TYRP1

Gene Summary

Gene:TYRP1; tyrosinase related protein 1
Aliases: TRP, CAS2, CATB, GP75, OCA3, TRP1, TYRP, b-PROTEIN
Location:9p23
Summary:This gene encodes a melanosomal enzyme that belongs to the tyrosinase family and plays an important role in the melanin biosynthetic pathway. Defects in this gene are the cause of rufous oculocutaneous albinism and oculocutaneous albinism type III. [provided by RefSeq, Mar 2009]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:5,6-dihydroxyindole-2-carboxylic acid oxidase
Source:NCBIAccessed: 31 August, 2019

Ontology:

What does this gene/protein do?
Show (14)
Pathways:What pathways are this gene/protein implicaed in?
Show (1)

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.

  • Phenotype
  • Oxidoreductases
  • Receptor, Melanocortin, Type 1
  • Cell Differentiation
  • gp100 Melanoma Antigen
  • Translocation
  • Agouti Signaling Protein
  • Messenger RNA
  • Base Sequence
  • Eye Cancer
  • Neoplasm Proteins
  • Cancer Gene Expression Regulation
  • Waardenburg Syndrome
  • Biomarkers, Tumor
  • Skin Cancer
  • Tumor Antigens
  • Cell Line
  • Genome-Wide Association Study
  • Pigmentation
  • Membrane Glycoproteins
  • Polymerase Chain Reaction
  • Gene Expression
  • Melanoma
  • Molecular Sequence Data
  • Intramolecular Oxidoreductases
  • Genotype
  • Chromosome 9
  • Young Adult
  • Uveal Neoplasms
  • Microphthalmia-Associated Transcription Factor
  • Melanocytes
  • Genetic Predisposition
  • Single Nucleotide Polymorphism
  • Gene Expression Profiling
  • Transcription Factors
  • Monophenol Monooxygenase
  • Proteins
  • Promoter Regions
  • Thrombospondin 1
  • Melanins
  • Tumor Suppressor Proteins
Tag cloud generated 31 August, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (3)

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

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

Latest Publications: TYRP1 (cancer-related)

Kang M, Park SH, Park SJ, et al.
p44/42 MAPK signaling is a prime target activated by phenylethyl resorcinol in its anti-melanogenic action.
Phytomedicine. 2019; 58:152877 [PubMed] Related Publications
BACKGROUND: Melanin plays a crucial role in protecting human skin against exposure to ultraviolet (UV) radiation. However, its overproduction induces hyperpigmentation disorders of the skin.
PURPOSE: To investigate effects of phenylethyl resorcinol as one resorcinol derivative on melanogenesis and its mechanisms using B16F10 mouse melanoma cells and human epidermal melanocytes.
METHODS: Effects of phenylethyl resorcinol on melanogenesis and its mechanism of action were examined using several in vitro assays (i.e., cell survival, melanin content, cellular tyrosinase activity, real-time PCR analysis, luciferase-reporter assay, Western blot analysis, and ELISAs for cyclic AMP (cAMP), protein kinase A (PKA), cAMP response element binding (CREB) protein, and mitogen-activated protein kinases (MAPKs)).
RESULTS: Phenylethyl resorcinol reduced both melanin content and tyrosinase activity in these cells. Phenylethyl resorcinol also suppressed tyrosinase activity in cell-free tyrosinase enzyme assay. Although phenylethyl resorcinol decreased mRNA levels of tyrosinase and tyrosinase-related protein (TRP)-2, it did not affect mRNA levels of melanogenic gene microphthalmia-associated transcriptional factor (MITF) or TRP-1. Phenylethyl resorcinol had no effects on cAMP signaling or NF-κB signaling based on results of cyclic AMP response element (CRE)-luciferase reporter assay, cAMP production, protein kinase A (PKA) activity, Western blot assays for phosphorylated CRE-binding protein (CREB), NF-κB-luciferase reporter assay, and Western blot assays for phosphorylated NF-κB. However, phenylethyl resorcinol induced activation of activator protein-1 (AP-1) signaling. Specifically, phenylethyl resorcinol increased AP-1 reporter activity and increased phosphorylation of p44/42 MAPK, but not p38 MAPK or c-Jun N-terminal kinase (JNK). MEK1/2 and Src, upstream molecules of p44/42 MAPK were also phosphorylated by phenylethyl resorcinol. In addition, phenylethyl resorcinol-induced decreases in melanin content, tyrosinase activity, and MITF protein levels were attenuated by PD98059, a p44/42 MAPK inhibitor.
CONCLUSION: These data indicate that the anti-melanogenic activity of phenylethyl resorcinol is mediated by activation of p44/42 MAPK, indicating that phenylethyl resorcinol may be a potential therapeutic agent for treating hyperpigmentation skin disorders.

Ku KE, Choi N, Oh SH, et al.
Src inhibition induces melanogenesis in human G361 cells.
Mol Med Rep. 2019; 19(4):3061-3070 [PubMed] Free Access to Full Article Related Publications
The Src kinase family (SKF) includes non‑receptor tyrosine kinases that interact with many cellular cytosolic, nuclear and membrane proteins, and is involved in the progression of cellular transformation and oncogenic activity. However, there is little to no evidence on the effect of SKF or its inhibitors on melanogenesis. Therefore, the present study investigated whether C‑terminal Src kinase inhibition can induce melanogenesis and examined the associated signaling pathways and mRNA expression of melanogenic proteins. First, whether stimulators of melanogenesis, such as ultraviolet B and α‑melanocyte‑stimulating hormone, can dephosphorylate Src protein was evaluated, and the results revealed that SU6656 and PP2 inhibited the phosphorylation of Src in G361 cells. Src inhibition by these chemical inhibitors induced melanogenesis in G361 cells and upregulated the mRNA expression levels of melanogenesis‑associated genes encoding microphthalmia‑associated transcription factor, tyrosinase‑related protein 1 (TRP1), TRP2, and tyrosinase. In addition, Src inhibition by small interfering RNA induced melanogenesis and upregulated the mRNA expression levels of melanogenesis‑associated genes. As the p38 mitogen‑activated protein kinase (MAPK) and cyclic adenosine monophosphate response element binding (CREB) pathways serve key roles in melanogenesis, the present study further examined whether Src mediates melanogenesis via these pathways. As expected, Src inhibition via SU6656 or PP2 administration induced the phosphorylation of p38 or CREB, as determined by western blotting analysis, and increased the levels of phosphorylated p38 or CREB, as determined by immunofluorescence staining. In addition, the induced pigmentation and melanin content of G361 cells by Src inhibitors was significantly inhibited by p38 or CREB inhibitors. Taken together, these data indicate that Src is associated with melanogenesis, and Src inhibition induces melanogenesis via the MAPK and CREB pathways in G361 cells.

