Gene Summary

Gene:PMEL; premelanosome protein
Aliases: P1, SI, SIL, ME20, P100, SILV, ME20M, gp100, ME20-M, PMEL17, D12S53E
Summary:This gene encodes a melanocyte-specific type I transmembrane glycoprotein. The encoded protein is enriched in melanosomes, which are the melanin-producing organelles in melanocytes, and plays an essential role in the structural organization of premelanosomes. This protein is involved in generating internal matrix fibers that define the transition from Stage I to Stage II melanosomes. This protein undergoes a complex pattern of prosttranslational processing and modification that is essential to the proper functioning of the protein. A secreted form of this protein that is released by proteolytic ectodomain shedding may be used as a melanoma-specific serum marker. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Jan 2011]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:melanocyte protein PMEL
Source:NCBIAccessed: 31 August, 2019


What does this gene/protein do?
Show (10)

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.

  • Monophenol Monooxygenase
  • Messenger RNA
  • Cancer DNA
  • Membrane Glycoproteins
  • HLA-A2 Antigen
  • Cytotoxicity, Immunologic
  • Epitopes
  • Melanocytes
  • Molecular Sequence Data
  • DNA Primers
  • Cancer Vaccines
  • T-Lymphocytes
  • Cancer Gene Expression Regulation
  • Intramolecular Oxidoreductases
  • Melanoma
  • Tumor Antigens
  • Melanoma, Experimental
  • Cell Differentiation
  • Amino Acid Sequence
  • Epitopes, T-Lymphocyte
  • Cell Line
  • Peptide Fragments
  • Genetic Vectors
  • Transcription Factors
  • Antigen Presentation
  • Mutation
  • Gene Expression
  • Neoplasm Proteins
  • Proteins
  • gp100 Melanoma Antigen
  • Transduction
  • MART1
  • Biomarkers, Tumor
  • Skin Cancer
  • CD8-Positive T-Lymphocytes
  • Chromosome 12
  • Base Sequence
  • T-Lymphocytes, Cytotoxic
  • Protein Binding
Tag cloud generated 31 August, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (2)

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: PMEL (cancer-related)

Zhou X, Jiao D, Dou M, et al.
Association of glutathione-S-transferase p1 gene promoter methylation and the incidence of prostate cancer: a systematic review and meta-analysis.
J Cancer Res Clin Oncol. 2019; 145(8):1939-1948 [PubMed] Related Publications
OBJECTIVE: Some studies have shown that the methylation status of the GSTP1 gene promoter is related to the incidence of prostate cancer, but this finding is still controversial. The aim of this study was to evaluate the association between glutathione-S-transferase p1 (GSTP1) promoter methylation and the incidence of prostate cancer.
METHODS: The Medline, Embase, Web of Science, and Cochrane CENTRAL databases were searched from their inception to February 22, 2019. According to the inclusion criteria, studies of the association between the methylation status of the GSTP1 gene promoter and prostate cancer were included. The difference in the incidence of GSTP1 promoter methylation in tissues, blood, or urine between patients with prostate cancer and those without prostate cancer were compared, and the results were expressed as the odds ratio (OR) and 95% confidence interval (CI). The pooled OR of each study was estimated using a fixed-effects model or a random-effects model to generate forest plots.
RESULTS: Ultimately, 15 studies (1540 samples) were included. The estimated effect from our meta-analysis showed that the incidence of GSTP1 promoter methylation was higher in patients with prostate cancer than in those without prostate cancer (OR 18.58, 95% CI 9.60-35.95, P = 0.000). GSTP1 promoter methylation was highly correlated with the incidence of prostate cancer.
CONCLUSIONS: Methylation of the GSTP1 promoter may increase the risk of prostate cancer. This study may provide a strategic direction for prostate cancer research. Pending validation of these findings, the methylation of the GSTP1 promoter may be a potential biomarker to diagnose prostate cancer.

Cezar-Dos-Santos F, Ferreira RS, Okuyama NCM, et al.
FOXP3 immunoregulatory gene variants are independent predictors of human papillomavirus infection and cervical cancer precursor lesions.
J Cancer Res Clin Oncol. 2019; 145(8):2013-2025 [PubMed] Related Publications
PURPOSE: FOXP3 is a marker of the T regulatory (Treg) cell subset and drives its function and homeostasis. Its expression maintains the host immunosuppressive state that favors persistence of human papillomavirus (HPV) infection and squamous intraepithelial lesion (SIL) appearance. The present study evaluated the effects of the rs3761548 and rs2232365 intronic single-nucleotide variants (SNVs) and their haplotypes on HPV infection and SIL diagnosis in HPV-infected and -uninfected women.
METHODS: HPV DNA-based detection in cervical specimens was performed by PCR. FOXP3 variants were genotyped by PCR-restriction fragment length polymorphism and haplotype recombination sites were inferred for 208 HPV-infected and 218 HPV-uninfected women diagnosed or not with low- or high-grade intraepithelial lesions of cervix. Case-control analyses were carried out by logistic regression adjusted for several socio-demographic, sexual lifestyle, and clinical data.
RESULTS: The homozygous genotype of the rs3761548 variants (A/A) (related to decreased FOXP3 expression) may exert a protective role against HPV infection in women (OR
CONCLUSIONS: Our results reveal the significant and independent associations between FOXP3 genetic variants and susceptibility to HPV infection and SIL diagnosis and their role as biomarkers of HPV infection and cervical lesion management.

Macuer-Guzmán J, Bernal G, Jamett-Díaz F, et al.
Selective and Apoptotic Action of Ethanol Extract of Annona cherimola Seeds against Human Stomach Gastric Adenocarcinoma Cell Line AGS.
Plant Foods Hum Nutr. 2019; 74(3):322-327 [PubMed] Related Publications
Annona cherimola is a tree belonging to the family Annonacea, whose fruit (cherimoya) is very desirable, but its seeds are considered waste. Present in these seeds are compounds that have been described as selective antiproliferative agents for cancer cells. The aim of this study was to evaluate the antiproliferative activity of ethanol macerate extract (EMCHS) obtained from A. cherimola seeds against the human stomach gastric adenocarcinoma (AGS) cell line and the normal human gastric epithelial cell line (GES-1). The EMCHS extract presented an IC

Liu L, Ma J, Qin L, et al.
Interleukin-24 enhancing antitumor activity of chimeric oncolytic adenovirus for treating acute promyelocytic leukemia cell.
Medicine (Baltimore). 2019; 98(22):e15875 [PubMed] Related Publications
BACKGROUND: Acute promyelocytic leukaemia (APL) is a clonal disease arising by hematopoietic stem cell (HSC), which characterized by inappropriate proliferation/differentiation or survival of immature myeloid progenitors. Oncolytic adenoviruses have been under widespread investigation as anticancer agents. Recently, our data suggested that tumor cells were cured by AdCN205-IL-24, an adenovirus serotype 5-based conditionally replicating adenovirus expressing IL-24 after infection.
METHODS: In this study, we created a novel fiber chimeric oncolytic adenovirus AdCN306-IL-24 that has Ad11 tropism and approved CAR (coxsackie adenovirus receptor, CAR)-independent cell entry, which could allow development of selective cytopathic effects (CPE) in APL cells in vitro.
RESULTS: Formidable cytotoxic effect was specifically implemented in APL cells after infection with AdCN306-IL-24. The expression of IL-24 was up-regulated upon treated with accepted tumors. And the vector also induced superior cytolytic effects activity in APL cells by activation of programmed cell death.
CONCLUSIONS: Taken together, our data suggested that chimeric oncolytic adenovirus AdCN306-IL-24 could express IL-24 gene, representing a potential therapeutics for acute promyelocytic leukemia.

