Gene Summary

Gene:PAEP; progestagen associated endometrial protein
Aliases: GD, GdA, GdF, GdS, PEP, PAEG, PP14, ZIF-1
Summary:This gene is a member of the kernel lipocalin superfamily whose members share relatively low sequence similarity but have highly conserved exon/intron structure and three-dimensional protein folding. Most lipocalins are clustered on the long arm of chromosome 9. The encoded glycoprotein has been previously referred to as pregnancy-associated endometrial alpha-2-globulin, placental protein 14, and glycodelin, but has been officially named progestagen-associated endometrial protein. Three distinct forms, with identical protein backbones but different glycosylation profiles, are found in amniotic fluid, follicular fluid and seminal plasma of the reproductive system. These glycoproteins have distinct and essential roles in regulating a uterine environment suitable for pregnancy and in the timing and occurrence of the appropriate sequence of events in the fertilization process. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Oct 2015]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Source:NCBIAccessed: 31 August, 2019


What does this gene/protein do?
Show (4)

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.

  • Breast
  • Transfection
  • Up-Regulation
  • Down-Regulation
  • bcl-X Protein
  • Ovarian Cancer
  • Endometrial Cancer
  • Transcription
  • ran GTP-Binding Protein
  • Messenger RNA
  • Adenoma
  • Pregnancy
  • Glycoproteins
  • Immunohistochemistry
  • Cell Differentiation
  • Lentivirus
  • Oligonucleotide Array Sequence Analysis
  • ras Proteins
  • p53 Protein
  • siRNA
  • Cancer Gene Expression Regulation
  • Sensitivity and Specificity
  • Non-Small Cell Lung Cancer
  • Tumor Antigens
  • In Situ Hybridization
  • Cell Division
  • Gene Expression Profiling
  • Adenocarcinoma
  • Glycodelin
  • Chromosome 9
  • Cell Proliferation
  • Case-Control Studies
  • Tumor Suppressor Proteins
  • Breast Cancer
  • Transforming Growth Factor beta
  • Nanoparticles
  • Immunosuppressive Agents
  • Biomarkers, Tumor
  • Pregnancy Proteins
  • Melanoma
Tag cloud generated 31 August, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (5)

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: PAEP (cancer-related)

Glorie N, Baert T, VAN DEN Bosch T, Coosemans AN
Circulating Protein Biomarkers to Differentiate Uterine Sarcomas from Leiomyomas.
Anticancer Res. 2019; 39(8):3981-3989 [PubMed] Related Publications
Uterine sarcomas are rare but very aggressive. Uterine myomas, on the other hand, are the most common benign tumors of the uterus. Currently there is no diagnostic technique available to distinguish them with certainty. This study aimed to summarize the published literature concerning protein-based biomarkers in the peripheral blood that can assist in this difficult differential diagnosis. In total, 48 articles, published between 1990 and 2017, were included. Most studies (n=37) concerned soft tissue sarcomas, while 11 discussed uterine sarcomas specifically. Vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), interleukins (IL), cancer antigen 125 (CA 125), lactate dehydrogenase, gangliosides (LDH) and growth differentiation factor 15 (GDF-15) are the most studied proteins in soft tissue sarcomas, including uterine sarcomas. Future research on improving sarcoma diagnosis should include these proteins.

Loriot Y, Necchi A, Park SH, et al.
Erdafitinib in Locally Advanced or Metastatic Urothelial Carcinoma.
N Engl J Med. 2019; 381(4):338-348 [PubMed] Related Publications
BACKGROUND: Alterations in the gene encoding fibroblast growth factor receptor (
METHODS: In this open-label, phase 2 study, we enrolled patients who had locally advanced and unresectable or metastatic urothelial carcinoma with prespecified
RESULTS: A total of 99 patients in the selected-regimen group received a median of five cycles of erdafitinib. Of these patients, 43% had received at least two previous courses of treatment, 79% had visceral metastases, and 53% had a creatinine clearance of less than 60 ml per minute. The rate of confirmed response to erdafitinib therapy was 40% (3% with a complete response and 37% with a partial response). Among the 22 patients who had undergone previous immunotherapy, the confirmed response rate was 59%. The median duration of progression-free survival was 5.5 months, and the median duration of overall survival was 13.8 months. Treatment-related adverse events of grade 3 or higher, which were managed mainly by dose adjustments, were reported in 46% of the patients; 13% of the patients discontinued treatment because of adverse events. There were no treatment-related deaths.
CONCLUSIONS: The use of erdafitinib was associated with an objective tumor response in 40% of previously treated patients who had locally advanced and unresectable or metastatic urothelial carcinoma with

Liu M, Gong C, Xu R, et al.
MicroRNA-5195-3p enhances the chemosensitivity of triple-negative breast cancer to paclitaxel by downregulating EIF4A2.
Cell Mol Biol Lett. 2019; 24:47 [PubMed] Free Access to Full Article Related Publications
Background: Chemotherapy based on paclitaxel (PTX) is the standard treatment for a range of cancers, including triple-negative breast cancer (TNBC), but the increasing development of resistance has reduced/has negatively impacted its clinical utility. A previous study demonstrated that miR-5195-3p could suppress lung cancer cell growth. This study was designed to investigate whether miR-5195-3p attenuates chemoresistance to PTX by regulating target genes in TNBC cells.
Methods: The study used both PTX-resistant tumor tissues and PTX-resistant TNBC cell lines. The expression of miR-5195-3p was determined using quantitative real-time PCR. Cell viability, cell cycle distribution and apoptosis were analyzed using CCK-8 and flow cytometry assays. The target genes of miR-5195-3p were predicted with bioinformatics analysis and confirmed using the luciferase reporter assay.
Results: MiR-5195-3p expression was lower in PTX-resistant tumor tissues and PTX-resistant TNBC cell lines. Upregulation of miR-5195-3p enhanced the sensitivity of PTX-resistant TNBC cells to PTX treatment. EIF4A2 was confirmed as a potential target of miR-5195-3p. EIF4A2 knockdown imitated the effects of miR-5195-3p on chemosensitivity, while restoration of EIF4A2 rescued them.
Conclusion: These data demonstrate that miR-5195-3p might be a potential therapeutic target to reverse chemoresistance in TNBC through its targeting of EIF4A2.