Lemos H, Huang L, Prendergast GC, Mellor AL
Immune control by amino acid catabolism during tumorigenesis and therapy.
Nat Rev Cancer. 2019; 19(3):162-175 [PubMed] Related Publications
Immune checkpoints arise from physiological changes during tumorigenesis that reprogramme inflammatory, immunological and metabolic processes in malignant lesions and local lymphoid tissues, which constitute the immunological tumour microenvironment (TME). Improving clinical responses to immune checkpoint blockade will require deeper understanding of factors that impact local immune balance in the TME. Elevated catabolism of the amino acids tryptophan (Trp) and arginine (Arg) is a common TME hallmark at clinical presentation of cancer. Cells catabolizing Trp and Arg suppress effector T cells and stabilize regulatory T cells to suppress immunity in chronic inflammatory diseases of clinical importance, including cancers. Processes that induce Trp and Arg catabolism in the TME remain incompletely defined. Indoleamine 2,3 dioxygenase (IDO) and arginase 1 (ARG1), which catabolize Trp and Arg, respectively, respond to inflammatory cues including interferons and transforming growth factor-β (TGFβ) cytokines. Dying cells generate inflammatory signals including DNA, which is sensed to stimulate the production of type I interferons via the stimulator of interferon genes (STING) adaptor. Thus, dying cells help establish local conditions that suppress antitumour immunity to promote tumorigenesis. Here, we review evidence that Trp and Arg catabolism contributes to inflammatory processes that promote tumorigenesis, impede immune responses to therapy and might promote neurological comorbidities associated with cancer.

Lee A, Kim JY, Heo J, et al.
The Inhibition of Melanogenesis Via the PKA and ERK Signaling Pathways by
J Microbiol Biotechnol. 2018; 28(12):2121-2132 [PubMed] Related Publications
Abnormal melanin synthesis results in several hyperpigmentary disorders such as freckles, melanoderma, age spots, and other related conditions. In this study, we investigated the antimelanogenic effects of an extract from the microalgae

Benonisson H, Sow HS, Breukel C, et al.
High FcγR Expression on Intratumoral Macrophages Enhances Tumor-Targeting Antibody Therapy.
J Immunol. 2018; 201(12):3741-3749 [PubMed] Related Publications
Therapy with tumor-specific Abs is common in the clinic but has limited success against solid malignancies. We aimed at improving the efficacy of this therapy by combining a tumor-specific Ab with immune-activating compounds. In this study, we demonstrate in the aggressive B16F10 mouse melanoma model that concomitant application of the anti-TRP1 Ab (clone TA99) with TLR3-7/8 or -9 ligands, and IL-2 strongly enhanced tumor control in a therapeutic setting. Depletion of NK cells, macrophages, or CD8

Katifelis H, Lyberopoulou A, Mukha I, et al.
Ag/Au bimetallic nanoparticles induce apoptosis in human cancer cell lines via P53, CASPASE-3 and BAX/BCL-2 pathways.
Artif Cells Nanomed Biotechnol. 2018; 46(sup3):S389-S398 [PubMed] Related Publications
Au/Ag bimetallic nanoparticles (BNPs) exhibit a wide range of excellent electronic, chemical, biological, mechanical and thermal properties due to synergistic effects. However, critical questions regarding stability, biocompatibility and their cytotoxic effects remain to be answered. In this study, Ag/Au BNPs have been synthesized as "alloy" via a chemical reduction method using double molar excess of tryptophan [ν(M):ν(Trp) = 1:2]. We then estimated their toxicity in HCT116, 4T1, HUH7 and HEK293 cell lines in monocellular and spheroid cultures. Ag/Au nanoparticles with metal ratio 3:1, had the maximal antitumor effect in cancer cell lines, while the toxicity was found significantly decreased in non-cancerous cell lines. Our results were also compared to previous data regarding Ag/Au using single molar excess of tryptophan [ν(M):ν(Trp) = 1:1], suggesting that tryptophan has a protective effect on HEK293 and not in cancer cells. Aiming to investigate the molecular mechanism behind nanopartricles cytotoxicity, we studied the expression of cell cycle and apoptosis related genes on HCT116, 4T1, and HUH7 monocellular culture. Hence, we showed that bimetallic cytotoxicity is mediated via the caspase and the p53/Bax/Bcl-2 apoptotic pathway. In conclusion, our study suggests tryptophan ratio along with metal ratio used in Ag/Au BNPs as a successful way to control the toxicity in cancer cells towards non-cancerous cells, underlying the potency of bimetallic nanoparticles as selective anti-tumor agents.