Jia H, Xu M, Bo Y, et al.
Ras-ERK1/2 signaling accelerates the progression of colorectal cancer via mediation of H2BK5ac.
Life Sci. 2019; 230:89-96 [PubMed] Related Publications
AIMS: Extracellular signal-regulated protein kinases 1 and 2 (ERK1/2) is a key downstream gene of Ras pathway. Activation of Ras-ERK1/2 has been testified to be linked to the progression of diverse cancers. Nonetheless, whether Ras-ERK1/2-tumorigenic pathway is mediated by epigenetic factors remains indistinct. The purpose of the research attempted to disclose the functions of H2BK5ac in Ras-ERK1/2-evoked CRC cell phenotypes.
MATERIALS AND METHODS: Western blot assay was implemented for exploration of the relevancy between Ras-ERK1/2 and H2BK5ac. H2BK5Q was established and its functions in cell viability, colony formation and migration were appraised via utilizing MTT, soft-agar colony formation and Transwell assays. The mRNA and transcription of ERK1/2 downstream genes were estimated via RT-qPCR and ChIP assays. HDAC2 functions in SW48 cell phenotypes were evaluated after co-transfection with pEGFP-Ras
KEY FINDINGS: H2BK5ac expression was evidently repressed by Ras-ERK1/2 pathway in SW48 cells. Moreover, Ras-ERK1/2-elevated cell viability, the number of colonies and migration were both impeded by H2BK5ac. The mRNA and transcriptions of CYR61, IGFBP3, WNT16B, NT5E, GDF15 and CARD16 were both mediated by H2BK5ac. Additionally, HDAC2 silence overtly recovered H2BK5ac expression inhibited by Ras-ERK1/2, meanwhile abated Ras-ERK1/2-affected SW48 cell phenotypes. Beyond that, restrained H2BK5ac induced by Ras-ERK1/2 was concerned with MDM2-mediated ATF2 degradation.
SIGNIFICANCE: These investigations testified that Ras-ERK1/2 pathway affected SW48 cell phenotypes through repressing H2BK5ac expression. Otherwise, declined H2BK5ac might be linked to MDM2-mediated ATF2 degradation.

Herreño AM, Ramírez AC, Chaparro VP, et al.
Role of RUNX2 transcription factor in epithelial mesenchymal transition in non-small cell lung cancer lung cancer: Epigenetic control of the RUNX2 P1 promoter.
Tumour Biol. 2019; 41(5):1010428319851014 [PubMed] Related Publications
Lung cancer has a high mortality rate in men and women worldwide. Approximately 15% of diagnosed patients with this type of cancer do not exceed the 5-year survival rate. Unfortunately, diagnosis is established in advanced stages, where other tissues or organs can be affected. In recent years, lineage-specific transcription factors have been associated with a variety of cancers. One such transcription factor possibly regulating cancer is RUNX2, the master gene of early and late osteogenesis. In thyroid and prostate cancer, it has been reported that RUNX2 regulates expression of genes important in tumor cell migration and invasion. In this study, we report on RUNX2/ p57 overexpression in 16 patients with primary non-small cell lung cancer and/or metastatic lung cancer associated with H3K27Ac at P1 gene promoter region. In some patients, H3K4Me3 enrichment was also detected, in addition to WDR5, MLL2, MLL4, and UTX enzyme recruitment, members of the COMPASS-LIKE complex. Moreover, transforming growth factor-β induced RUNX2/ p57 overexpression and specific RUNX2 knockdown supported a role for RUNX2 in epithelial mesenchymal transition, which was demonstrated through loss of function assays in adenocarcinoma A549 lung cancer cell line. Furthermore, RUNX2 increased expression of epithelial mesenchymal transition genes VIMENTIN, TWIST1, and SNAIL1, which reflected increased migratory capacity in lung adenocarcinoma cells.

Dutta S, Mahalanobish S, Saha S, et al.
Natural products: An upcoming therapeutic approach to cancer.
Food Chem Toxicol. 2019; 128:240-255 [PubMed] Related Publications
Cancer is one of the leading causes of death across the world. Different environmental and anthropogenic factors initiate mutations in different functional genes of growth factors and their receptors, anti-apoptotic proteins, self-renewal developmental proteins, tumor suppressors, transcription factors, etc. This phenomenon leads to altered protein homeostasis of the cell which in turn induces cancer initiation, development, progression and survival. From ancient times various natural products have been used as traditional medicine against different diseases. Natural products are readily applicable, inexpensive, accessible and acceptable therapeutic approach with minimum cytotoxicity. As most of the target-specific anticancer drugs failed to achieve the expected result so far, new multi-targeted therapies using natural products have become significant. In this review, we have summarized the efficacy of different natural compounds against cancer. They are capable of modulating cancer microenvironment and diverse cell signaling cascades; thus playing a major role in combating cancer. These compounds are found to be effective against several signaling pathways, mainly cell death pathways (apoptosis and autophagy) and embryonic developmental pathways (Notch pathway, Wnt pathway and Hedgehog pathway). This review article is expected to be helpful in understanding the recent progress of natural product research for the development of anticancer drug.

Chen W, Liu H, Wang T, et al.
Downregulation of AIF-2 Inhibits Proliferation, Migration, and Invasion of Human Glioma Cells via Mitochondrial Dysfunction.
J Mol Neurosci. 2019; 68(2):304-310 [PubMed] Related Publications
Glioma remains the leading cause of brain tumor-related death worldwide. Apoptosis inducing factor (AIF) is a family of mitochondrial oxidoreductases that play important roles in mitochondrial metabolism and redox control. AIF-1 has been demonstrated to exert cell-killing effect via apoptosis in cancer cells, whereas the role of AIF-2 in cancer cells has not been determined. This study aimed to investigate the role of AIF-2 in human glioma cells. We found that AIF-2 was upregulated in human glioma tissues and cell lines, especially in U251 cells. Downregulation of AIF-2 using specific siRNA (Si-AIF-2) significantly reduced cell proliferation, induced G1 cell cycle arrest and differently regulated the expression of cell cycle regulator proteins in U251 cells. In addition, the results of Matrigel invasion assay and live-cell tracking assay showed that knockdown of AIF-2 inhibited cell invasion and migration. The results of immunocytochemistry indicated that knockdown of AIF-2 significantly attenuated the nuclear translocation of AIF-1, which was confirmed by western blot analysis. Furthermore, downregulation of AIF-2 resulted in mitochondrial dysfunction in U251 cells, as evidenced by reduced mitochondrial membrane potential (MMP), mitochondrial complex I activity, and mitochondrial Ca