Chen Z, Ou H, Wu H, et al.
Role of microRNA in the Pathogenesis of Polycystic Ovary Syndrome.
DNA Cell Biol. 2019; 38(8):754-762 [PubMed] Related Publications
Polycystic ovary syndrome (PCOS) is the most typical metabolic syndrome in women of reproductive age, with a high prevalence and an increased risk of long-term complications. PCOS mainly manifests as hyperandrogenism (HA), ovulatory dysfunction, and polycystic ovaries, in addition to being relevant to infertility, insulin resistance (IR), obesity, lipid abnormalities, and chronic low-grade inflammation. The etiology of this syndrome remains largely unknown. microRNAs (miRNAs), small, noncoding RNAs (nearly 22 nucleotides long), regulate gene expression at the posttranscriptional level. Abnormal miRNA levels are closely associated with the occurrence of diseases, such as diabetes, cancers, and atherosclerosis, and miRNAs can be used as predictors and diagnostic biomarkers for cancer. Interestingly, the roles of miRNAs in PCOS pathology have attracted considerable attention in recent years. Research has established that alterations in miRNA expression in women with PCOS compared with healthy women may act as noninvasive biomarkers and new therapeutic targets in PCOS. This article aims to summarize the latest research on the relationship between miRNAs and the clinical manifestations of PCOS while also providing a few mechanisms based on previous studies. Understanding the relationship between miRNAs and PCOS will provide guidance for researchers to further explore the complexity and heterogeneity of PCOS.

Maehana S, Matsumoto Y, Kojima F, Kitasato H
Interleukin-24 Transduction Modulates Human Prostate Cancer Malignancy Mediated by Regulation of Anchorage Dependence.
Anticancer Res. 2019; 39(7):3719-3725 [PubMed] Related Publications
BACKGROUND: Hormone therapy and chemotherapy are not effective for castrate-resistant prostate cancer, thus development of novel treatment strategies is required. Gene therapy involving transient high-copy transfection of interleukin (IL)-24 with an adenoviral vector can exert antitumor activity; however, the effects of stable IL-24 transfection are not fully understood. The aim of this study was to investigate the effects of IL-24 overexpression in prostate cancer cells, in vitro.
MATERIALS AND METHODS: DU145 cells were transfected the IL-24 gene using a retroviral vector. Apoptosis induction was investigated by the cell death detection ELISA, and the gene expression was analyzed by real time RT-PCR.
RESULTS: IL-24 transduction suppressed the growth of prostate cancer and induced tumor cell apoptosis. In addition, up-regulation of epithelial markers and down-regulation of mesenchymal markers were noted, suggesting that tumor aggressiveness was reduced.
CONCLUSION: Introduction of IL-24 displays antitumor activity both by induction of apoptosis and regulation of anchorage dependence.

Chen Y, Tsai YH, Tseng SH
Regulation of BS69 Expression in Cancers.
Anticancer Res. 2019; 39(7):3347-3351 [PubMed] Related Publications
BS69 is encoded by a gene located on chromosome 10, in a region frequently deleted in human cancers and BS69 expression is often down-regulated in human cancers. In addition, BS69 acts as a transcriptional repressor via interaction with transcriptional factors associated with tumorigenesis, such as cellular homolog of the avian myeloblastosis viral oncoprotein, v-ets erythroblastosis virus E26 oncogene homolog 2 oncoprotein, MYC-associated protein X gene-associated protein. Overexpression of BS69 can suppress proliferation of osteosarcoma, breast cancer and glioma cells in vitro; and inhibits tumor growth in xenograft models. Therefore, BS69 may act as a tumor suppressor, and may be a new target for cancer therapy. However, BS69 down-regulation has been found to be involved in cellular senescence and is associated with the reversion of the malignant phenotype of breast cancer cells. Therefore, additional studies are necessary to clarify the role of BS69 in tumor development.

Zhang H, Luo C, Zhang G
DNA Cell Biol. 2019; 38(8):857-864 [PubMed] Related Publications
Hepatocellular carcinoma (HCC) has been reported to be one of the major tumors in the world. There is a study indicating that MCM3AP-AS1 is an oncogenic factor in HCC; however, the mechanism by which MCM3AP-AS1 regulates HCC remains not fully understood. Reverse Transcription-quantitative PCR and Western blot approaches were used to detect mRNA and protein levels of various genes. To examine invasion of HCC cells and lymphatic vessel formation of human dermal lymphatic endothelial cells (HDLECs), we employed transwell invasion assay and lymphatic vessel assay. Bioinformatic analysis and luciferase reporter assay were used to establish direct interactions between MCM3AP-AS1 and miR-455. Besides, The Cancer Genome Atlas analyses of HCCs were performed to determine the association of MCM3AP-AS1 and epidermal growth factor receptor (EGFR) with overall survival. MCM3AP-AS1 knockdown impaired invasion of HCC cells and lymphatic vessel formation of HDLECs. MCM3AP-AS1 directly interacted with miR-455. Furthermore, miR-455 inhibitor-transfected HepG2 cells enhanced the invasion and lymphatic vessel formation abilities. The rescue experiments indicated that EGFR was critical for MCM3AP-AS1- and miR-455-regulated invasion and lymphatic vessel formation. More interestingly, autophagy-related genes (Beclin1, LC3 II/I, and ATG7) were abnormally regulated in miR-455 mimic or inhibitor HepG2 cells. miR-455 mimic inhibited cell invasion and lymphatic vessel formation, which was evidently abrogated by ATG7 overexpression. Finally, we analyzed The Cancer Genome Atlas data sets to test the upregulated expression levels of MCM3AP-AS1 and EGFR. In addition, the results showed that low levels of both genes facilitate survival of HCC patients. In this study, we reveal a novel mechanism underlying MCM3AP-AS1-induced HCC metastasis by regulating miR-455. The conclusions provide more insights into understanding mechanism underlying HCC and help development of therapeutical approaches for treating HCC.