Oh TI, Jung HJ, Lee YM, et al.
Zerumbone, a Tropical Ginger Sesquiterpene of
Int J Mol Sci. 2018; 19(10) [PubMed] Free Access to Full Article Related Publications
Zerumbone (ZER), an active constituent of the Zingiberaceae family, has been shown to exhibit several biological activities, such as anti-inflammatory, anti-allergic, anti-microbial, and anti-cancer; however, it has not been studied for anti-melanogenic properties. In the present study, we demonstrate that ZER and

Lee CS, Nam GB, Park JS
Protopanaxatriol inhibits melanin synthesis through inactivation of the pCREB-MITF-tyrosinase signalling pathway in melanocytes.
Clin Exp Dermatol. 2019; 44(3):295-299 [PubMed] Related Publications
Ginsenosides are major active components of ginseng, and have diverse pharmacological properties in traditional medicine. Recent reports have shown that ginsenosides modify skin physiology and mitigate skin disorders such as photoageing and hyperpigmentation. We evaluated the antimelanogenic efficacy of protopanaxatriol, a major category of ginsenosides, as a depigmenting agent. Protopanaxatriol significantly reduced intracellular and extracellular melanin content in a concentration-dependent manner in B16 melanoma cells treated with α-melanocyte-stimulating hormone. In normal human epidermal melanocytes, protopanaxatriol clearly decreased melanin synthesis and dendrite elongation. In addition, protopanaxatriol dramatically suppressed the expression of genes encoding the melanogenic proteins tyrosinase, tyrosinase-related protein-1 and -2, and microphthalmia-associated transcription factor through dephosphorylation of cAMP response element-binding protein. These results suggest that protopanaxatriol could be an effective candidate anti-melanogenic agent.

Hsu YL, Chen YJ, Chang WA, et al.
Interaction between Tumor-Associated Dendritic Cells and Colon Cancer Cells Contributes to Tumor Progression via CXCL1.
Int J Mol Sci. 2018; 19(8) [PubMed] Free Access to Full Article Related Publications
Crosstalk of a tumor with its microenvironment is a critical factor contributing to cancer development. This study investigates the soluble factors released by tumor-associated dendritic cells (TADCs) responsible for increasing cancer stem cell (CSC) properties, cell mobility, and epithelial-to-mesenchymal transition (EMT). Dendritic cells (DCs) of colon cancer patients were collected for phenotype and CXCL1 expression by flow cytometry and Luminex assays. The transcriptome of CXCL1-treated cancer cells was established by next generation sequencing. Inflammatory chemokine CXCL1, present in large amounts in DCs isolated from colon cancer patients, and SW620-conditioned TADCs, enhance CSC characteristics in cancer, supported by enhanced anchorage-independent growth, CD133 expression and aldehyde dehydrogenase activity. Additionally, CXCL1 increases the metastatic ability of a cancer by enhancing cell migration, matrix metalloproteinase-7 expression and EMT. The enhanced CXCL1 expression in DCs is also noted in mice transplanted with colon cancer cells. Transcriptome analysis of CXCL1-treated SW620 cells indicates that CXCL1 increases potential oncogene expression in colon cancer, including

Sun S, Du G, Xue J, et al.
PCC0208009 enhances the anti-tumor effects of temozolomide through direct inhibition and transcriptional regulation of indoleamine 2,3-dioxygenase in glioma models.
Int J Immunopathol Pharmacol. 2018 Jan-Dec; 32:2058738418787991 [PubMed] Free Access to Full Article Related Publications
Indoleamine 2,3-dioxygenase (IDO), which is highly expressed in human glioblastoma and involved in tumor immune escape and resistance to chemotherapy, is clinically correlated with tumor progression and poor clinical outcomes, and is a promising therapeutic target for glioblastoma. IDO inhibitors are marginally efficacious as single-agents; therefore, combination with other therapies holds promise for cancer therapy. The aim of this study was to investigate the anti-tumor effects and mechanisms of the IDO inhibitor PCC0208009 in combination with temozolomide. The effects of PCC0208009 on IDO activity inhibition, and mRNA and protein expression in HeLa cells were observed. In the mouse glioma GL261 heterotopic model, the effects of PCC0208009 on l-kynurenine/tryptophan (Kyn/Trp), tumor growth, flow cytometry for T cells within tumors, and immunohistochemistry for IDO and Ki67 were examined. In the rat glioma C6 orthotopic model, animal survival, flow cytometry for T cells within tumors, and immunohistochemistry for proliferating cell nuclear antigen (PCNA) and IDO were examined. The results show that PCC0208009 is a highly effective IDO inhibitor, not only directly inhibiting IDO activity but also participating in the gene regulation of IDO expression at the transcription and translation levels. PCC0208009 significantly enhanced the anti-tumor effects of temozolomide in GL261 and C6 models, by increasing the percentages of CD3

Kim KI, Jo JW, Lee JH, et al.
Induction of pigmentation by a small molecule tyrosine kinase inhibitor nilotinib.
Biochem Biophys Res Commun. 2018; 503(4):2271-2276 [PubMed] Related Publications
Skin color is determined by the melanin pigments that are produced in melanocytes then transferred to surrounding keratinocytes. Despite the growing number of commercial products claiming the pigmentation-regulatory effects, there is still a demand for the development of new materials that are safe and more efficacious. We tried to screen the pigmentation-regulatory materials using a commercially available drugs, and found that nilotinib could induce pigmentation in melanoma cells. When HM3KO melanoma cells were treated with nilotinib, melanin content was increased together with increase of tyrosinase activity. Nilotinib increased the expression of pigmentation-related genes such as MITF, tyrosinase and TRP1. Consistent with these results, the protein level for MITF, tyrosinase, and TRP1 was significantly increased by nilotinib. To delineate the action mechanism of nilotinib, we investigated the effects of nilotinib on intracellular signaling. As a result, nilotinib decreased the phosphorylation of AKT, while increased the phosphorylation of CREB. The pretreatment of PKA inhibitor H89 markedly blocked the nilotinib-induced phosphorylation of CREB. In accordance with, pretreatment of H89 significantly inhibited the nilotinib-induced pigmentation, indicating that nilotinib induces pigmentation via the activation of PKA signaling. Together, our data suggest that nilotinib can be developed for the treatment of hypopigmentary disorder such as vitiligo.

