PM stage. Currently, the OM- and PM-metastatic cancer patients can be identified by traditional imaging methods. However, the current methods are found to be insufficient for the discrimination. It hence is meaningful and important to develop new diagnostic methods for a better prediction to the patients following by selecting a correct metastasis-directed treatment.MicroRNAs (miRNAs) can be used as the genetic probes for the new diagnostic methods. In this study, a bioinformatics strategy was employed to screen the microRNAs as potential diagnostic probes for distinguishing the OM and PM lung metastases patients. The expression profiles of microarray data of GSE38698 were downloaded from Gene Expression Omnibus ( including the information from 63 patients: 24 PM and 39 OM patients. The microRNA expression patterns of tumor samples were identified for the OM and PM patients who were treated with the high-dose radiotherapy. Followed by analyzing the functional enrichment pathways, an early diagnosis model of OM and PM groups was identified with different expression genes (DEGs). The ratios of PM/OM were calculated by setting a high significance in the expressions of 377 mature miRNAs in the profile [log2 (PM/OM) >1 and P < .05]. Through a high combination power [area under the curve (AUC) ≥ 0.875] with the superior sensitivity and specificity, a panel of 10 miRNAs including 7 upregulation and 3 downregulation expressions were identified as potential probes for discriminating the PM and OM patients from the receiving operation characteristic (ROC). Considering the possible involvements of cancer progress, the interconnected axon guidance, cancer metastasis pathways, proteoglycans, and Mitogen-activated protein kinases signaling pathway and endocytosis were suggested for the subsequent miRNA target analysis. The results may reveal a biological significance that a profile of miRNAs can be used as the potential probes to identify the patients at the OM or PM stages and figure out the metastasis-directed treatment methods for the patients at the different metastasis stages.

Fougère B, Landkocz Y, Lepers C, et al.
Influence of aging in the modulation of epigenetic biomarkers of carcinogenesis after exposure to air pollution.
Exp Gerontol. 2018; 110:125-132 [PubMed] Related Publications
BACKGROUND: Classified as carcinogenic to humans by the IARC in 2013, fine air particulate matter (PM
METHODS: In order to estimate the influence of age on the development of early cellular epigenetic alterations involved in carcinogenesis, peripheral blood mononuclear cells sampled from 90 patients from three age classes (25-30, 50-55 and 75-80 years old) were ex vivo exposed to urban PM
RESULTS: Particles exposure led to variations in telomerase activity and telomeres length in all age groups without any influence of age. Conversely, P16
CONCLUSION: Hence, our results demonstrated several tendencies in cells modification depending on age, even if all epigenetic assays were carried out after a limited exposure time allowing only one or two cell cycles. Since lung cancer symptoms appear only at an advanced stage, our results underline the needs for further investigation on the studied biomarkers for early diagnosis of carcinogenesis to improve survival.

Quezada-Maldonado EM, Sánchez-Pérez Y, Chirino YI, et al.
miRNAs deregulation in lung cells exposed to airborne particulate matter (PM
Environ Pollut. 2018; 241:351-358 [PubMed] Related Publications
Particulate matter (PM) is an environmental pollutant that has been associated with an increased risk for lung cancer. PM exposure induces cellular alterations and the deregulation of cell signaling pathways. However other mechanisms such as microRNAs deregulation, might be involved in the development and progression of some types of epithelial cancer. The aim of this work was to evaluate miRNA expression in epithelial lung cells after exposure to PM

Ji Y, Shao Z, Liu J, et al.
The correlation between mammographic densities and molecular pathology in breast cancer.
Cancer Biomark. 2018; 22(3):523-531 [PubMed] Related Publications
This study aimed to analyze the correlation between mammographic density obtained by density analysis software (DAS)/radiologists visual (RV) classification with molecular subtype, and the expression levels of estrogen receptor (ER), progesterone receptor (PR), Ki67 antigen (Ki-67), p53 gene (p53), and human epidermal growth factor receptor-2 (HER2). A total of 688 breast cancer patients with digital mammography and complete molecular pathological results in Tianjin Medical University Cancer Institute and Hospital between February 2015 and February 2016 were collected. The DAS-density grade (DASD) and the radiologists visually classified density grade (RVD) were evaluated by 3 radiologists. The correlation between density grade and the expression levels of ER, PR, Ki-67, p53, HER2 and breast cancer molecular subtype (PMS) were analyzed. The agreement between DASD and RVD was explored. ER, PR and HER-2 positive rate were significantly different among patients with different RVD grades (P< 0.05). HER2 positive rates showed an increasing trend following RVD upgrading (P𝑡𝑟𝑒𝑛𝑑< 0.05). HER-2 positive rate in RVD D1 + D2 was 7.69%, which was higher than that in D3 + D4 (P< 0.05). The ER and Ki-67 expressions in patients were markedly different among DASD (P= 0.009 and 0.002) and RVD (P= 0.012 and 0.036) with different grades. The kappa value of each DASD to RVD was 0.31 (P< 0.01). The RVD 3 proportion was 14.58% (63/432) in HER2 Over-expressing subtype, which was apparently higher than RVD1 (2.43%, 1/41) (P< 0.05). Breast density may be partial correlated with molecular pathology in breast cancer.