Liu D, Qiao X, Ge Z, et al.
IMB0901 inhibits muscle atrophy induced by cancer cachexia through MSTN signaling pathway.
Skelet Muscle. 2019; 9(1):8 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Cancer cachexia as a metabolic syndrome can lead to at least 25% of cancer deaths. The inhibition of muscle atrophy is a main strategy to treat cancer cachexia. In this process, myostatin (MSTN) can exert a dual effect on protein metabolism, including inhibition of protein biosynthesis and enhancement of protein degradation. In this study, we will test the effect on muscle atrophy induced by cancer cachexia of IMB0901, a MSTN inhibitor.
METHODS: Two high-throughput screening models against MSTN were developed. By screening, IMB0901, 2-((1-(3,4-dichlorophenyl)-1H-pyrazolo [3,4-d] pyrimidin-4-yl) amino) butan-1-ol, was picked out from the compound library. The in vitro cell model and the C26 animal model of muscle atrophy induced by cancer cachexia were used to determine the pharmacological activity of IMB0901. Whether IMB0901 could inhibit the aggravating effect of doxorubicin on muscle wasting was examined in vitro and in vivo.
RESULTS: IMB0901 inhibited the MSTN promoter activity, the MSTN signaling pathway, and the MSTN positive feedback regulation. In atrophied C2C12 myotubes, IMB0901 had a potent efficiency of decreasing MSTN expression and modulating MSTN signaling pathway which was activated by C26-conditioned medium (CM). In C2C12 myotubes, the expressions of three common myotube markers, myosin heavy chain (MyHC), myogenic differentiation 1 (MyoD), and myogenin (MyoG), were downregulated by CM, which could be efficiently reversed by IMB0901 via reduction of ubiquitin-mediated proteolysis and enhancement of AKT/mTOR-mediated protein synthesis. In the C26 animal model, IMB0901 mitigated the weight loss of body, quadricep and liver, and protected the quadriceps cell morphology. Furthermore, IMB0901 decreased the expression of two E3 ligases Atrogin-1 and MuRF-1 in the quadriceps in vivo. At the cellular level, IMB0901 had no influence on anti-tumor effect of three chemotherapeutic agents (cisplatin, doxorubicin, and gemcitabine) and lowered doxorubicin-induced upregulation of MSTN in C2C12 myotubes. IMB0901 did not affect the inhibitory effect of doxorubicin on C26 tumor and delayed the weight loss of muscle and adipose tissue caused by C26 tumor and doxorubicin.
CONCLUSIONS: IMB0901 inhibits muscle atrophy induced by cancer cachexia by suppressing ubiquitin-mediated proteolysis and promoting protein synthesis. These findings collectively suggest that IMB0901 is a promising leading compound for the management of muscle atrophy induced by cancer cachexia.

Jia Y, Lin R, Jin H, et al.
MicroRNA-34 suppresses proliferation of human ovarian cancer cells by triggering autophagy and apoptosis and inhibits cell invasion by targeting Notch 1.
Biochimie. 2019; 160:193-199 [PubMed] Related Publications
Ovarian cancer is one the prevalent cancers in women and is responsible for 5% of all the cancer related mortalities in women. Owing to late diagnosis, frequent relapses, side effects of chemotherapy, development of drug resistance, there is pressing need to screen out novel and effective treatment options. Accumulating evidences suggest that miRNAs may prove essential therapeutic targets for the treatment of cancer. This study was designed to investigate the role and therapeutic potential of miR-34 in ovarian cancer. It was found that miR-34 is significantly downregulated in ovarian cancer cell lines. Overexpression of miR-34 causes significant decrease in the proliferation of OVACAR-3 ovarian cancer cells via activation of apoptosis and autophagy. The miR-34 overexpression was concomitant with upsurge of apoptosis related proteins (Bax) and the autophagy associated protein (LC3 II and p62). TargetScan analysis showed Notch 1 to be the main target of miR-34 in OVACAR-3 cells which was further validated by luciferase reporter assay. The qRT-PCR results showed Notch 1 to be 3.2-4.1 fold higher in the ovarian cancer cell lines relative to the non-cancerous cells. Nonetheless, miR-34 overexpression in OVACAR-3 cells resulted in the post-transcriptional suppression of Notch 1 expression. Silencing of Notch 1 also caused inhibition of OVACAR-3 cell proliferation via induction of apoptosis and autophagy. Overexpression of Notch 1 could partially rescue the effects of miR-34 overexpression on the proliferation of OVACAR-3 cells. Moreover, overexpression of miR-34 causes significant inhibition of the invasion of the OVACAR-3 cells. The findings of the present study indicate the tumor suppressive role of miR-34 in ovarian cancer and may therefore prove to be a potential therapeutic target.

Liu F, Yin R, Chen X, et al.
Over-expression of miR-206 decreases the Euthyrox-resistance by targeting MAP4K3 in papillary thyroid carcinoma.
Biomed Pharmacother. 2019; 114:108605 [PubMed] Related Publications
PURPOSE: microRNAs (miRNAs) play a critical role in drug resistance of multiple cancers including papillary thyroid carcinoma (PTC), indicating the potential of miRNAs as chemoresistance regulators in cancer treatment. The aim of this paper is to explore the relationship between miR-206 and chemoresistance of PTC.
METHODS: qRT-PCR was conducted to examine the expression of miR-206 in PTC tissues, parental and TPC-1/euthyrox. The CCK-8 assay, EdU assay and flow cytometry were performed to test cells viability, proliferation and apoptosis, respectively. Luciferase reporter assay was used to confirm the potential target of miR-206. Western blotting analysis was performed to evaluate the expressions of related-proteins.
RESULTS: miR-206 was significantly down-regulated in PTC tissues, parental and TPC-1/euthyrox. Moreover, the expression of miR-206 was exceptionally lower in TPC-1/euthyrox cells than that in TPC-1 cells. Furthermore, we found that over-expression of miR-206 could notably decrease the IC
CONCLUSION: miR-206 contributed to euthyrox resistance in PTC cells through blockage p38 and JNK signaling pathway by targeting MAP4K3, providing a potential therapeutic application for the treatment of patients with euthyrox-resistant PTC in the further.