Takahashi N, Chen HY, Harris IS, et al.
Cancer Cells Co-opt the Neuronal Redox-Sensing Channel TRPA1 to Promote Oxidative-Stress Tolerance.
Cancer Cell. 2018; 33(6):985-1003.e7 [PubMed] Free Access to Full Article Related Publications
Cancer cell survival is dependent on oxidative-stress defenses against reactive oxygen species (ROS) that accumulate during tumorigenesis. Here, we show a non-canonical oxidative-stress defense mechanism through TRPA1, a neuronal redox-sensing Ca

Lee CS, Baek HS, Bae IH, et al.
Depigmentation efficacy of galacturonic acid through tyrosinase regulation in B16 murine melanoma cells and a three-dimensional human skin equivalent.
Clin Exp Dermatol. 2018; 43(6):708-712 [PubMed] Related Publications
Sugar is a well-known cosmetic ingredient for moisturizing skin with minimal side-effects. Several reports have demonstrated an antimelanogenic effect of sugar in melanocytes. We evaluated the whitening efficacy of galacturonic acid (GA), the main component of pectin, as an anti-melanogenic agent. GA significantly suppressed melanin synthesis and secretion in a concentration-dependent manner in α-melanocyte stimulating hormone-treated B16 melanoma cells, and inhibited tyrosinase activity and expression at a dose of 10 mmol/L. In a three-dimensional human skin equivalent (MelanoDerm), GA clearly brightened tissue colour. Haematoxylin and eosin and Fontana-Masson (F&M) staining of tissue sections revealed decreased melanin production without skin tissue collapse in the presence of GA. Interestingly, GA dramatically suppressed gene expression of the melanogenic proteins tyrosinase, tyrosinase-related protein (TYRP)-1 and microphthalmia-associated transcription factor, but not TYRP-2. The results support the utility of GA as an effective candidate antimelanogenic agent.

Wei L, Zhu S, Li M, et al.
High Indoleamine 2,3-Dioxygenase Is Correlated With Microvessel Density and Worse Prognosis in Breast Cancer.
Front Immunol. 2018; 9:724 [PubMed] Free Access to Full Article Related Publications
Indoleamine 2,3-dioxygenase (IDO), which catalyzes the breakdown of the essential amino acid tryptophan into kynurenine, is understood to have a key role in cancer immunotherapy. IDO has also received more attention because of its non-immune functions including regulating angiogenesis. The purpose of this study was to investigate the effects of IDO on microvessel density (MVD), and to explore its prognostic role in breast cancer. We showed IDO expression was positively correlated with MVD labeled by CD105 (MVD-CD105) rather than MVD labeled by CD31 (MVD-CD31) in breast cancer specimens. Both IDO expression and MVD-CD105 level were associated with initial TNM stage, histological grade, and tumor-draining lymph nodes (TDLNs) metastasis in breast cancer. In the prognostic analysis, TDLNs metastasis, an advanced TNM stage (III) and high histological grade (III) significantly predicted shorter survival in univariate analysis. Concentrating on IDO and MVD, the patients with IDO expression or high MVD level had poorer prognosis compared with no IDO expression [

Bidaux G, Gordienko D, Shapovalov G, et al.
4TM-TRPM8 channels are new gatekeepers of the ER-mitochondria Ca
Biochim Biophys Acta Mol Cell Res. 2018; 1865(7):981-994 [PubMed] Related Publications
Calcium (Ca

Hotblack A, Holler A, Piapi A, et al.
Tumor-Resident Dendritic Cells and Macrophages Modulate the Accumulation of TCR-Engineered T Cells in Melanoma.
Mol Ther. 2018; 26(6):1471-1481 [PubMed] Free Access to Full Article Related Publications
Ongoing clinical trials explore T cell receptor (TCR) gene therapy as a treatment option for cancer, but responses in solid tumors are hampered by the immunosuppressive microenvironment. The production of TCR gene-engineered T cells requires full T cell activation in vitro, and it is currently unknown whether in vivo interactions with conventional dendritic cells (cDCs) regulate the accumulation and function of engineered T cells in tumors. Using the B16 melanoma model and the inducible depletion of CD11c

He RQ, Qin MJ, Lin P, et al.
Prognostic Significance of LncRNA PVT1 and Its Potential Target Gene Network in Human Cancers: a Comprehensive Inquiry Based Upon 21 Cancer Types and 9972 Cases.
Cell Physiol Biochem. 2018; 46(2):591-608 [PubMed] Related Publications
BACKGROUND/AIMS: Whether the level of long noncoding RNA plasmacytoma variant translocation 1 gene (lncRNA PVT1) expression influences the clinical development and outcome of human cancers has not been thoroughly elucidated to date. Inconsistencies still exist regarding the associations between PVT1 and the clinicopathological features, including patient survival data. Additionally, the regulatory mechanism of PVT1 among human cancers remains unclear.
METHODS: we conducted a comprehensive inquiry to verify the implication of PVT1 expression in cancer patients by conducting a meta-analysis of 19 selected studies and The Cancer Genome Atlas (TCGA) database to examine the relationship between PVT1 expression and both the prognosis and clinicopathological features of cancer patients using STATA 12.0. In addition, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses of the potential mRNA target genes of PVT1 gathered from TANRIC and Multi Experiment Matrix (MEM) were performed.
RESULTS: The level of PVT1 expression in tumor tissues was higher than in paired non-cancer tissues and was significantly associated with a poorer prognosis in cancer patients. Additionally, overexpression of PVT1 was significantly correlated with histological differentiation, tumor (T) classification, lymph node (N) classification and TNM stages. Furthermore, a total of 462 validated target genes were identified, and the GO and KEGG analyses demonstrated that the validated targets of PVT1 were significantly enriched in several pathways, including the GnRH signaling pathway, the Cytokine-cytokine receptor interaction pathway, the Inflammatory mediator regulation of TRP channels pathway, and the Neuroactive ligand-receptor interaction pathway.
CONCLUSION: PVT1 may serve as a potential biomarker associated with the progression and prognosis of human cancers.