Malinverno M, Maderna C, Abu Taha A, et al.
Endothelial cell clonal expansion in the development of cerebral cavernous malformations.
Nat Commun. 2019; 10(1):2761 [PubMed] Free Access to Full Article Related Publications
Cerebral cavernous malformation (CCM) is a neurovascular familial or sporadic disease that is characterised by capillary-venous cavernomas, and is due to loss-of-function mutations to any one of three CCM genes. Familial CCM follows a two-hit mechanism similar to that of tumour suppressor genes, while in sporadic cavernomas only a small fraction of endothelial cells shows mutated CCM genes. We reported that in mouse models and in human patients, endothelial cells lining the lesions have different features from the surrounding endothelium, as they express mesenchymal/stem-cell markers. Here we show that cavernomas originate from clonal expansion of few Ccm3-null endothelial cells that express mesenchymal/stem-cell markers. These cells then attract surrounding wild-type endothelial cells, inducing them to express mesenchymal/stem-cell markers and to contribute to cavernoma growth. These characteristics of Ccm3-null cells are reminiscent of the tumour-initiating cells that are responsible for tumour growth. Our data support the concept that CCM has benign tumour characteristics.

Sai E, Miwa Y, Takeyama R, et al.
Identification of candidates for driver oncogenes in scirrhous-type gastric cancer cell lines.
Cancer Sci. 2019; 110(8):2643-2651 [PubMed] Free Access to Full Article Related Publications
Scirrhous-type gastric cancer (SGC) is one of the most intractable cancer subtypes in humans, and its therapeutic targets have been rarely identified to date. Exploration of somatic mutations in the SGC genome with the next-generation sequencers has been hampered by markedly increased fibrous tissues. Thus, SGC cell lines may be useful resources for searching for novel oncogenes. Here we have conducted whole exome sequencing and RNA sequencing on 2 SGC cell lines, OCUM-8 and OCUM-9. Interestingly, most of the mutations thus identified have not been reported. In OCUM-8 cells, a novel CD44-IGF1R fusion gene is discovered, the protein product of which ligates the amino-terminus of CD44 to the transmembrane and tyrosine-kinase domains of IGF1R. Furthermore, both CD44 and IGF1R are markedly amplified in the OCUM-8 genome and abundantly expressed. CD44-IGF1R has a transforming ability, and the suppression of its kinase activity leads to rapid cell death of OCUM-8. To the best of our knowledge, this is the first report describing the transforming activity of IGF1R fusion genes. However, OCUM-9 seems to possess multiple oncogenic events in its genome. In particular, a novel BORCS5-ETV6 fusion gene is identified in the OCUM-9 genome. BORCS5-ETV6 possesses oncogenic activity, and suppression of its message partially inhibits cell growth. Prevalence of these novel fusion genes among SGC awaits further investigation, but we validate the significance of cell lines as appropriate reagents for detailed genomic analyses of SGC.

Yarahmadi S, Abdolvahabi Z, Hesari Z, et al.
Inhibition of sirtuin 1 deacetylase by miR-211-5p provides a mechanism for the induction of cell death in breast cancer cells.
Gene. 2019; 711:143939 [PubMed] Related Publications
Sirtuin 1 is one of the regulators of cell growth and survival and its inhibition is suggested as a suitable mechanism to overcome breast cancer development. In this study we explored the role of miR-211-5p in SIRT1/p53 pathway and its influence on breast cancer cell viability and apoptosis. Cells were transfected with miR-211-5p mimic and inhibitor to modulate cellular miR-211-5p levels in breast cancer cell lines, MDA-MB-231 and MCF-7. Gene expression of miR-211-5p and SIRT1 were measured with real-time PCR. SIRT1 protein level and the acetylation of p53 as well as SIRT1 activity were evaluated by Western blotting and fluorometry, respectively. In order to explore the direct attachment of miR-211-5p to the 3'-UTR of SIRT1 mRNA, luciferase reporter assay was applied. Cell viability in response to miR-211-5p was studied by MTT assay and apoptosis was assessed by annexin V labeling followed by flow cytometry. Results showed that SIRT1 gene and protein expression were inhibited by miR-211-5p and the 3'-UTR of SIRT1 was found to be directly targeted by miR-211-5p. Inhibition of SIRT1 expression resulted in its reduced activity. Up-regulation of miR-211-5p was also followed by a significant decline in the acetylation status of p53 which was associated with remarkable decreased cell viability and induction of apoptosis in breast cancer cells. Antisense oligonucleotide of miR-211-5p acted as its inhibitor and exerted opposite effects both on SIRT1 expression and cell apoptosis. In conclusion, inhibition of SIRT1 by miR-211-5p could effectively reduce breast cancer cell survival and cause cell death and therefore might be considered a seemly mechanism for designing anticancer therapies.