Afshar E, Hashemi-Arabi M, Salami S, et al.
Screening of acetaminophen-induced alterations in epithelial-to-mesenchymal transition-related expression of microRNAs in a model of stem-like triple-negative breast cancer cells: The possible functional impacts.
Gene. 2019; 702:46-55 [PubMed] Related Publications
Current protocols for therapy inefficiently targets triple negative breast cancer and barely eradicate cancer stem cells. Elucidation of the pleiotropic effect of clinically proven therapeutics on cancer cells shed light on novel application of old friends. The pleiotropic effect of acetaminophen (APAP) on breast cancer was previously reported. In a cell model of triple negative breast cancer with stem-like CD44

Zhang H, Wang JS, Chen XG, et al.
Overexpression of c-Ski promotes cell proliferation, invasion and migration of gastric cancer associated fibroblasts.
Kaohsiung J Med Sci. 2019; 35(4):214-221 [PubMed] Related Publications
The present study aimed to investigate the effects of c-Ski on cell proliferation, invasion and migration of gastric cancer associated fibroblasts (CAFs). Expression of c-Ski in gastric cancer (GC) tissues was determined using immunohistochemistry. Both CAFs and non-cancerous gastric fibroblasts (NGFs) were isolated and cultured. c-Ski and Smad3 were over-expressed or knocked down using pcDNA3.0-c-Ski/Smad3 or siRNA, respectively. Cell viability, invasion and migration were measured and expression of c-Ski, α-SMA, and Smad3 in cells was determined using real time quantitative PCR (RT-qPCR) and Western blotting. Expression of c-Ski was significantly higher in both in GC tissues and cell lines, and was the highest in tissues of diffuse type. Both c-Ski and α-SMA were significantly over-expressed in CAFs compared with that in the NGFs. When c-Ski was over-expressed in NGFs, cell viability, cell invasion and migration were all enhanced and expression of Smad3 was downregulated. When c-Ski was inhibited, cell viability, cell invasion, and migration were all suppressed and expression of Smad3 was upregulated. Meanwhile, overexpression of Smad3 significantly reversed the effects of over-expressed c-Ski in NGFs, and knockdown of Smad3 dramatically reversed the effects of si-c-Ski in CAFs. Over-expressed c-Ski could enhance cell viability, promote cell invasion, and migration of GC CAFs, and the effects might be through regulation of Smad3 signaling. This study may give deeper insights for relationship between c-Ski and CAFs, as well as role of c-Ski in cancer development, and also provide some novel research targets for treatment of GC.

Chen C, Shan H
Keratin 6A gene silencing suppresses cell invasion and metastasis of nasopharyngeal carcinoma via the β‑catenin cascade.
Mol Med Rep. 2019; 19(5):3477-3484 [PubMed] Free Access to Full Article Related Publications
Nasopharyngeal carcinoma (NPC) is a type of head and neck cancer. This study aimed to study the mechanisms of ectopic keratin 6A (KRT6A) in NPC. Reverse transcription‑quantitative polymerase chain reaction (RT‑qPCR) and western blotting were performed to detect KRT6A levels in NPC cell lines (C666‑1, 5‑8F and SUNE‑1) and a nasopharyngeal epithelial cell line (NP69, as a control). After SUNE‑1 NPC cells had been silenced by KRT6A, cell viability, metastasis and invasion were determined using Cell Counting Kit‑8, wound healing and Transwell assays, respectively. KRT6A levels, metastasis‑associated factors and the Wnt/β‑catenin pathway were measured using RT‑qPCR and western blotting. It was demonstrated that KRT6A was upregulated in all detected NPC cells, among which KRT6A was the highest in SUNE‑1 cells. In SUNE‑1 cells, cell viability was inhibited at 24 and 48 h, and that cell metastasis and invasion were demonstrated to be suppressed by KRT6A silencing. Both the mRNA and protein levels of KRT6A, matrix metalloproteinase (MMP)‑2, MMP‑9, β‑catenin, lymphoid enhancer binding factor 1 and T‑cell specific factor 4 were reduced in the small interfering (si)KRT6A group. However, the results demonstrated that the levels of epithelial‑cadherin and tissue inhibitor of metalloproteinase‑2 (TIMP‑2) were promoted in the siKRT6A group. The activation of the Wnt/β‑catenin pathway by lithium chloride reversed the effect of si‑KRT6A by modulating the expression of MMP‑2/9 and TIMP2. It was observed that KRT6A silencing suppressed cell invasion and metastasis of NPC via the β‑catenin cascade. Together these results provide important insights into a novel approach for the diagnosis and treatment of NPC.

Lian S, Xie R, Ye Y, et al.
Simultaneous blocking of CD47 and PD-L1 increases innate and adaptive cancer immune responses and cytokine release.
EBioMedicine. 2019; 42:281-295 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Treatment multiple tumors by immune therapy can be achieved by mobilizing both innate and adaptive immunity. The programmed death ligand 1 (PD-L1; or CD274, B7-H1) is a critical "don't find me" signal to the adaptive immune system. Equally CD47 is a critical "don't eat me" signal to the innate immune system and a regulator of the adaptive immune response.
METHOD: Both of CD47 and PD-L1 are overexpressed on the surface of cancer cells to enable to escape immune-surveillance. We designed EpCAM (epithelial cell adhesion molecule)-targeted cationic liposome (LPP-P4-Ep) containing si-CD47 and si-PD-L1 could target high-EpCAM cancer cells and knockdown both CD47 and PD-L1 proteins.
FINDINGS: Efficient silencing of CD47 and PD-L1 versus single gene silencing in vivo by systemic administration of LPP-P4-Ep could significantly inhibited the growth of solid tumors in subcutaneous and reduced lung metastasis in lung metastasis model. Target delivery of the complexes LPP-P4-Ep increased anti-tumor T cell and NK cell response, and release various cytokines including IFN-γ and IL-6 in vivo and in vitro.
INTERPRETATION: This multi-nanoparticles showed significantly high-EpCAM tumor targeting and lower toxicity, and enhanced immune therapeutic efficacy. Our data indicated that dual-blockade tumor cell-specific innate and adaptive checkpoints represents an improved strategy for tumor immunotherapy. FUND: This research supported by the Ministry of Science and Technology of the People's Republic of China (grant number 2015CB931804); the National Natural Science Foundation of China (NSFC, grant numbers 81703555, U1505225 and 81773063), and the China Postdoctoral Science Foundation (grant number 2017 M620268).