Miskolczi Z, Smith MP, Rowling EJ, et al.
Collagen abundance controls melanoma phenotypes through lineage-specific microenvironment sensing.
Oncogene. 2018; 37(23):3166-3182 [PubMed] Free Access to Full Article Related Publications
Despite the general focus on an invasive and de-differentiated phenotype as main driver of cancer metastasis, in melanoma patients many metastatic lesions display a high degree of pigmentation, indicative for a differentiated phenotype. Indeed, studies in mice and fish show that melanoma cells switch to a differentiated phenotype at secondary sites, possibly because in melanoma differentiation is closely linked to proliferation through the lineage-specific transcriptional master regulator MITF. Importantly, while a lot of effort has gone into identifying factors that induce the de-differentiated/invasive phenotype, it is not well understood how the switch to the differentiated/proliferative phenotype is controlled. We identify collagen as a contributor to this switch. We demonstrate that collagen stiffness induces melanoma differentiation through a YAP/PAX3/MITF axis and show that in melanoma patients increased collagen abundance correlates with nuclear YAP localization. However, the interrogation of large patient datasets revealed that in the context of the tumour microenvironment, YAP function is more complex. In the absence of fibroblasts, YAP/PAX3-mediated transcription prevails, but in the presence of fibroblasts tumour growth factor-β suppresses YAP/PAX3-mediated MITF expression and induces YAP/TEAD/SMAD-driven transcription and a de-differentiated phenotype. Intriguingly, while high collagen expression is correlated with poorer patient survival, the worst prognosis is seen in patients with high collagen expression, who also express MITF target genes such as the differentiation markers TRPM1, TYR and TYRP1, as well as CDK4. In summary, we reveal a distinct lineage-specific route of YAP signalling that contributes to the regulation of melanoma pigmentation and uncovers a set of potential biomarkers predictive for poor survival.

Nair-Shalliker V, Egger S, Chrzanowska A, et al.
Associations between sun sensitive pigmentary genes and serum prostate specific antigen levels.
PLoS One. 2018; 13(3):e0193893 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Melanoma and prostate cancer may share risk factors. This study examined the association between serum PSA levels, which is a risk factor for prostate cancer, and variants in some melanoma-associated pigmentary genes.
METHODS: We studied participants, all aged 70+ years, in the Concord Health and Ageing in Men Project who had no history of prostatitis or received treatment for prostate disease (n = 1033). We genotyped variants in MC1R (rs1805007, rs1805008), ASIP (rs4911414, rs1015362), SLC45A2 (rs28777, rs16891982), IRF4 (rs12203592), TYRP1 (rs1408799), TYR (rs1126809, rs1042602), SLC24A2 (rs12896399), and OCA2 (rs7495174). Generalised linear dominant models with Poisson distribution, log link functions and robust variance estimators estimated adjusted percentage differences (%PSA) in mean serum PSA levels (ng/mL) between variant and wildtype (0%PSA = reference) genotypes, adjusting for age, body mass index, serum 25OHD levels and birth regions (Australia or New Zealand (ANZ), Europe or elsewhere).
RESULTS: Serum PSA levels were strongly associated with advancing age and birth regions: mean PSA levels were lower in Europe-born (-29.7%) and elsewhere-born (-11.7%) men than ANZ-born men (reference). Lower %PSA was observed in men with variants in SLC45A2: rs28777 (-19.6;95%CI: -33.5, -2.7), rs16891982 (-17.3;95%CI:-30.4,-1.7) than in wildtype men (reference). There were significant interactions between birth regions and PSA levels in men with variants in MC1R (rs1805007; p-interaction = 0.0001) and ASIP (rs4911414; p-interaction = 0.007). For these genes %PSA was greater in ANZ-born men and lower in Europe- and elsewhere-born men with the variant than it was in wildtype men. In a post hoc analysis, serum testosterone levels were increased in men with MC1R rs1805007 and serum dihydrotestosterone in men with ASIP rs1015362.
CONCLUSION: Men with SNPs in SLC45A2, who have less sun sensitive skin, have lower PSA levels. Men with SNPs in MC1R and ASIP, who have more sun sensitive skin, and were born in ANZ, have higher PSA levels. Androgens may modify these apparent associations of pigmentary genes and sun exposure with PSA levels.
IMPACT: PSA levels and possibly prostate cancer risk may vary with sun sensitivity and sun exposure, the effects of which might be modified by androgen levels.

Juang LJ, Gao XY, Mai ST, et al.
Safety assessment, biological effects, and mechanisms of Myrica rubra fruit extract for anti-melanogenesis, anti-oxidation, and free radical scavenging abilities on melanoma cells.
J Cosmet Dermatol. 2019; 18(1):322-332 [PubMed] Related Publications
OBJECTIVE: Currently, the cosmetic and medical industries are paying considerable attention to solve or prevent skin damage or diseases, such as hyperpigmentation and oxidation and free radical damage. In this study, the effective compounds in Myrica rubra fruit were extracted and studied the biological effects of these M. rubra fruit extracts.
METHODS: In this study, we extracted M. rubra fruit using solutions with various ratios of water to ethanol (100:0, 50:50, 5:95) and studied the anti-melanogenesis, anti-oxidation and radical scavenging effects of these M. rubra fruit extracts on two melanoma cell lines: mouse melanoma (B16-F0) and human melanoma (A2058). The cytotoxicity, melanin synthesis, mushroom and cellular tyrosinase activities, enzyme kinetics, melanogenesis-related gene expression, melanogenesis-related protein secretion, radical DPPH scavenging activity and ROS inhibition after treatment with M. rubra fruit extracts were determined.
RESULTS: The results showed that the water extract of M. rubra fruit was less cytotoxic to the melanoma cell lines, effectively inhibited melanin synthesis and tyrosinase activity and down-regulated the gene expression and protein secretion of MITF and TRP-1. In addition, the M. rubra fruit extracts also showed the abilities to scavenge DPPH free radicals and suppress ROS production. Finally, the effective compounds in the water extract were Myricetin-O-deoxyhexoside, Quercetin-O-deoxyhexoside, and Kaempferol-O-hexoside determined by LC/MS/MS assay.
CONCLUSION: Overall, the water extract of M. rubra fruit is a safe and effective melanin inhibitor and anti-oxidant and can be applied widely in the fields of cosmetics and medicine.