Ye J, Luo D, Yu J, Zhu S
Transcriptome analysis identifies key regulators and networks in Acute myeloid leukemia.
Hematology. 2019; 24(1):487-491 [PubMed] Related Publications
OBJECTIVES: Acute myeloid leukemia (AML) is a heterogeneous and highly recurrent hematological malignancy. Studies have shown an association between microRNAs and drive genes in AMLs. However, the regulatory roles of miRNAs in AML and how they act on downstream targets and the signaling pathway has been little studied.
METHODS: As to understand the mechanism of mRNA-miRNA interaction in the blood malignancy from a large scale of transcriptomic sequencing studies, we applied a comprehensive miRNA-mRNA association, co-expression gene network and ingenuity pathway analysis using TCGA AML datasets.
RESULTS: Our results showed that his-mir-335 was a critical regulatory of homeobox A gene family. PBX3, KAT6A, MEIS1, and COMMD3-BMI1 were predicted as top transcription regulators in the regulatory network of the HOXA family. The most significantly enriched functions were cell growth, proliferation, and survival in the mRNA-miRNA network.
CONCLUSION: Our work revealed that regulation of the HOXA gene family and its regulation played an important role in the development of AML.

Liu J, Song S, Lin S, et al.
Circ-SERPINE2 promotes the development of gastric carcinoma by sponging miR-375 and modulating YWHAZ.
Cell Prolif. 2019; 52(4):e12648 [PubMed] Related Publications
OBJECTIVES: Circular RNAs (circRNAs) exist extensively in the eukaryotic genome. The study aimed to identify the role of hsa_circ_0008365 (Circ-SERPINE2) in gastric carcinoma (GC) cells and its downstream mechanisms.
MATERIALS AND METHODS: Gene Expression Omnibus (GEO) database was applied to screen differentially expressed circRNAs. CircInteractome, TargetScan and miRecords websites were used to predict target relationships. qRT-PCR and RNase R treatment were utilised to detect molecule expression and confirm the existence of circ-SERPINE2. RNA pull-down assay and dual-luciferase reporter assay were performed for interaction between circRNA and miRNA or mRNA. EdU assay, colony formation assay, and flow cytometry for apoptosis and cell cycle detections were utilised to assess cell function. Western blot and immunohistochemistry (IHC) assays were applied for detection of proteins in tissues or cells.
RESULTS: Circ-SERPINE2 and YWHAZ were upregulated, and miR-375 was downregulated in GC tissues and cells. Circ-SERPINE2 and YWHAZ targetedly bound to miR-375. Circ-SERPINE2 promoted cell proliferation and cell cycle progress and inhibited cell apoptosis by sponging miR-375 and regulating YWHAZ expression in vitro. Circ-SERPINE2 repressed solid tumour growth through enhancing miR-375 expression and reducing YWHAZ expression in vivo.
CONCLUSIONS: Circ-SERPINE2 is a novel proliferative promoter through the regulation of miR-375/YWHAZ. Circ-SERPINE2/miR-375/YWHAZ axis might provide a novel therapeutic target of GC.

Kumar KJS, Vani MG, Hsieh HW, et al.
Antcin-A Modulates Epithelial-to-Mesenchymal Transition and Inhibits Migratory and Invasive Potentials of Human Breast Cancer Cells via p53-Mediated miR-200c Activation.
Planta Med. 2019; 85(9-10):755-765 [PubMed] Related Publications
Antcin-A (ATA) is a steroid-like phytochemical isolated from the fruiting bodies of a precious edible mushroom

Jorda R, Lopes SMM, Řezníčková E, et al.
Tetrahydropyrazolo[1,5-a]pyridine-fused steroids and their in vitro biological evaluation in prostate cancer.
Eur J Med Chem. 2019; 178:168-176 [PubMed] Related Publications
The androgen receptor (AR) is a steroid hormone receptor and its high expression and disruption of its regulation are strongly implicated in prostate cancer (PCa) development. One of the current therapies includes application of steroidal antiandrogens leading to blockade of the AR action by the abrogation of AR-mediated signaling. We introduced here novel 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-fused steroidal compounds, described their synthesis based on [8π+2π] cycloaddition reactions of diazafulvenium methides with different steroidal scaffolds and showed their biological evaluation in different prostate cancer cell lines in vitro. Our results showed the ability of novel compounds to suppress the expression of known androgen receptor targets, Nkx3.1 and PSA in two prostate cell lines, 22Rv1 and VCaP. Candidate compound diminished the transcription of AR-regulated genes in the reporter cell line in a concentration-dependent manner. Antiproliferative activity of the most promising steroid was studied by clonogenic assay and induction of apoptosis in treated cells was documented by immunoblot detection of cleaved PARP.

Drobková H, Jurečeková J, Sivoňová MK, et al.
Associations Between Gene Polymorphisms of Vascular Endothelial Growth Factor and Prostate Cancer.
Anticancer Res. 2019; 39(6):2903-2909 [PubMed] Related Publications
BACKGROUND/AIM: The aim of this study was to evaluate the association between selected polymorphisms of the vascular endothelial growth factor gene (rs699947, rs144854329, rs833061, rs2010963, rs3025039) and the risk of prostate cancer development and progression.
MATERIALS AND METHODS: The present study included 446 patients with prostate cancer and 241 healthy men. Genotyping was performed by polymerase-chain reaction-restriction fragment length polymorphism analysis.
RESULTS: No significant association between the individual polymorphisms studied and the risk of prostate cancer development was detected. A statistically significantly increased risk of prostate cancer development associated with the presence of 9 or 10 risky alleles was found considering the whole group of patients, as well as in patients with low-grade carcinomas (Gleason score <7).
CONCLUSION: Individual polymorphisms of VEGF do not appear to contribute to prostate cancer. However, a combination of risky alleles of the studied polymorphisms significantly increases the risk of prostate cancer in Slovak patients.