Wang J, Si L, Wang G, et al.
Increased Sulfiredoxin Expression in Gastric Cancer Cells May Be a Molecular Target of the Anticancer Component Diallyl Trisulfide.
Biomed Res Int. 2019; 2019:4636804 [PubMed] Free Access to Full Article Related Publications
Sulfiredoxin (Srx) is a newly discovered antioxidant enzyme playing a role in the catalytic reduction of oxidative modifications. Srx is overexpressed in a variety of cancers. It may promote carcinogenesis as well as tumor progression. In this study, we report for the first time that Srx expression might be positively associated with the development of gastric cancer and tumor malignancy. Immunohistochemistry showed that, compared to normal tissues (42%, 20/47), Srx expression in gastric tumors (85%, 40/47) was much more common (chi-square test,

Hong X, Yu JJ
Silencing of lysyl oxidase‑like 2 inhibits the migration, invasion and epithelial‑to‑mesenchymal transition of renal cell carcinoma cells through the Src/FAK signaling pathway.
Int J Oncol. 2019; 54(5):1676-1690 [PubMed] Free Access to Full Article Related Publications
The aim of the present study was to investigate the effects of lysyl oxidase‑like 2 (LOXL2) on the invasion, migration and epithelial‑to‑mesenchymal transition (EMT) of renal cell carcinoma (RCC) cells through the steroid receptor coactivator (Src)/focal adhesion kinase (FAK) signaling pathway. RCC tissues and adjacent normal tissues were collected from 80 patients with RCC. Immunohistochemistry was used to determine the positive expression rate of the LOXL2 protein. The expression levels of LOXL2 in the HK‑2, 786‑O, ACHN, Caki1 and A498 cell lines were detected by reverse transcription‑quantitative polymerase chain reaction (RT‑qPCR). The high LOXL2‑expressing 786‑O cells were selected for gene silencing experiments, whereas Caki1 cells, which exhibited low LOXL2 expression, were used for overexpression experiments. RT‑qPCR and western blot analysis were applied to determine the expression of LOXL2, FAK, Src, matrix metalloproteinase (MMP)‑9, epithelial (E)‑cadherin, neuronal (N)‑cadherin and vimentin. A MTT assay, a Transwell assay, a wound healing assay and flow cytometry were performed to detect cell proliferation, invasion, migration, cell cycle distribution and apoptosis, respectively. The protein expression rate of LOXL2 in RCC tissues was higher compared with that in adjacent normal tissues. Compared with adjacent normal tissues, the mRNA and protein expression levels of LOXL2, FAK, Src, MMP‑9, N‑cadherin and vimentin and the levels of FAK and Src phosphorylation were increased, while the mRNA and protein expression levels of E‑cadherin were decreased in RCC tissues. Following the transfection of 786‑O cells with small interfering (si) RNA against LOXL2, the mRNA and protein expression levels of FAK, Src, MMP‑9, N‑cadherin and vimentin and the levels of phosphorylated FAK and Src were notably decreased in the si‑LOXL2 and PP2 inhibitor treated groups, while that of E‑cadherin was substantially increased. Additionally, cell proliferation, invasion, migration and the percentage of RCC cells in the G1 phase were reduced, and cell apoptosis was increased. Additionally, Caki1 cells transfected with LOXL2 exhibited an opposite trend. In summary, these results indicate that LOXL2 silencing inhibits the invasion, migration and EMT in RCC cells through inhibition of the Src/FAK signaling pathway.

Li S, Ma J, Si Y, et al.
Differential expression and functions of Ehm2 transcript variants in lung adenocarcinoma.
Int J Oncol. 2019; 54(5):1747-1758 [PubMed] Related Publications
Ehm2 [also known as erythrocyte membrane protein band 4.1‑like protein 4B (EPB41L4B)] is a member of the NF2/ERM/4.1 superfamily. The overexpression of Ehm2 has been observed in metastatic cancer cells. Through alternative splicing, the Ehm2 gene produces two transcript variants that encode the two different isoforms, Ehm2/1 and Ehm2/2. The biological functions of these different Ehm2 transcript variants remain unclear. The present study aimed to determine the expression of the Ehm2 variants in lung adenocarcinoma and their involvement in the disease progression of the patients. The expression of Ehm2 transcript variants in human lung adenocarcinoma tissues was analyzed using immunohistochemistry and western blot analysis. Ehm2 variants were overexpressed or knocked down in A549 human lung adenocarcinoma cells. The consequent effects of the genetic modifications on the cellular functions of lung cancer cells were then examined using in vitro cell viability, invasion and migration assays. The expression of epithelial‑mesenchymal transition (EMT)‑related markers was evaluated by western blot analysis in the cell models. The association of Ehm2 variant expression with patient survival was analyzed using Kaplan‑Meier survival analysis. The expression of Ehm2/1 was significantly decreased in lung cancers compared with the paired normal lung tissues (P<0.05), while the Ehm2/2 protein levels were higher in the tumors than in the paired normal lung tissues, although this was not statistically significant. The overexpression of Ehm2/1 exerted inhibitory effects, while the knockdown of Ehm2/1 promoted the growth, invasion and migration of A549 cells in vitro. Ehm2/2 was expressed at low levels in the A549 cells and the enforced expression of Ehm2/2 significantly increased the invasiveness and migration of the A549 cells. Immunofluorescence staining revealed that Ehm2/1 was confined to the plasma membrane, while Ehm2/2 was observed at both the plasma membrane and cytoplasm. The overexpression of Ehm2/1 resulted in the upregulation of the epithelial marker, E‑cadherin, and in the decreased expression of the mesenchymal markers, N‑cadherin and Snail1, while the knockdown of Ehm2/1 and the enforced expression of Ehm2/2 had the opposite effects on the protein levels of EMT‑related markers. Kaplan‑Meier survival analysis revealed that higher Ehm2/1 transcript levels were associated with the longer survival of patients with lung adenocarcinoma, while the lower expression of Ehm2/2 exhibited a similar association with patient survival. Taken together, the two Ehm2 variants appear to be differentially expressed in lung adenocarcinoma. Ehm2/1 may function as a putative tumor suppressor in the disease progression of lung adenocarcinoma, while Ehm2/2 may have an opposite function.

Meng B, Xing Y, Li H, et al.
Knockdown of Long Noncoding RNA POU5F1B Promotes Radiosensitivity in Esophageal Carcinoma.
Med Sci Monit. 2019; 25:1214-1219 [PubMed] Free Access to Full Article Related Publications
BACKGROUND POU5F1B, serving as a carcinogen, participates in radiosensitivity of several tumors. However, in esophageal cancer, its potential mechanism and function in regulating radiosensitivity remain unclear. MATERIAL AND METHODS The expression level of POU5F1B was detected in plasma of esophageal tumor patients and cancer cell lines. The effect of POU5F1B knockdown on cell proliferation and colony formation was determined using CCK-8 assay and colony formation assay. Cell apoptosis rate was detected by flow cytometry. RESULTS POU5F1B expression level declined after radiotherapy in the plasma of esophageal cancer patients (p=0.025). Compared with HEEPIC, the level of POU5F1B was upregulated in ECA109 (p<0.01), ECA9706 (p<0.01), KYSE410 (p<0.01), and KYSE510 (p=0.036). The silencing of POU5F1B played a role in inhibiting colony formation. After radiotherapy, the apoptosis rates in the ECA109 with 4Gy si-POU5F1B group and 4Gy si-NC group were 39.1±0.1% and 35.3±0.1%, respectively (p=0.0193). The rate was 21.00±0.1 and 29.1±0.1% (p<0.0072) in the si-NC group and si-POU5F1B group, respectively. For proliferation rate, 4Gy si-POU5F1B ECA109 performed better than 4Gy si-NC. CONCLUSIONS Radiotherapy contributed to the decline in the expression level of POU5F1B in plasma, which was upregulated in ECA109, ECA9706, KYSE410, and KYSE510, but not in HEEPIC. The knockdown of POU5F1B increased the radiosensitivity of esophageal cancer cell lines.

