Gene Summary

Gene:ATP7B; ATPase copper transporting beta
Aliases: WD, PWD, WC1, WND
Summary:This gene is a member of the P-type cation transport ATPase family and encodes a protein with several membrane-spanning domains, an ATPase consensus sequence, a hinge domain, a phosphorylation site, and at least 2 putative copper-binding sites. This protein functions as a monomer, exporting copper out of the cells, such as the efflux of hepatic copper into the bile. Alternate transcriptional splice variants, encoding different isoforms with distinct cellular localizations, have been characterized. Mutations in this gene have been associated with Wilson disease (WD). [provided by RefSeq, Jul 2008]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:copper-transporting ATPase 2
Source:NCBIAccessed: 31 August, 2019


What does this gene/protein do?
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Cancer Overview

Research Indicators

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

Literature Analysis

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

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

Specific Cancers (5)

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

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

Latest Publications: ATP7B (cancer-related)

Liu F, Zou Y, Wang F, et al.
Genet Test Mol Biomarkers. 2019; 23(6):409-417 [PubMed] Related Publications

Sugita S, Yoshino H, Yonemori M, et al.
Tumor‑suppressive microRNA‑223 targets WDR62 directly in bladder cancer.
Int J Oncol. 2019; 54(6):2222-2236 [PubMed] Related Publications
miRNA‑223 (miR‑223) has been reported to function not only as a tumor suppressor, but also as an oncogenic microRNA (miRNA or miR) in various cancer cells. Therefore, the functional role of miR‑223 has not been elucidated to date, at least to the best of our knowledge. We previously performed the deep sequencing analysis of clinical bladder cancer (BC) specimens. It was revealed that miR‑223 expression was significantly downregulated in BC, suggesting that miR‑223 functions as a tumor suppressor miRNA in BC. The aim of this study was to investigate the functional roles of miR‑223 and to identify its targets in BC. The expression levels of miR‑223 were significantly decreased in our clinical BC specimens. The Cancer Genome Atlas (TCGA) database indicated that miR‑223 expression was related to lymphovascular invasion and distant metastasis. The restoration of miR‑223 expression significantly inhibited tumor aggressiveness and induced apoptosis via caspase‑3/7 activation in BC cells. WD repeat domain 62 (WDR62), a candidate target of miR‑223 according to in silico analyses, has been previously proposed to play a role in neurodevelopment. Direct binding between WDR62 and miR‑223 was confirmed by luciferase assay. The TCGA database revealed positive associations between WDR62 mRNA expression and a higher tumor grade and stage in BC. The knockdown of WDR62 significantly inhibited tumor aggressiveness and induced the apoptosis of BC cells. On the whole, the findings of this study reveal a novel miR‑223 target, oncogenic WDR62, and provided insight into the oncogenesis of BC.

Qin Y, Hu Q, Xu J, et al.
PRMT5 enhances tumorigenicity and glycolysis in pancreatic cancer via the FBW7/cMyc axis.
Cell Commun Signal. 2019; 17(1):30 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: The epigenetic factor protein arginine methyltransferase 5 (PRMT5) has been reported to play vital roles in a wide range of cellular processes, such as gene transcription, genomic organization, differentiation and cell cycle control. However, its role in pancreatic cancer remains unclear. Our study aimed to investigate the roles of PRMT5 in pancreatic cancer prognosis and progression and to explore the underlying molecular mechanism.
METHODS: Real-time PCR, immunohistochemistry and analysis of a dataset from The Cancer Genome Atlas (TCGA) were performed to study the expression of PRMT5 at the mRNA and protein levels in pancreatic cancer. Cell proliferation assays, including cell viability, colony formation ability and subcutaneous mouse model assays, were utilized to confirm the role of PRMT5 in cell proliferation and tumorigenesis. A Seahorse extracellular flux analyzer, a glucose uptake kit, a lactate level measurement kit and the measurement of
RESULTS: PRMT5 expression was significantly upregulated in pancreatic cancer tissues compared with that in adjacent normal tissues. Clinically, elevated expression of PRMT5 was positively correlated with worse overall survival in pancreatic cancer patients. Silencing PRMT5 expression inhibited the proliferation of pancreatic cancer cells both in vitro and in vivo. Moreover, PRMT5 regulated aerobic glycolysis in vitro in cell lines, in vivo in pancreatic cancer patients and in a xenograft mouse model used to measure 18F-FDG uptake. We found that mechanistically, PRMT5 posttranslationally regulated cMyc stability via F-box/WD repeat-containing protein 7 (FBW7), an E3 ubiquitin ligase that controls cMyc degradation. Moreover, PRMT5 epigenetically regulated the expression of FBW7 in pancreatic cancer cells.
CONCLUSIONS: The present study demonstrated that PRMT5 epigenetically silenced the expression of the tumor suppressor FBW7, leading to increased cMyc levels and the subsequent enhancement of the proliferation of and aerobic glycolysis in pancreatic cancer cells. The PRMT5/FBW7/cMyc axis could be a potential therapeutic target for the treatment of pancreatic cancer.