Wang X, Wang JG, Geng YY, et al.
An enhanced anti-tumor effect of apoptin-cecropin B on human hepatoma cells by using bacterial magnetic particle gene delivery system.
Biochem Biophys Res Commun. 2018; 496(2):719-725 [PubMed] Related Publications
The gene therapy of cancer, due to the limit of its efficiency and safety, has not been widely used in clinical. Recently, bacterial magnetic particles (BMPs), which are membrane-bound nanocrystals found in magnetotactic bacteria, have been exploited as a new gene delivery system. However, its application on gene therapy remains to be explored. In our previous study, we found that a combination of cecropin B (ABPs) and apoptin (VP3) could serve as an effective gene therapeutic agent. Thus, in this study, we used BMPs to deliver the co-expression plasmid of these two gene, namely pVAX1-VA, and evaluated its therapeutic effect on human hepatocellular carcinoma (HepG2). Our results showed that BMPs significantly improved the efficiency of gene transfection (almost 3-fold than Lipofectamine 2000 at 48 h, P < .001), which led to stronger apoptosis (in a peak almost 2-fold than Lipofectamine 2000-pVAX1-VA, P < .01) and growth inhibition of HepG2 cells. More importantly, compared with Lipofectamine 2000-pVAX1-VA group, BMP-pVAX1-VA strikingly inhibited tumor growth (0.60 ± 0.09 g vs. 0.88 ± 0.11 g, P < .05) in nude mouse tumor models and increased the tumor-infiltrating lymphocytes considerably without apparent cytotoxicity. These findings suggest that BMPs could be an attractive gene delivery system for gene therapy and provide a potential available treatment for human hepatocellular carcinoma and maybe some other kinds of tumors.

Almasi S, Kennedy BE, El-Aghil M, et al.
TRPM2 channel-mediated regulation of autophagy maintains mitochondrial function and promotes gastric cancer cell survival via the JNK-signaling pathway.
J Biol Chem. 2018; 293(10):3637-3650 [PubMed] Free Access to Full Article Related Publications
A lack of effective treatment is one of the main factors contributing to gastric cancer-related death. Discovering effective targets and understanding their underlying anti-cancer mechanism are key to achieving the best response to treatment and to limiting side effects. Although recent studies have shown that the cation channel transient receptor potential melastatin-2 (TRPM2) is crucial for cancer cell survival, the exact mechanism remains unclear, limiting its therapeutic potential. Here, using molecular and functional assays, we investigated the role of TRPM2 in survival of gastric cancer cells. Our results indicated that TRPM2 knockdown in AGS and MKN-45 cells decreases cell proliferation and enhances apoptosis. We also observed that the TRPM2 knockdown impairs mitochondrial metabolism, indicated by a decrease in basal and maximal mitochondrial oxygen consumption rates and ATP production. These mitochondrial defects coincided with a decrease in autophagy and mitophagy, indicated by reduced levels of autophagy- and mitophagy-associated proteins (

Silva JL, Cino EA, Soares IN, et al.
Targeting the Prion-like Aggregation of Mutant p53 to Combat Cancer.
Acc Chem Res. 2018; 51(1):181-190 [PubMed] Related Publications
Prion-like behavior of several amyloidogenic proteins has been demonstrated in recent years. Despite having functional roles in some cases, irregular aggregation can have devastating consequences. The most commonly known amyloid diseases are Alzheimer's, Parkinson's, and Transmissible Spongiform Encephalopathies (TSEs). The pathophysiology of prion-like diseases involves the structural transformation of wild-type (wt) proteins to transmissible forms that can convert healthy proteins, generating aggregates. The mutant form of tumor suppressor protein, p53, has recently been shown to exhibit prion-like properties. Within the context of p53 aggregation and the search for ways to avert it, this review emphasizes discoveries, approaches, and research from our laboratory and others. Although its standard functions are strongly connected to tumor suppression, p53 mutants and aggregates are involved in cancer progression. p53 aggregates are heterogeneous assemblies composed of amorphous aggregates, oligomers, and amyloid-like fibrils. Evidence of these structures in tumor tissues, the in vitro capability for p53 mutants to coaggregate with wt protein, and the detection of cell-to-cell transmission indicate that cancer has the basic characteristics of prion and prion-like diseases. Various approaches aim to restore p53 functions in cancer. Methods include the use of small-molecule and peptide stabilizers of mutant p53, zinc administration, gene therapy, alkylating and DNA intercalators, and blockage of p53-MDM2 interaction. A primary challenge in developing small-molecule inhibitors of p53 aggregation is the large number of p53 mutations. Another issue is the inability to recover p53 function by dissociating mature fibrils. Consequently, efforts have emerged to target the intermediate species of the aggregation reaction. Φ-value analysis has been used to characterize the kinetics of the early phases of p53 aggregation. Our experiments using high hydrostatic pressure (HHP) and chemical denaturants have helped to clarify excited conformers of p53 that are prone to aggregation. Molecular dynamics (MD) and phasor analysis of single Trp fluorescence signals point toward the presence of preamyloidogenic conformations of p53, which are not observed for p63 or p73. Exploring the features of competent preamyloidogenic states of wt and different p53 mutants may provide a framework for designing personalized drugs for the restoration of p53 function. Protection of backbone hydrogen bonds (BHBs) has been shown to be an important factor for the stability of amyloidogenic proteins and was employed to identify and stabilize the structural defect resulting from the p53 Y220C mutation. Using MD simulations, we compared BHB protection factors between p53 family members to determine the donor-acceptor pairs in p53 that exhibit lower protection. The identification of structurally vulnerable sites in p53 should provide new insights into rational designs that can rapidly be screened using our experimental methodology. Through continued and combined efforts, the outlook is positive for the development of strategies for regulating p53 amyloid transformation.