Gay DM, Ridgway RA, Müller M, et al.
Loss of BCL9/9l suppresses Wnt driven tumourigenesis in models that recapitulate human cancer.
Nat Commun. 2019; 10(1):723 [PubMed] Free Access to Full Article Related Publications
Different thresholds of Wnt signalling are thought to drive stem cell maintenance, regeneration, differentiation and cancer. However, the principle that oncogenic Wnt signalling could be specifically targeted remains controversial. Here we examine the requirement of BCL9/9l, constituents of the Wnt-enhanceosome, for intestinal transformation following loss of the tumour suppressor APC. Although required for Lgr5+ intestinal stem cells and regeneration, Bcl9/9l deletion has no impact upon normal intestinal homeostasis. Loss of BCL9/9l suppressed many features of acute APC loss and subsequent Wnt pathway deregulation in vivo. This resulted in a level of Wnt pathway activation that favoured tumour initiation in the proximal small intestine (SI) and blocked tumour growth in the colon. Furthermore, Bcl9/9l deletion completely abrogated β-catenin driven intestinal and hepatocellular transformation. We speculate these results support the just-right hypothesis of Wnt-driven tumour formation. Importantly, loss of BCL9/9l is particularly effective at blocking colonic tumourigenesis and mutations that most resemble those that occur in human cancer.

Liu P, Xiang Y, Liu X, et al.
Cucurbitacin B Induces the Lysosomal Degradation of EGFR and Suppresses the CIP2A/PP2A/Akt Signaling Axis in Gefitinib-Resistant Non-Small Cell Lung Cancer.
Molecules. 2019; 24(3) [PubMed] Free Access to Full Article Related Publications
Non-small cell lung cancer (NSCLC) patients carrying an epidermal growth factor receptor (EGFR) mutation are initially sensitive to EGFR-tyrosine kinase inhibitors (TKIs) treatment, but soon develop an acquired resistance. The treatment effect of EGFR-TKIs-resistant NSCLC patients still faces challenges. Cucurbitacin B (CuB), a triterpene hydrocarbon compound isolated from plants of various families and genera, elicits anticancer effects in a variety of cancer types. However, whether CuB is a viable treatment option for gefitinib-resistant (GR) NSCLC remains unclear. Here, we investigated the anticancer effects and underlying mechanisms of CuB. We report that CuB inhibited the growth and invasion of GR NSCLC cells and induced apoptosis. The inhibitory effect of CuB occurred through its promotion of the lysosomal degradation of EGFR and the downregulation of the cancerous inhibitor of protein phosphatase 2A/protein phosphatase 2A/Akt (CIP2A/PP2A/Akt) signaling axis. CuB and cisplatin synergistically inhibited tumor growth. A xenograft tumor model indicated that CuB inhibited tumor growth in vivo. Immunohistochemistry results further demonstrated that CuB decreased EGFR and CIP2A levels in vivo. These findings suggested that CuB could suppress the growth and invasion of GR NSCLC cells by inducing the lysosomal degradation of EGFR and by downregulating the CIP2A/PP2A/Akt signaling axis. Thus, CuB may be a new drug candidate for the treatment of GR NSCLC.

Liu L, Liu L, Lu S
lncRNA H19 promotes viability and epithelial-mesenchymal transition of lung adenocarcinoma cells by targeting miR-29b-3p and modifying STAT3.
Int J Oncol. 2019; 54(3):929-941 [PubMed] Free Access to Full Article Related Publications
Considering the joint contribution of long non‑coding RNAs (lncRNAs) and microRNAs (miRNAs/miRs) to tumorigenesis, the aim of the present study was to investigate whether and how lncRNA H19 targets miR‑29b‑3p to affect the progression of lung adenocarcinoma by the modulation of signal transducer and activator of transcription 3 (STAT3). A total of 305 lung adenocarcinoma tissues and four human lung adenocarcinoma cell lines (i.e. Calu‑3, NCI‑H1975, A549 and NCI‑H23) were used. pcDNA3.1‑H19, short interfering RNA (si‑)H19, miR‑29b‑3p mimic, miR‑29b‑3p inhibitor and negative control (NC) were transfected into the cells, and the proliferation, viability and apoptosis of the cells were determined using a Cell Counting Kit‑8 assay, colony formation assay and flow cytometry, respectively. The results indicated that highly expressed H19 and poorly expressed miR‑29b‑3p could serve as predictors for the poor prognosis of lung adenocarcinoma patients. Additionally, si‑H19 and miR‑29b‑3p mimic significantly increased the apoptosis of lung adenocarcinoma cells, and decreased the survival rate and viability of cells. Simultaneously, expression of epithelial‑mesenchymal transition (EMT)‑specific proteins was significantly altered, i.e. increased epithelial cadherin expression, as well as decreased vimentin, Snail and Slug expression. Furthermore, miR‑29b‑3p was verified to be targeted and regulated by H19, and STAT3 was targeted and modified by miR‑29b‑3p. Ultimately, STAT3 was identified to decrease lung adenocarcinoma cell viability, survival, apoptosis and EMT imposed by miR‑29b‑3p. In conclusion, the results of the present study indicated that lncRNA H19/miR‑29b‑3p/STAT3 signaling was involved in the development of lung adenocarcinoma, which may be critical for developing effective diagnostic and treatment strategies for lung adenocarcinoma.

Arnoldussen YJ, Kringlen Ervik T, Samulin Erdem J, et al.
Mechanisms of Toxicity of Industrially Relevant Silicomanganese Dust on Human 1321N1 Astrocytoma Cells: An In Vitro Study.
Int J Mol Sci. 2019; 20(3) [PubMed] Free Access to Full Article Related Publications
Tremendous efforts are applied in the ferroalloy industry to control and reduce exposure to dust generated during the production process, as inhalable Mn-containing particulate matter has been linked to neurodegenerative diseases. This study aimed to investigate the toxicity and biological effects of dust particles from laboratory-scale processes where molten silicomanganese (SiMn) was exposed to air, using a human astrocytoma cell line, 1321N1, as model system. Characterization of the dust indicated presence of both nano-sized and larger particles averaging between 100 and 300 nm. The dust consisted mainly of Si, Mn and O. Investigation of cellular mechanisms showed a dose- and time-dependent effect on cell viability, with only minor changes in the expression of proteins involved in apoptosis. Moreover, gene expression of the neurotoxic biomarker