Povedano E, Valverde A, Montiel VR, et al.
Rapid Electrochemical Assessment of Tumor Suppressor Gene Methylations in Raw Human Serum and Tumor Cells and Tissues Using Immunomagnetic Beads and Selective DNA Hybridization.
Angew Chem Int Ed Engl. 2018; 57(27):8194-8198 [PubMed] Related Publications
We report a rapid and sensitive electrochemical strategy for the detection of gene-specific 5-methylcytosine DNA methylation. Magnetic beads (MBs) modified with an antibody for 5-methylcytosines (5-mC) are used for the capture of any 5-mC methylated single-stranded (ss)DNA sequence. A flanking region next to the 5-mCs of the captured methylated ssDNA is recognized by hybridization with a synthetic biotinylated DNA sequence. Amperometric transduction at disposable screen-printed carbon electrodes (SPCEs) is employed. The developed biosensor has a dynamic range from 3.9 to 500 pm and a limit of detection of 1.2 pm for the methylated synthetic sequence of the tumor suppressor gene O-6-methylguanine-DNA methyltransferase (MGMT) promoter region. The method is applied in the 45-min analysis of specific methylation in the MGMT promoter region directly in raw spiked human serum samples and in genomic DNA extracted from U-87 glioblastoma cells and paraffin-embedded brain tumor tissues without any amplification and pretreatment step.

Li X, Chen D, Li M, et al.
Plantamajoside inhibits lipopolysaccharide-induced epithelial-mesenchymal transition through suppressing the NF-κB/IL-6 signaling in esophageal squamous cell carcinoma cells.
Biomed Pharmacother. 2018; 102:1045-1051 [PubMed] Related Publications
Plantamajoside (PMS) is a major compound of Plantago asiatica and possesses anti-tumor activity. However, the effect of PMS on esophageal squamous cell carcinoma (ESCC) and the underlying mechanism of action are unclear. The present study aimed to evaluate the effect of PMS on lipopolysaccharide (LPS)-induced epithelial-mesenchymal transition (EMT) in ESCC. The results showed that PMS inhibited viability of ESCC cell lines (Eca-109 and TE-1) in a concentration-dependent manner. PMS also inhibited LPS-induced EMT in ESCC cells. PMS inhibited LPS-induced activation of the NF-κB pathway and IL-6 expression. PMS also suppressed IL-6-induced EMT in ESCC cells. Treatment of BAY11-7082 (an inhibitor of NF-κB) or antibody against IL-6 alleviated the effect of LPS-induced EMT in ESCC cells. Besides, inhibition of NF-κB decreased IL-6 expression. In conclusion, the results indicated that PMS inhibited LPS-induced EMT through suppressing the NF-κB/IL-6 signaling in ESCC cell lines, suggesting that PMS might be a useful agent for the treatment of ESCC.

Senthil Kumar S, Muthuselvam P, Pugalenthi V, et al.
Toxicoproteomic analysis of human lung epithelial cells exposed to steel industry ambient particulate matter (PM) reveals possible mechanism of PM related carcinogenesis.
Environ Pollut. 2018; 239:483-492 [PubMed] Related Publications
Toxicoproteomic analysis of steel industry ambient particulate matter (PM) that contain high concentrations of PAHs and metals was done by treating human lung cancer cell-line, A549 and the cell lysates were analysed using quantitative label-free nano LC-MS/MS. A total of 18,562 peptides representing 1576 proteins were identified and quantified, with 196 proteins had significantly altered expression in the treated cells. Enrichment analyses revealed that proteins associated to redox homeostsis, metabolism, and cellular energy generation were inhibited while, proteins related to DNA damage and repair and other stresses were over expressed. Altered activities of several tumor associated proteins were observed. Protein-protein interaction network and biological pathway analysis of these differentially expressed proteins were carried out to obtain a systems level view of proteome changes. Together it could be inferred that PM exposure induced oxidative stress which could have lead into DNA damage and tumor related changes. However, lowering of cellular metabolism, and energy production could reduce its ability to overcome these stress. This kind of disequilibrium between the DNA damage and ability of the cells to repair the DNA damage may lead into genomic instability that is capable of acting as the driving force during PM induced carcinogenesis.

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