Yu X, Liang Q, Liu W, et al.
Deguelin, an Aurora B Kinase Inhibitor, Exhibits Potent Anti-Tumor Effect in Human Esophageal Squamous Cell Carcinoma.
EBioMedicine. 2017; 26:100-111 [PubMed] Free Access to Full Article Related Publications
Aurora B kinase has emerged as a key regulator of mitosis and deregulation of Aurora B activity is closely related to the development and progression of human cancers. In the present study, we found that Aurora B is overexpressed in human esophageal squamous cell carcinoma (ESCC), high levels of Aurora B protein were associated with a worse overall survival rate in ESCC patients. Depleting of Aurora B blunted the malignant phenotypes in ESCC cells. Importantly, we demonstrated that a natural compound, deguelin, has a profound anti-tumor effect on ESCC via inhibiting Aurora B activity. Deguelin potently inhibited in vitro Aurora B kinase activity. The in silico docking study further indicated that deguelin was docked into the ATP-binding pocket of Aurora B. Inhibition of Aurora B activity attenuated growth of ESCC cells, resulted in G2/M cell cycle arrest, polyploidy cells formation, and apoptosis induction. Knocking down of Aurora B decreased the sensitivity of ESCC cells to deguelin. The in vivo results showed that deguelin blocked the phosphorylation of histone H3 and inhibited the growth of ESCC tumor xenografts. Overall, we identified deguelin as an effective Aurora B inhibitor, which deserves further studies in other animal models and ESCC treatment.

Pappa KI, Kontostathi G, Makridakis M, et al.
High Resolution Proteomic Analysis of the Cervical Cancer Cell Lines Secretome Documents Deregulation of Multiple Proteases.
Cancer Genomics Proteomics. 2017 Nov-Dec; 14(6):507-521 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Oncogenic infection by HPV, eventually leads to cervical carcinogenesis, associated by deregulation of specific pathways and protein expression at the intracellular and secretome level. Thus, secretome analysis can elucidate the biological mechanisms contributing to cervical cancer. In the present study we systematically analyzed its constitution in four cervical cell lines employing a highly sensitive proteomic technology coupled with bioinformatics analysis.
MATERIALS AND METHODS: LC/MS-MS proteomics and bioinformatics analysis were performed in the secretome of four informative cervical cell lines SiHa (HPV16
RESULTS: The proteomic pattern of each cancer cell line compared to HCK1T was identified and a detailed bioinformatics analysis disclosed inhibition of matrix metalloproteases in cancer cell lines. This prediction was further confirmed via zymography for MMP-2 and MMP-9, western blot analysis for ADAM10 and by MRM for TIMP1. The differential expression of important secreted proteins such as CATD, FUCA1 and SOD2 was also confirmed by western blot analysis. MRM-targeted proteomics analysis confirmed the differential expression of CATD, CATB, SOD2, QPCT and NEU1.
CONCLUSION: High resolution proteomics analysis of cervical cancer secretome revealed significantly deregulated biological processes and proteins implicated in cervical carcinogenesis.

Masaki A, Ishida T, Maeda Y, et al.
Clinical significance of tryptophan catabolism in Hodgkin lymphoma.
Cancer Sci. 2018; 109(1):74-83 [PubMed] Free Access to Full Article Related Publications
Indoleamine 2,3-dioxygenase 1 (IDO) is an enzyme catabolizing tryptophan (Trp) into the kynurenine (Kyn) pathway. The purpose of the present study was to determine the clinical significance of Trp catabolism in newly diagnosed Hodgkin lymphoma (HL) patients. We quantified serum Trp and Kyn in 52 HL patients, and analyzed their associations with different clinical parameters including serum soluble CD30 concentration. The IDO expression was evaluated in the patients' affected lymph nodes. The cohort comprised 22 male and 30 female patients (age range, 15-81 years; median, 45 years), with a 5-year overall survival (OS) of 88.6%. The OS was significantly shorter for patients with a high Kyn/Trp ratio (OS at 5 years, 60.0% vs 92.2%), for those with stage IV disease, and for those with lymphocytopenia (<600/mm

Goldstein AM, Xiao Y, Sampson J, et al.
Rare germline variants in known melanoma susceptibility genes in familial melanoma.
Hum Mol Genet. 2017; 26(24):4886-4895 [PubMed] Free Access to Full Article Related Publications
Known high-risk cutaneous malignant melanoma (CMM) genes account for melanoma risk in <40% of melanoma-prone families, suggesting the existence of additional high-risk genes or perhaps a polygenic mechanism involving multiple genetic modifiers. The goal of this study was to systematically characterize rare germline variants in 42 established melanoma genes among 144 CMM patients in 76 American CMM families without known mutations using data from whole-exome sequencing. We identified 68 rare (<0.1% in public and in-house control datasets) nonsynonymous variants in 25 genes. We technically validated all loss-of-function, inframe insertion/deletion, and missense variants predicted as deleterious, and followed them up in 1, 559 population-based CMM cases and 1, 633 controls. Several of these variants showed disease co-segregation within families. Of particular interest, a stopgain variant in TYR was present in five of six CMM cases/obligate gene carriers in one family and a single population-based CMM case. A start gain variant in the 5'UTR region of PLA2G6 and a missense variant in ATM were each seen in all three affected people in a single family, respectively. Results from rare variant burden tests showed that familial and population-based CMM patients tended to have higher frequencies of rare germline variants in albinism genes such as TYR, TYRP1, and OCA2 (P < 0.05). Our results suggest that rare nonsynonymous variants in low- or intermediate-risk CMM genes may influence familial CMM predisposition, warranting further investigation of both common and rare variants in genes affecting functionally important pathways (such as melanogenesis) in melanoma risk assessment.