Jiang L, Lv L, Liu X, et al.
MiR-223 promotes oral squamous cell carcinoma proliferation and migration by regulating FBXW7.
Cancer Biomark. 2019; 24(3):325-334 [PubMed] Free Access to Full Article Related Publications
Abnormally expressed microRNAs (miRNAs) contribute widely to human cancer, including oral squamous cell carcinoma (OSCC), by regulating their downstream targets. MiR-223 has been proved to be up-regulated in both gastric cancer and ovarian cancer. However, the effect of miR-223 on OSCC is still unclear. Here, we showed that miR-223 was over-expressed in OSCC tissues using qRT-PCR. Next, we investigated the biological mechanism of miR-223 in OSCC. The results demonstrated that miR-223 facilitated the cell proliferation and migration of OSCC using MTT assay and Transwell assay. Furthermore, we stated that the FBXW7 expression was decreased in OSCC and re-expression of FBXW7 inhibited the proliferation and migration of OSCC. In addition, FBXW7 mimic inversed the promotion effect of miR-223 in regulating of OSCC cells. In short, miR-223 promoted OSCC cell proliferation and migration by downregulating FBXW7, which provided a novel therapeutic strategy for OSCC.

Zhang Y, Tao L, Fan LX, et al.
Cx32 mediates cisplatin resistance in human ovarian cancer cells by affecting drug efflux transporter expression and activating the EGFR‑Akt pathway.
Mol Med Rep. 2019; 19(3):2287-2296 [PubMed] Related Publications
Our previous study demonstrated that connexin 32 (Cx32) was upregulated and redistributed to the cytoplasm in A2780 human ovarian cancer cells with acquired resistance to cisplatin; this increased Cx32 feedback promoted cisplatin resistance. To further investigate the mechanism underlying Cx32‑mediated cisplatin resistance, alterations in drug transporters, the DNA repair system and the anti‑apoptotic signalling pathway were investigated by overexpressing or knocking down Cx32 in parental cells (A2780); cisplatin‑resistant human ovarian cancer cells (A2780/CDDP) were also acquired. Upregulation of efflux transporters [multi‑drug resistance protein 2 (MRP‑2), ATPase copper transporting α (ATP7A) and ATPase copper transporting β] and downregulation of the influx transporter copper uptake protein 1 mediated cisplatin resistance in A2780/CDDP cells. A2780/CDDP cells also exhibited increased expression of the DNA repair enzyme excision repair cross‑complementation group 1 (ERCC1) and activation of the epidermal growth factor receptor (EGFR) signalling pathway. Small interfering RNA‑mediated knockdown of Cx32 in A2780/CDDP cells decreased the expression of efflux transporters (MRP‑2 and ATP7A). Knockdown of Cx32 in A2780/CDDP cells also decreased the expression of ERCC1, inhibited the activation of the EGFR signalling pathway and enhanced the cytotoxicity of cisplatin. When Cx32 was overexpressed in A2780 cells, an opposite effect on the expression of efflux transporters (MRP‑2 and ATP7A) and the activation of the EGFR signalling pathway was observed, which resulted in insensitivity to cisplatin‑induced apoptosis. Thus, Cx32 expression may induce cisplatin resistance by modulating drug efflux transporter expression and activating the EGFR‑protein kinase B signalling pathway in ovarian cancer cells.