Gong H, Tang Y, Xiao J, et al.
Evaluation of early changes of macular function and morphology by multifocal electroretinograms in patients with nasopharyngeal carcinoma after radiotherapy.
Doc Ophthalmol. 2019; 138(2):137-145 [PubMed] Related Publications
OBJECTIVE: To assess the role of multifocal electroretinograms (mfERGs) and optical coherence tomography (OCT) for detecting early changes in macular functions of patients with nasopharyngeal carcinoma (NPC) after radiotherapy.
METHODS: mfERGs and OCT were used to examine a NPC group (36 NPC patients after radiotherapy without clinically visible radiation retinopathy, 36 eyes) and a normal control group (25 healthy individuals, 25 eyes) with the same procedure and parameters. The two groups of mfERG were summarized by calculating ring averages, response density, N1 amplitude and P1 and N1 latencies were analysed. OCT scan thickness was summarized into ETDRS regions for comparison.
RESULTS: Compared with controls, the NPC group had significantly decreased P1 response densities in 1-4 ring regions and N1 amplitudes in 1-3 rings (P < 0.01). P1 latencies were obviously prolonged in rings 1 (P < 0.01). In four quadrants (inferonasal, superonasal, inferotemporal and superotemporal) of the mfERG response waveforms, the NPC group had significantly decreased P1 response densities and N1 amplitudes mainly in the inferonasal and inferotemporal quadrants, showing statistically significant differences from the control group (P < 0.0125). But for the OCT results, there is no statistically significant difference between the NPC group and the control group.
CONCLUSIONS: In NPC patients after radiotherapy, there may be changes in the mfERGs before any visible fundus lesions appeared as radiation macular oedema. Since the global OCT macular thickness analysis cannot reveal early changes, the mfERGs can objectively and quantitatively assess the earlier changes in macular function in NPC patients.

Liang C, Yang P, Han T, et al.
Long non-coding RNA DILC promotes the progression of gallbladder carcinoma.
Gene. 2019; 694:102-110 [PubMed] Related Publications
Increasing evidence has demonstrated that long non-coding RNAs (lncRNAs) contribute to tumorigenesis, progression and recurrence of various malignancies including Gallbladder carcinoma (GBC). Lnc-DILC is reported to be the tumor suppressor gene to play an important role in liver cancer stem cells (CSCs). However, the role of lnc-DILC in GBC remains to be elucidated. Herein, we show that lnc-DILC is upregulated in gallbladder CSCs and GBC patients' tissues. Knockdown of lnc-DILC attenuates the self-renewal, tumorigenicity, proliferation and metastasis of gallbladder CSCs. Mechanistically, lnc-DILC promotes gallbladder CSCs expansion via Wnt/β-catenin pathway. Special Wnt/β-catenin inhibitor FH535 diminishes the discrepancy of self-renewal, growth and metastasis between lnc-DILC interference GBC cells and their control cells. In conclusion, lnc-DILC drives gallbladder CSCs self-renewal, tumorigenicity, proliferation and metastasis by activating Wnt/β-catenin signaling, and may therefore prove to be a potential therapeutic target for GBC patients.

Dietrich P, Gaza A, Wormser L, et al.
Neuroblastoma RAS Viral Oncogene Homolog (NRAS) Is a Novel Prognostic Marker and Contributes to Sorafenib Resistance in Hepatocellular Carcinoma.
Neoplasia. 2019; 21(3):257-268 [PubMed] Free Access to Full Article Related Publications
Inhibition of the RAS-RAF-ERK-pathway using sorafenib as a first-line and regorafenib as a second-line treatment approach is the only effective therapeutic strategy for advanced hepatocellular carcinoma (HCC). Recent studies suggest that wild-type KRAS and HRAS isoforms could majorly contribute to HCC progression and sorafenib resistance. In contrast, the role of neuroblastoma RAS viral oncogene homolog (NRAS) in HCC remained elusive. In this study, wild-type NRAS was found to be overexpressed in HCC cell lines, preclinical HCC models, and human HCC tissues. Moreover, NRAS overexpression correlated with poor survival and proliferation in vivo. However, si-RNA-pool-mediated NRAS knockdown showed only slight effects on HCC proliferation, clonogenicity, and AKT activity. We determined that KRAS upregulation served as a functional compensatory mechanism in the absence of NRAS, which was overcome by combined inhibition of NRAS and KRAS in HCC cells. Furthermore, NRAS expression was elevated in sorafenib-resistant compared to nonresistant HCC cells, and NRAS knockdown enhanced sorafenib efficacy in resistant cells. In summary, NRAS appears to be a prognostic marker in HCC and contributes to sorafenib resistance. Regarding potential therapeutic strategies, NRAS inhibition in HCC should be combined with KRAS inhibition to prevent KRAS-mediated rescue effects.

Wang T, Li W, Huang H, Wang C
Metastasis-Associated 1 (MTA1) Gene Expression Promotes Angiogenesis in Mouse Xenografts from Human Non-Small Cell Lung Cancer (NSCLC) Cells.
Med Sci Monit. 2019; 25:484-491 [PubMed] Free Access to Full Article Related Publications
BACKGROUND This study aimed to investigate the effects of metastasis-associated 1 (MTA1) gene expression and gene silencing in human non-small cell lung cancer (NSCLC) cells in vitro and on angiogenesis in tumor xenografts in vivo in nude mice. MATERIAL AND METHODS Human H460 and H1299 NSCLC cell lines underwent transfection with lentiviral transfer plasmids (lenti) and short-interfering RNA (si-RNA) and included a control group, a lenti-MTA1 group, a lenti-si-MTA1 group, a lenti control group, and a si-RNA control group. Quantitative reverse transcription polymerase chain reaction (qRT-PCR) was used to detect MTA1 gene expression after cell transfection. MTA1 transfection was more effective in H460 cells, which were selected for further in vivo studies. Sixty Balb/c nude mice, containing human H460 cell tumor xenografts, included a control group (N=20), a lenti-MTA1 group (N=20), and a lenti-si-MTA1 group (N=20). Tumor tissue immunohistochemistry was used to detect the expression of MTA1 protein and microvessel density (MVD) using CD31. Western blot was used to quantify the expression of cyclooxygenase-2 (COX-2), angiopoietin 1/2 (Ang1/2), hypoxia-inducible factor 1-a (HIF-1a), and vascular endothelial growth factor (VEGF). RESULTS MTA1 silencing with si-RNA significantly reduced the tumor growth rate in nude mice (p<0.01), reduced tumor MVD, and 70% of mice survived for more than 30 days. MTA1 overexpression resulted in the death of all mice at 30 days after tumor inoculation and upregulated the expression of COX-2, Ang1/2, HIF-1a and VEGF, which were down-regulated by MTA1 silencing. CONCLUSIONS MTA1 gene expression promoted angiogenesis in mouse xenografts from human NSCLC cells.