Shiota M, Fujimoto N, Takeuchi A, et al.
The Association of Polymorphisms in the Gene Encoding Gonadotropin-Releasing Hormone with Serum Testosterone Level during Androgen Deprivation Therapy and Prognosis of Metastatic Prostate Cancer.
J Urol. 2018; 199(3):734-740 [PubMed] Related Publications
PURPOSE: Serum testosterone suppression during androgen deprivation therapy has been reported to affect the efficacy of androgen deprivation therapy. However, the factors impacting hormonal variations during androgen deprivation therapy remain unclear. Therefore, in this study we investigated the significance of missense polymorphisms in the gene encoding GNRH in men treated with primary androgen deprivation therapy for metastatic prostate cancer.
MATERIALS AND METHODS: This study included 80 Japanese patients with metastatic prostate cancer with available serum testosterone levels during androgen deprivation therapy. We examined the association of GNRH1 (rs6185, S20W) and GNRH2 (rs6051545, A16V) gene polymorphisms with clinicopathological parameters, including serum testosterone levels during androgen deprivation therapy, as well as prognosis, including progression-free and overall survival.
RESULTS: The CT and CT/TT alleles in the GNRH2 gene (rs6051545) were associated with higher serum testosterone during androgen deprivation therapy compared with those of the CC allele. Consequently the CT alleles were associated with a higher risk of progression after adjustment for age and serum testosterone during androgen deprivation therapy (HR 1.73, 95% CI 1.00-3.00, p = 0.049).
CONCLUSIONS: Taken together these findings suggest that rs6051545 (GNRH2) genetic variation may result in inadequate suppression of serum testosterone during androgen deprivation therapy. This may lead to detrimental effects of androgen deprivation therapy on prognosis in men with metastatic prostate cancer.

Wang S, Huo D, Kupfer S, et al.
Genetic variation in the vitamin D related pathway and breast cancer risk in women of African ancestry in the root consortium.
Int J Cancer. 2018; 142(1):36-43 [PubMed] Free Access to Full Article Related Publications
The vitamin D related pathway has been evaluated in carcinogenesis but its genetic contribution remains poorly understood. We examined single-nucleotide polymorphisms (SNPs) in the vitamin D related pathway genes using data from a genome-wide association study (GWAS) of breast cancer in the African Diaspora that included 3,686 participants (1,657 cases). Pathway- and gene-level analyses were conducted using the adaptive rank truncated product test. Odds ratios (OR) and 95% confidence intervals (CI) were estimated at SNP-level. After stringent Bonferroni corrections, we observed no significant association between variants in the vitamin D pathway and breast cancer risk at the pathway-, gene-, or SNP-level. In addition, no association was found for either the reported signals from GWASs of vitamin D related traits, or the SNPs within vitamin D receptor (VDR) binding regions. Furthermore, a decrease in genetically predicted 25(OH)D levels by Mendelian randomization was not associated with breast cancer (p = 0.23). However, an association for breast cancer with the pigment synthesis/metabolism pathway almost approached significance (pathway-level p = 0.08), driven primarily by a nonsense SNP rs41302073 in TYRP1, with an OR of 1.54 (95% CI = 1.24-1.91, p

Li Y, Liu X, Tang H, et al.
RNA Sequencing Uncovers Molecular Mechanisms Underlying Pathological Complete Response to Chemotherapy in Patients with Operable Breast Cancer.
Med Sci Monit. 2017; 23:4321-4327 [PubMed] Free Access to Full Article Related Publications
BACKGROUND This study aimed to identify key genes contributing to pathological complete response (pCR) to chemotherapy by mRNA sequencing (RNA-seq). MATERIAL AND METHODS RNA was extracted from the frozen biopsy tissue of patients with pathological complete response and patients with non-pathological complete response. Sequencing was performed on the HiSeq2000 platform. Differentially expressed genes (DEGs) were identified between the pCR group and non-pCR (NpCR) group. Pathway enrichment analysis of DEGs was performed. A protein-protein interaction network was constructed, then module analysis was performed to identify a subnetwork. Finally, transcription factors were predicted. RESULTS A total of 673 DEGs were identified, including 419 upregulated ones and 254 downregulated ones. The PPI network constructed consisted of 276 proteins forming 471 PPI pairs, and a subnetwork containing 18 protein nodes was obtained. Pathway enrichment analysis revealed that PLCB4 and ADCY6 were enriched in pathways renin secretion, gastric acid secretion, gap junction, inflammatory mediator regulation of TRP channels, retrograde endocannabinoid signaling, melanogenesis, cGMP-PKG signaling pathway, calcium signaling pathway, chemokine signaling pathway, cAMP signaling pathway, and rap1 signaling pathway. CNR1 was enriched in the neuroactive ligand-receptor interaction pathway, retrograde endocannabinoid signaling pathway, and rap1 signaling pathway. The transcription factor-gene network consists of 15 transcription factors and 16 targeted genes, of which 5 were downregulated and 10 were upregulated. CONCLUSIONS We found key genes that may contribute to pCR to chemotherapy, such as PLCB4, ADCY6, and CNR1, as well as some transcription factors.

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