Cao Y, Liu H, Xia SL, et al.
PTEN downregulates WD repeat‑containing protein 66 in salivary adenoid cystic carcinoma.
Oncol Rep. 2019; 41(3):1827-1836 [PubMed] Article available free on PMC after 01/03/2020 Related Publications
Salivary adenoid cystic carcinoma (SACC) is one of the most common types of salivary gland cancer that causes substantial morbidity and mortality. Despite the substantial health burden of SACC, the molecular mechanisms underlying its development and progression remain poorly understood. We previously reported the loss of phosphatase and tensin homolog (PTEN) expression to be common among SACC tumors, and the PTEN deficiency to be correlated with enrichment of epithelial‑mesenchymal transition (EMT) genes based on expression array analysis. The aim of the present study was to investigate further the functional function of WD repeat‑containing protein 66 (WDR66), one of the enriched EMT genes, in the context of PTEN deficiency and SACC pathogenesis. WDR66 was identified to be required to maintain the EMT phenotype and the expression of cancer stem cell genes in the context of PTEN deficiency. Furthermore, knockdown of WDR66 decreased cellular proliferation, migration and invasion. Finally, WDR66 expression was identified to be inversely associated with PTEN expression and negatively correlated with the overall survival of patients with SACC. Collectively, the results of the present study revealed a novel function of WDR66 in mediating the progression of PTEN‑deficient SACCs, thereby suggesting WDR66 inhibition to be a potential therapeutic approach towards successful management of SACC disease progression, particularly against tumors with decreased PTEN expression levels.

Zhang Y, Zhu J
Ten genes associated with MGMT promoter methylation predict the prognosis of patients with glioma.
Oncol Rep. 2019; 41(2):908-916 [PubMed] Article available free on PMC after 01/03/2020 Related Publications
Glioma originates from the glial cells of the spine or brain, and promoter methylation of O6‑methylguanine‑DNA methyltransferase (MGMT) can promote the chemosensitivity of glioma. The present study aimed to reveal the key genes implicated in MGMT promoter methylation in patients with glioma. RNA‑sequencing data and methylation data for glioma were extracted from The Cancer Genome Atlas database. Following expression characteristic analysis and differential expression analysis using unsupervised hierarchical clustering and a rank sum test, the feature genes were identified between high and low methylation groups. Furthermore, multivariate survival analysis for the feature genes was performed using the survival package in R. Additionally, the independent glioma RNA expression datasets GSE7696 and GSE42669 were used to validate the prognostic efficiency of the gene combination. The results indicated that the prognosis of the low methylation group was significantly worse than that of the high methylation group. The ten genes corresponding to the cut‑off value of 0.56 (Rho GTPase‑activating protein 21, CECR2, histone acetyl‑lysine reader, endosulfine α, G‑patch domain‑containing 8, KIAA1109, MGMT, protocadherin β 13, selenoprotein M, sperm‑associated antigen 9 and WD repeat domain 6) were able to significantly predict prognosis and were differentially expressed between the two groups. Multivariate survival analysis suggested that the ten genes were effective for sample classification and prognostic prediction. Furthermore, the validation datasets confirmed the correlation of the ten genes with prognosis. In conclusion, these 10 genes may be mediated by MGMT promoter methylation in glioma. In addition, the ten‑gene combination may be associated with the prognosis of patients with glioma.

Jiang G, Shi W, Fang H, Zhang X
miR‑27a promotes human breast cancer cell migration by inducing EMT in a FBXW7‑dependent manner.
Mol Med Rep. 2018; 18(6):5417-5426 [PubMed] Article available free on PMC after 01/03/2020 Related Publications
Increasingly, evidence has revealed that aberrant microRNA (miRNA) expression is involved in breast cancer carcinogenesis and further progression, including metastasis. miRNA (miR)‑27a was previously identified to be abnormally expressed and to serve pro‑oncogenic functions in multiple human cancer types, including breast cancer. However, its functions and underlying mechanisms in breast cancer remain poorly understood. In the present study, it was demonstrated that miR‑27a was significantly upregulated in breast cancer tissues and cell lines compared with their normal counterparts. Overexpression of miR‑27a resulted in enhanced cell migration by inducing epithelial‑to‑mesenchymal transition, while its knockdown effectively reversed these cellular events. The present study additionally confirmed for the first time, to the best of our knowledge, that F‑box and WD repeat domain containing 7 (FBXW7) is a downstream target gene of miR‑27a in human breast cancer cells. FBXW7 is underexpressed in breast cancer tissues and cell lines, and is an independent positive factor for the overall survival rate of patients with breast cancer. Notably, the ectopic expression of FBXW7 may effectively suppress the epithelial‑to‑mesenchymal transition and migratory activity of breast cancer cells, in addition to reversing the cell migration mediated by miR‑27a. Altogether, the results of the present study indicated the important function of miR‑27a in regulating the metastasis of breast cancer in a FBXW7‑dependent manner, and provide evidence for the potential application of miR‑27a in breast cancer therapy.