Yan Q, Chen T, Yang H, et al.
The Effect of FERMT1 Regulated by miR-24 on the Growth and Radiation Resistance of Esophageal Cancer.
J Biomed Nanotechnol. 2019; 15(3):621-631 [PubMed] Related Publications
The present study addresses the role and underlying mechanism of FERMT1 in the development of esophageal cancer (EC). High level of FERMT1 expression was found in human EC tissues and was significantly correlated with poor overall survival. Overexpression of FERMT1 by a lentiviral vector markedly promoted EC cell proliferation and radiation resistance

Cao C, Wang Q, Li Q, et al.
Development and Preliminary Clinical Application of Circulating Tumor Cell Detection System for Prostate Cancer.
J Biomed Nanotechnol. 2019; 15(3):612-620 [PubMed] Related Publications
Real-time detection of circulating tumor cell (CTC) markers that are constantly changing and renewing during disease progression is of great significance for the timely regimen switch or individualized target therapy. The abnormally expressed special AT-rich sequence binding protein 1 (SATB1), a nuclear matrix attachment region binding protein, in various tumors, promotes the growth and metastasis of tumor cells by regulating gene expression. In this paper, a CTC detection system for prostate cancer (PCa) was developed on the basis of epithelial cell adhesion molecule (EpCAM)-targeted immunomagnetic separation and CK-FITC and SATB-1-APC immunofluorescence assay, and the recovery rate of tumor cells in PBS and simulated whole blood by this system was detected. Subsequently, we isolated, identified, and counted SATB-1 ositive CTCs in the peripheral blood and urine samples of 60 tumor-bearing nude mice, 5 healthy volunteers and 13 PCa patients. Combined with the clinicopathological factors, the clinical value of the system was analyzed, and the possibility of SATB-1-positive CTCs in the diagnosis of PCa was evaluated. The results showed that the CTC sorting and identification system for prostate cancer constructed in this study had a recovery rate of more than 85% for CTC in PBS, urine and blood simulation samples. The expression level of SATB-1 was different in different PCa cell lines, which was relatively high in the highly invasive PCa DU-145 cell line. The expression of SATB-1 in CTCs in the blood samples of PCa patients with different clinical characteristics and in the urine samples of a few PCa patients with bone metastases were different, and the detection sensitivity of peripheral blood was higher than that of urine. This study has important clinical reference value for the early diagnosis of PCa and the evaluation of bone metastasis based on the CTC counting and the SATB-1 expression in CTCs.

Recagni M, Greco ML, Milelli A, et al.
Distinct biological responses of metastatic castration resistant prostate cancer cells upon exposure to G-quadruplex interacting naphthalenediimide derivatives.
Eur J Med Chem. 2019; 177:401-413 [PubMed] Related Publications
Small molecules able to bind non-canonical G-quadruplex DNA structures (G4) have been recently tested as novel potential agents for the treatment of prostate cancer thanks to their repression of aberrant androgen receptor gene. However, metastatic castration-resistant prostate cancer (mCRPC), a letal form of prostate cancer, is still incurable. Here we tested two naphthalenediimide derivatives, previously reported as multitarget agents, on a couple of relevant mCRPC cell models (DU145 and PC-3). We showed that these compounds interfere with the RAS/MEK/ERK and PI3K/AKT pathways. Interestingly, both these two biological processes depend upon Epidermal Growth Factor Receptor (EGFR) activation. By means of biological and analytical tools we showed that our compounds are efficient inducers of the structural transition of the EGFR promoter towards a G-quadruplex conformation, ultimately leading to a reduction of the receptor production. The overall result is an interesting cytotoxic profile for these two derivatives. Thanks to their activity at different steps, these compounds can open the way to novel therapeutic approaches for mCRPC that could contribute to escape resistance to selective treatments.

Saha T, Makar S, Swetha R, et al.
Estrogen signaling: An emanating therapeutic target for breast cancer treatment.
Eur J Med Chem. 2019; 177:116-143 [PubMed] Related Publications
Breast cancer, a most common malignancy in women, was known to be associated with steroid hormone estrogen. The discovery of estrogen receptor (ER) gave us not only a powerful predictive and prognostic marker, but also an efficient target for the treatment of hormone-dependent breast cancer with various estrogen ligands. ER consists of two subtypes i.e. ERα and ERβ, that are mostly G-protein-coupled receptors and activated by estrogen, specially 17β-estradiol. The activation is followed by translocation into the nucleus and binding with DNA to modulate activities of different genes. ERs can manage synthesis of RNA through genomic actions without directly binding to DNA. Receptors are tethered by protein-protein interactions to a transcription factor complex to communicate with DNA. Estrogens also exhibit nongenomic actions, a characteristic feature of steroid hormones, which are so rapid to be considered by the activation of RNA and translation. These are habitually related to stimulation of different protein kinase cascades. Majority of post-menopausal breast cancer is estrogen dependent, mostly potent biological estrogen (E2) for continuous growth and proliferation. Estrogen helps in regulating the differentiation and proliferation of normal breast epithelial cells. In this review we have investigated the important role of ER in development and progression of breast cancer, which is complicated by receptor's interaction with co-regulatory proteins, cross-talk with other signal transduction pathways and development of treatment strategies viz. selective estrogen receptor modulators (SERMs), selective estrogen receptor down regulators (SERDs), aromatase and sulphatase inhibitors.