Wang F, Zhu W, Yang R, et al.
LncRNA ZEB2-AS1 contributes to the tumorigenesis of gastric cancer via activating the Wnt/β-catenin pathway.
Mol Cell Biochem. 2019; 456(1-2):73-83 [PubMed] Related Publications
Studies have shown that long noncoding RNA Zinc finger E-box-binding homeobox 2 antisense RNA 1 (ZEB2-AS1) is involved in the progression of lung cancer, bladder cancer, and hepatocellular carcinoma. However, its role in the pathogenesis of gastric cancer remains unknown. The Wnt/β-catenin pathway contributes to the development of gastric cancer. ZEB2-AS1 expression was firstly detected in the gastric carcinoma tissue samples as well as in gastric cancer cells. Knockdown of ZEB2-AS1 was performed by ZEB2-AS1-shRNA, and the viability, migration, invasion, and apoptosis of gastric cancer cells were determined by CCK-8, scratch assay, transwell, and flow cytometry, respectively. Furthermore, levels of Ki-67, PCNA, VEGF, MMP9, epithelial-mesenchymal transition (EMT) markers (E-cadherin, Vimentin and ZEB2), cleaved caspase 3/8/9 and PARP, active β-catenin, c-Myc, cyclinD1, and AXIN2 were assayed by Western blot or real-time PCR. Additionally, the role and mechanism of ZEB2-AS1 were confirmed in a xenograft nude mouse model. We found ZEB2-AS1 expression was increased in gastric carcinoma samples, and it was correlated with tumor progression. Also, its expression was elevated in gastric cancer cells. Knockdown of ZEB2-AS1 reduced the proliferation, migration, invasion, and EMT, but increased the apoptosis of gastric carcinoma cells. Furthermore, ZEB2-AS1 downregulation remarkably suppressed the expression of Ki-67, PCNA, VEGF and MMP9, and the activation of Wnt/β-catenin signaling, whereas elevated the levels of cleaved caspase 3/8/9 and PARP in gastric cancer cells. And ZEB2 overexpression reversed the effects of ZEB2-AS1 downregulation on the proliferation, EMT and inactivation of Wnt/β-catenin signaling. Additionally, ZEB2-AS1 knockdown inhibited tumor growth, Ki-67 staining, and the expression of VEGF, MMP9, active β-catenin, c-Myc, cyclinD1, and AXIN2 in mice. In conclusion, ZEB2-AS1 promotes the tumorigenesis of gastric carcinoma that is related to the upregulation of ZEB2 and the activation of the Wnt/β-catenin pathway.

Wang JR, Liu B, Zhou L, Huang YX
MicroRNA-124-3p suppresses cell migration and invasion by targeting ITGA3 signaling in bladder cancer.
Cancer Biomark. 2019; 24(2):159-172 [PubMed] Related Publications
BACKGROUND: A growing body of studies have demonstrated the aberrant expression of microRNAs (miRNAs) contributes to human tumor metastasis. MicroRNA-124-3p (miR-124-3p), which is down-regulated in various cancers, has been found to be involved in several signaling pathways relevant to tumor cell migration and invasion. However, the roles of miR-124-3p in human bladder cancer remain unclear. This study aims to investigate the functional significance of miR-124-3p and to understand how it targets the integrin receptor, and thus affects the progression of human bladder cancer.
METHODS: Clinical specimens from 36 patients and three human bladder cancer cell lines were analyzed for miR-124-3p and integrin α3 (ITGA3) . To investigate the effects of miR-124-3p and ITGA3 on proliferation of bladder cancer cells, the MTT assay, colon-formation assay and flow cytometry were performed. In addition, wound healing assay and transwell assay were carried out to examine the migration and invasion of the bladder cancer cells transfected with miR-124-3p mimics or si-ITGA3. The luciferase reporter assay, quantitative real-time polymerase chain reaction (qRT-PCR) and western blot were applied to validate the miR-124-3p directly binding with ITGA3. Finally, western blot was used to examine the expression level of the proteins involved in FAK/PI3K/AKT and FAK/Src signal pathway as well as epithelial-mesenchymal transition (EMT) process.
RESULTS: The down-regulation of miR-124-3p and up-regulation of ITGA3 were observed in clinical specimens and bladder cancer cell lines. Overexpression of miR-124-3p or silencing ITGA3 inhibited tumor cell migration and invasion. Luciferase assay confirmed miR-124-3p directly targets ITGA3, and western blot suggested that miR-124-3p plays a crucial role in the EMT and metastasis of human bladder cancer through FAK/PI3K/AKT and FAK/Src signaling mechanism. Also, by targeting ITGA3, miR-124-3p can modulate the expression of N- and E-cadherin, and thus inhibit the EMT.
CONCLUSIONS: By targeting ITGA3 and downstream FAK/PI3K/AKT and FAK/Src signaling pathways, miR-124-3p suppresses cell migration and invasion in bladder cancer. Our study reasonably speculates that miR-124-3p can be potentially developed as a therapeutic target and prognostic biomarker for bladder cancer.

Chen Z, Zhao G, Zhang Y, et al.
MiR-199b-5p promotes malignant progression of osteosarcoma by regulating HER2.
J BUON. 2018 Nov-Dec; 23(6):1816-1824 [PubMed] Related Publications
PURPOSE: MicroRNAs (miRs) are endogenous, noncoding small RNAs that play a key role in regulating biological and pathological processes. The oncogenic properties of miR-199b-5p have been demonstrated in previous studies but the effect of miR-199b-5p on osteosarcoma (OS) has not yet been clarified. This study aimed to investigate the effect of miR-199b-5p on OS and the relationship between this miR and the pathological parameters and prognosis of OS.
METHODS: MiR-199b-5p expression in 57 pairs of OS tissues, corresponding adjacent normal tissues and OS cells was measured by quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR).The relationship between miR-199b-5p and the pathological features and prognosis of OS patients was examined. We constructed small interfering (si) RNA to knock down miR-199b-5p expression in OS cell lines MG63 and U2OS. Cell Counting Kit-8 (CCK-8), cell cloning assay and Transwell cell migration and invasion assay were applied for investigating the biological function of miR-199b-5p, respectively. Finally, western blot was used for exploring its underlying mechanism.
RESULTS: MiR-199b-5p expression in OS was significantly higher than that of normal tissues. Compared to patients w\sith low expression of miR-199b-5p, patients with high expression level tended to be with younger age, higher incidence of distant metastases and lower overall survival. Compared with interference sequence negative control (si-NC) group, the abilities of proliferation, invasion and metastasis of cells transfected with si-miR-199b-5p were significantly decreased. Western blot analysis indicated that expressions of key proteins related to epithelial to mesenchymal transition (EMT) signaling pathway, including N-cadherin, Vimentin, β-catenin and matrix metalloproteinase-9 (MMP9), were significantly decreased after transfection with si-miR-199b-5p. Furthermore, we found that miR-199b-5p promoted the progression of OS mainly through regulating HER2.
CONCLUSIONS: Upregulated miR-199b-5p is significantly related with stage, distant metastasis and poor prognosis of OS. This MiR may promote progression of OS through regulating HER2.

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