Mori A, Masuda K, Ohtsuka H, et al.
FBXW7 modulates malignant potential and cisplatin-induced apoptosis in cholangiocarcinoma through NOTCH1 and MCL1.
Cancer Sci. 2018; 109(12):3883-3895 [PubMed] Article available free on PMC after 01/03/2020 Related Publications
The ubiquitin ligase F-box and WD repeat domain-containing 7 (FBXW7) is responsible for degrading diverse oncoproteins and is considered a tumor suppressor in many human cancers. Inhibiting FBXW7 enhances the malignant potential of several cancers. In this study, we aimed to investigate the role of FBXW7 in cholangiocarcinoma. We found that FBXW7 expression was associated with clinicopathological outcomes in cholangiocarcinoma patients. Both disease-free and overall survival were significantly worse in the low-FBXW7 group than in the high-FBXW7 group (P = .001 and P < .001, respectively). Multivariate analysis with the Cox proportional hazards model indicated that FBXW7 was the most important independent prognostic factor for disease-free (P = .006) and overall (P = .0004) survival. We also showed that the two FBXW7 substrates, NOTCH1 and myeloid cell leukemia sequence 1 (MCL1), regulate cholangiocarcinoma progression. Depletion of FBXW7 resulted in NOTCH1 accumulation and increased cholangiocarcinoma cell migration and self-renewal. Interestingly, when cells were stimulated with cis-diamminedichloridoplatinum(II) (cisplatin), FBXW7 suppression induced MCL1 upregulation, which reduced the sensitivity of cholangiocarcinoma cells to apoptosis, indicating that FBXW7-mediated ubiquitylation is context-dependent. These results indicate that FBXW7 modulates the malignant potential of cholangiocarcinoma through independent regulation of NOTCH1 and MCL1.

Youssef O, Knuuttila A, Piirilä P, et al.
Hotspot Mutations Detectable by Next-generation Sequencing in Exhaled Breath Condensates from Patients with Lung Cancer.
Anticancer Res. 2018; 38(10):5627-5634 [PubMed] Related Publications
BACKGROUND: Genetic alterations occurring in lung cancer are the basis for defining molecular subtypes and essential for targeted therapies. Exhaled breath condensate (EBC) is a form of non-invasive sample that, amongst components, contains DNA from pulmonary tissue. Next-generation sequencing (NGS) was herein used to analyze mutations in EBC from patients with lung cancer.
MATERIALS AND METHODS: EBC was collected from 26 patients with cancer and 20 healthy controls. Amplicon-based sequencing using Ion Ampliseq Colon and Lung Cancer gene panel v2 was applied.
RESULTS: The sequencing was successful in 17 patients and 20 controls. EBC from patients revealed 39 hotspot mutations occurring in: adenomatous polyposis coli (APC), v-raf murine sarcoma viral oncogene homolog B (BRAF), discoidin domain receptor tyrosine kinase 2 (DDR2), epidermal growth factor receptor (EGFR), erb-b2 receptor tyrosine kinase 4 (ERBB4), F-box and WD repeat domain containing 7 (FBXW7), fibroblast growth factor receptor 1 (FGFR1), FGFR3 (fibroblast growth factor receptor 3), Kirsten rat sarcoma viral oncogene homolog (KRAS), mitogen-activated protein kinase kinase 1 (MAP2K1), met proto-oncogene (MET), neuroblastoma RAS viral (v-ras) oncogene homolog (NRAS), phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA), phosphatase and tensin homolog (PTEN), ret proto-oncogene (RET), SMAD family member 4 (SMAD4), serine/threonine kinase 11 (STK11), and tumor protein p53 (TP53) genes. EBC from controls revealed 35 hotspot mutations. The average mutant allele fraction was higher in patients than controls.
CONCLUSION: NGS can identify mutations in EBCs from patients with lung cancer. This could provide a promising non-invasive method for the assessment of gene mutations in lung cancer.