Rudnicka K, Backert S, Chmiela M
Genetic Polymorphisms in Inflammatory and Other Regulators in Gastric Cancer: Risks and Clinical Consequences.
Curr Top Microbiol Immunol. 2019; 421:53-76 [PubMed] Related Publications
Helicobacter pylori infection is associated with the development of a chronic inflammatory response, which may induce peptic ulcers, gastric cancer (GC), and mucosa-associated lymphoid tissue (MALT) lymphoma. Chronic H. pylori infection promotes the genetic instability of gastric epithelial cells and interferes with the DNA repair systems in host cells. Colonization of the stomach with H. pylori is an important cause of non-cardia GC and gastric MALT lymphoma. The reduction of GC development in patients who underwent anti-H. pylori eradication schemes has also been well described. Individual susceptibility to GC development depends on the host's genetic predisposition, H. pylori virulence factors, environmental conditions, and geographical determinants. Biological determinants are urgently sought to predict the clinical course of infection in individuals with confirmed H. pylori infection. Possible candidates for such biomarkers include genetic aberrations such as single-nucleotide polymorphisms (SNPs) found in various cytokines/growth factors (e.g., IL-1β, IL-2, IL-6, IL-8, IL-10, IL-13, IL-17A/B, IFN-γ, TNF, TGF-β) and their receptors (IL-RN, TGFR), innate immunity receptors (TLR2, TLR4, CD14, NOD1, NOD2), enzymes involved in signal transduction cascades (PLCE1, PKLR, PRKAA1) as well as glycoproteins (MUC1, PSCA), and DNA repair enzymes (ERCC2, XRCC1, XRCC3). Bacterial determinants related to GC development include infection with CagA-positive (particularly with a high number of EPIYA-C phosphorylation motifs) and VacA-positive isolates (in particular s1/m1 allele strains). The combined genotyping of bacterial and host determinants suggests that the accumulation of polymorphisms favoring host and bacterial features increases the risk for precancerous and cancerous lesions in patients.

Qiu S, Deng L, Liao X, et al.
Tumor-associated macrophages promote bladder tumor growth through PI3K/AKT signal induced by collagen.
Cancer Sci. 2019; 110(7):2110-2118 [PubMed] Free Access to Full Article Related Publications
The tumor microenvironment is associated with various tumor progressions, including cancer metastasis, immunosuppression, and tumor sustained growth. Tumor-associated macrophages (TAMs) are considered an indispensable component of the tumor microenvironment, participating in the progression of tumor microenvironment remodeling and creating various compounds to regulate tumor activities. This study aims to observe enriched TAMs in tumor tissues during bladder cancer development, which markedly facilitated the proliferation of bladder cancer cells and promoted tumor growth in vivo. We determined that TAMs regulate tumor sustained growth by secreting type I collagen, which can activate the prosurvival integrin α2β1/PI3K/AKT signaling pathway. Furthermore, traditional chemotherapeutic drugs combined with integrin α2β1 inhibitor showed intensive anticancer effects, revealing an innovative approach in clinical bladder cancer treatment.

Takahashi M, Miki S, Fujimoto K, et al.
Eribulin penetrates brain tumor tissue and prolongs survival of mice harboring intracerebral glioblastoma xenografts.
Cancer Sci. 2019; 110(7):2247-2257 [PubMed] Free Access to Full Article Related Publications
Glioblastoma is one of the most devastating human malignancies for which a novel efficient treatment is urgently required. This pre-clinical study shows that eribulin, a specific inhibitor of telomerase reverse transcriptase (TERT)-RNA-dependent RNA polymerase, is an effective anticancer agent against glioblastoma. Eribulin inhibited the growth of 4 TERT promoter mutation-harboring glioblastoma cell lines in vitro at subnanomolar concentrations. In addition, it suppressed the growth of glioblastoma cells transplanted subcutaneously or intracerebrally into mice, and significantly prolonged the survival of mice harboring brain tumors at a clinically equivalent dose. A pharmacokinetics study showed that eribulin quickly penetrated brain tumors and remained at a high concentration even when it was washed away from plasma, kidney or liver 24 hours after intravenous injection. Moreover, a matrix-assisted laser desorption/ionization mass spectrometry imaging analysis revealed that intraperitoneally injected eribulin penetrated the brain tumor and was distributed evenly within the tumor mass at 1 hour after the injection whereas only very low levels of eribulin were detected in surrounding normal brain. Eribulin is an FDA-approved drug for refractory breast cancer and can be safely repositioned for treatment of glioblastoma patients. Thus, our results suggest that eribulin may serve as a novel therapeutic option for glioblastoma. Based on these data, an investigator-initiated registration-directed clinical trial to evaluate the safety and efficacy of eribulin in patients with recurrent GBM (UMIN000030359) has been initiated.

Yang MH, Chang KJ, Li B, Chen WS
Arsenic Trioxide Suppresses Tumor Growth through Antiangiogenesis via Notch Signaling Blockade in Small-Cell Lung Cancer.
Biomed Res Int. 2019; 2019:4647252 [PubMed] Free Access to Full Article Related Publications
Small-cell lung cancer (SCLC) is a highly malignant type of lung cancer with no effective second-line chemotherapy drugs. Arsenic trioxide (As

Tanaka Y, Kosaka Y, Waraya M, et al.
Differential Prognostic Relevance of Promoter DNA Methylation of
Anticancer Res. 2019; 39(5):2289-2298 [PubMed] Related Publications
BACKGROUND/AIM: We previously identified that promoter DNA methylation of cysteine dioxygenase type 1 (CDO1) and homeobox only protein homeobox (HOPX) were both cancer specific, and have a clinical potential as prognostic biomarkers in breast cancer (BC). The present study compared the differential prognostic relevance of methylation status of the CDO1 and HOPX genes in BC.
MATERIALS AND METHODS: Methylation levels (TaqMethVs) were quantified in 7 BC cell lines and 133 BC patients by TaqMan methylation-specific PCR and functional traits were explored for CDO1.
RESULTS: TaqMethVs were associated between CDO1 and HOPX (r
CONCLUSION: CDO1 is a definite tumor suppressor gene, while its prognostic relevance was more than expected in the context of its functional relevance.

Atiya HI, Dvorkin-Gheva A, Hassell J, et al.
Intraductal Adaptation of the 4T1 Mouse Model of Breast Cancer Reveals Effects of the Epithelial Microenvironment on Tumor Progression and Metastasis.
Anticancer Res. 2019; 39(5):2277-2287 [PubMed] Related Publications
BACKGROUND: Low success rates in oncology drug development are prompting re-evaluation of preclinical models, including orthotopic tumor engraftment. In breast cancer models, tumor cells are typically injected into mouse mammary fat pads (MFP). However, this approach bypasses the epithelial microenvironment, potentially altering tumor properties in ways that affect translational application.
MATERIALS AND METHODS: Tumors were generated by mammary intraductal (MIND) engraftment of 4T1 carcinoma cells. Growth, histopathology, and molecular features were quantified.
RESULTS: Despite growth similar to that of 4T1 MFP tumors, 4T1 MIND tumors exhibit distinct histopathology and increased metastasis. Furthermore, >6,000 transcripts were found to be uniquely up-regulated in 4T1 MIND tumor cells, including genes that drive several cancer hallmarks, in addition to two known therapeutic targets that were not up-regulated in 4T1 MFP tumor cells.
CONCLUSION: Engraftment into the epithelial microenvironment generates tumors that more closely recapitulate the complexity of malignancy, suggesting that intraductal adaptation of orthotopic mammary models may be an important step towards improving outcomes in preclinical drug screening and development.

Wang J, Luo XX, Tang YL, et al.
The prognostic values of insulin-like growth factor binding protein in breast cancer.
Medicine (Baltimore). 2019; 98(19):e15561 [PubMed] Free Access to Full Article Related Publications
Insulin-like growth factor binding proteins (IGFBPs) are a family of proteins binding to insulin-like growth factors, generally consisting 6 high-affinity IGFBPs, namely IGFBP1 through IGFBP6. IGFBP family members have been indicated to be involved in the development and progression of tumors and may be useful prognostic biomarkers in various malignancies. However, the prognostic role of individual IGFBPs, especially at the mRNA level in breast cancer patients remains elusive.We accessed the prognostic roles of IGFBPs family (IGFBP1-6) in breast cancer through the "Kaplan-Meier plotter" online database and OncoLnc database.Our results showed that the high expression of IGFBP1 mRNA was associated with favorable relapsed free survival (RFS) in all breast cancer patients. The high expression of IGFBP2 mRNA was associated with favorable overall survival (OS) and RFS in all breast cancer patients. The high expression of IGFBP3 mRNA was significantly correlated to worsen RFS in all breast cancer patients. The high expression of IGFBP4 mRNA was associated with favorable OS, RFS, distant metastasis-free survival, and post-progression survival in all breast cancer patients.Our results indicated that expression of IGFBPs mRNA may have prognostic values in breast cancer patients, and have a benefit for developing tools to predict the prognosis more accurately.

Tang XJ, Wang W, Hann SS
Interactions among lncRNAs, miRNAs and mRNA in colorectal cancer.
Biochimie. 2019; 163:58-72 [PubMed] Related Publications
Long non-coding RNAs (lncRNAs) are longer than 200 nts non-coding transcripts and have recently emerged as one of the largest and significantly diverse RNA families whereas microRNAs (miRNAs) are highly conserved short single-stranded ncRNAs (∼18-22 nucleotides). As families of small and long evolutionarily conserved ncRNAs, lncRNAs activate and repress genes via a variety of mechanisms at both transcriptional and translational levels, while miRNAs regulate protein-coding gene expression mainly through mRNA degradation or silencing, These ncRNAs have been proved to be involved in multiple biological functions, such as proliferation, differentiation, migration, angiogenesis and apoptosis. Today, while majority of studies have focused on defining the regulatory functions of lncRNAs and miRNAs, limited information have now available for the mutual regulations of lncRNAs, miRNAs and mRNA. Thus, the underlying molecular mechanisms, in particularly the interactions among lncRNAs, miRNAs and mRNA in development, growth, metastasis and therapeutic potential of cancer still remain obscure. Colorectal cancer (CRC) is known as the third most common and fourth leading cancer death worldwide. Increasing evidence showed the close correlations among aberrant expressions of lncRNAs, miRNAs and the occurrence, development of CRC. This review summarize the potential links among these RNAs in following three areas: 1, The biogenesis and roles of miRNAs in CRC; 2, The biogenesis and functions of lncRNAs in CRC; 3, The interactions among lncRNAs, miRNAs and mRNA in tumorigensis, growth, progression, EMT formation, chemoradiotherapy resistance, and therapeutic potential in CRC. We believe that identifying diverging lncRNAs, miRNAs and relevant genes, their interactions and complex molecular regulatory networks will provide important clues for understanding the mechanism and developing novel diagnostic and therapeutic strategies for CRC. Further efforts are warranted to bring the promise of regulating their activities into clinical utilities.

Gan L, Lv L, Liao S
Long non‑coding RNA H19 regulates cell growth and metastasis via the miR‑22‑3p/Snail1 axis in gastric cancer.
Int J Oncol. 2019; 54(6):2157-2168 [PubMed] Related Publications
Gastric cancer (GC) is the fifth most prevalent type of malignancy and the third leading cause of cancer‑related mortality worldwide, with the prognosis of patients with late‑stage GC remaining at poor levels. Long non‑coding RNA (lncRNA) H19 (H19) is involved in the growth and metastasis of tumors, and it is upregulated under hypoxic conditions and in certain types of cancer; however, the underlying mechanisms of action of this lncRNA as regards the initiation and development of GC remain unknown. Thus, in the present study, we aimed to determine the role of lncRNA H19 in GC and to elucidate the underlying mechanisms. H19 was found to be upregulated in GC tissues and cells compared with the para‑cancerous tissues, and an elevated expression of H19 was associated with lymph node metastasis and TNM stage. Furthermore, the downregulation of H19 suppressed the proliferation, invasion, migration and epithelial‑mesenchymal transition of GC cells in vitro and suppressed tumor growth in vivo. H19 was also found to be able to bind with miR‑22‑3p, and H19‑induced cell growth and metastasis were shown to be reversed by the upregulation of miR‑22‑3p; the miR‑22‑3p level was found to inversely correlate with H19 expression in GC tissues. Furthermore, the overexpression of miR‑22‑3p notably suppressed the proliferation, migration and invasion of GC cells, and these effects were enhanced by the downregulation of Snail1. In addition, cell growth and metastasis induced by miR‑22‑3p downregulation were partially reversed by the knockdown of Snail1. Furthermore, a negative correlation was observed between the mRNA expression levels of miR‑22‑3p and Snail1 in GC tissues. On the whole, the findings of the present study revealed that H19 was upregulated in GC tissues, which promoted tumor growth and metastasis via the miR‑22‑3p/Snail1 signaling pathway. In summary, these findings provide novel insight into the potential regulatory roles of H19 in GC, and suggest that the H19/miR‑22‑3p/Snail1 axis may prove to be a promising therapeutic target for the treatment of patients with GC.

Meng L, Ji R, Dong X, et al.
Antitumor activity of ginsenoside Rg3 in melanoma through downregulation of the ERK and Akt pathways.
Int J Oncol. 2019; 54(6):2069-2079 [PubMed] Free Access to Full Article Related Publications
Advanced metastatic melanoma is a malignant tumor for which there is currently no effective treatment due to resistance development. Ginsenoside Rg3, a saponin component extracted from ginseng roots, has been shown to reduce melanoma cell proliferation by decreasing histone deacetylase 3 and increasing p53 acetylation. The availability of data on the role of Rg3 in melanoma is currently extremely limited. The aim of the present study was to further investigate the effects of Rg3 on B16 melanoma cells and the underlying molecular events. The findings demonstrated that Rg3 suppressed the proliferation and DNA synthesis of B16 cells. Rg3 exposure induced tumor cell cycle arrest at the S phase and reduced the expression of proliferating cell nuclear antigen (PCNA). Rg3 treatment also decreased metastasis of B16 cells in vitro and in vivo. The results indicated that this reduction was due to downregulation of matrix metalloproteinase (MMP)‑2 and MMP‑9. Moreover, Rg3 inhibited melanoma‑induced angiogenesis, most likely by downregulating vascular endothelial growth factor (VEGF) in B16 cells. Rg3 exposure decreased the expression of VEGF in B16 cells and the VEGF downregulation further suppressed angiogenesis by attenuating the proliferation and migration of vascular endothelial cells. Finally, the western blotting data demonstrated that Rg3 reduced the expression of extracellular signal‑regulated kinase (ERK) and protein kinase B (Akt) in vitro and in vivo. This result indicated that the antimelanoma effects of Rg3 may be mediated through suppression of ERK and Akt signaling. Further research is required to assess the value of Rg3 as a novel therapeutic strategy for melanoma in the clinical setting.

Moon JR, Oh SJ, Lee CK, et al.
TGF-β1 protects colon tumor cells from apoptosis through XAF1 suppression.
Int J Oncol. 2019; 54(6):2117-2126 [PubMed] Related Publications
Transforming growth factor-β1 (TGF-β1) is a multifunctional cytokine that functions as a growth suppressor in normal epithelial cells and early stage tumors, but acts as a tumor promoter during malignant progression. However, the molecular basis underlying the conversion of TGF‑β1 function remains largely undefined. X‑linked inhibitor of apoptosis‑associated factor 1 (XAF1) is a pro‑apoptotic tumor suppressor that frequently displays epigenetic inactivation in various types of human malignancies, including colorectal cancer. The present study explored whether the anti‑apoptotic effect of TGF‑β1 is linked to its regulatory effect on XAF1 induction in human colon cancer cells under stressful conditions. The results revealed that TGF‑β1 treatment protected tumor cells from various apoptotic stresses, including 5‑fluorouracil, etoposide and γ‑irradiation. XAF1 expression was activated at the transcriptional level by these apoptotic stresses and TGF‑β1 blocked the stress‑mediated activation of the XAF1 promoter. The study also demonstrated that mitogen‑activated protein kinase kinase inhibition or extracellular signal‑activated kinase (Erk)1/2 depletion induced XAF1 induction, while the activation of K‑Ras (G12C) led to its reduction. In addition, TGF‑β1 blocked the stress‑mediated XAF1 promoter activation and induction of apoptosis. This effect was abrogated if Erk1/2 was depleted, indicating that TGF‑β1 represses XAF1 transcription through Erk activation, thereby protecting tumor cells from apoptotic stresses. These findings point to a novel molecular mechanism underlying the tumor‑promoting function of TGF‑β1, which may be utilized in the development of a novel therapeutic strategy for the treatment of colorectal cancer.

Disclaimer: This site is for educational purposes only; it can not be used in diagnosis or treatment.

Cite this page: Cotterill SJ. PAEP, Cancer Genetics Web: Accessed:

Creative Commons License
This page in Cancer Genetics Web by Simon Cotterill is licensed under a Creative Commons Attribution-ShareAlike 4.0 International License.
Note: content of abstracts copyright of respective publishers - seek permission where appropriate.

 [Home]    Page last revised: 31 August, 2019     Cancer Genetics Web, Established 1999