Pan W, Zhang N, Liu W, et al.
The long noncoding RNA
J Biol Chem. 2018; 293(44):17154-17165 [PubMed] Article available free on PMC after 02/11/2019 Related Publications
Long noncoding RNAs (lncRNAs) are vital players in cancers, including hepatocellular carcinoma (HCC). We previously identified an lncRNA,

Ma Y, Wang Q, Liu F, et al.
KLF5 promotes the tumorigenesis and metastatic potential of thyroid cancer cells through the NF-κB signaling pathway.
Oncol Rep. 2018; 40(5):2608-2618 [PubMed] Article available free on PMC after 02/11/2019 Related Publications
The purpose of the present study was to identify the potential function of Kruppel-like factor 5 (KLF5) in thyroid cancer and investigate the underlying mechanisms. The protein levels of KLF5 in 98 thyroid cancer tissues were analyzed using an immunohistochemistry assay. SW579 cells transfected with small interfering RNA against KLF5 and B-CPAP cells transfected with KLF5 expressing vectors were used for functional studies. Western blot analysis, immunofluorescence and co-immunoprecipitation assays were used to investigate the mechanisms of KLF5. In vivo tumorigenicity was assessed using a subcutaneous xenograft experiment. The results revealed that KLF5 was highly expressed in thyroid cancer tissues and associated with lymph node metastasis. Knockdown of KLF5 in SW579 cells suppressed proliferation, anchorage-independent growth, migration and invasion in vitro, while the overexpression of KLF5 resulted in opposite effects in B-CPAP cells. Mechanistically, it was demonstrated that KLF5 promoted the cytoplasm-nuclear translocation of nuclear factor-κB. Additionally, it was revealed that insufficient F-box/WD repeat-containing protein 7 expression may be responsible for the dysfunction of KLF5 in thyroid cancer. These results revealed that KLF5 promotes the tumorigenesis and metastasis of thyroid cancer cells and may be a potential therapeutic target in patients with thyroid cancer.

Aziz D, Etemadmoghadam D, Caldon CE, et al.
19q12 amplified and non-amplified subsets of high grade serous ovarian cancer with overexpression of cyclin E1 differ in their molecular drivers and clinical outcomes.
Gynecol Oncol. 2018; 151(2):327-336 [PubMed] Related Publications
OBJECTIVES: Readily apparent cyclin E1 expression occurs in 50% of HGSOC, but only half are linked to 19q12 locus amplification. The amplified/cyclin E1
METHODS: 262 HGSOC cases were analyzed by in situ hybridization for 19q12 locus amplification and immunohistochemistry for cyclin E1, URI1 (another protein encoded by the 19q12 locus), FBXW7 and USP28 expression. Tumors were classified by 19q12 amplification status and correlated to cyclin E1 and URI1 expression, BRCA1/2 germline mutation, FBXW7 and USP28 expression, and clinical outcomes. Additionally, we assessed the relative genomic instability of amplified/cyclin E1
RESULTS: Of the 82 cyclin E1
CONCLUSIONS: Amplified/cyclin E1

Huang LY, Zhao J, Chen H, et al.
Nat Commun. 2018; 9(1):3569 [PubMed] Article available free on PMC after 02/11/2019 Related Publications
Brg1/SMARCA4 serves as the ATPase and the helicase catalytic subunit for the multi-component SWI/SNF chromatin remodeling complex, which plays a pivotal role in governing chromatin structure and gene transcription. However, the upstream signaling pathways regulating Brg1 protein stability and its physiological contribution to carcinogenesis remain largely elusive. Here we report that Brg1 is a bona fide ubiquitin substrate of SCF

Nikpey P, Nazari T, Khalili S, Ebrahimi A
The role of epidermal growth factor receptor (EGFR) common gene mutations in Iranian women with uterine fibroids.
Eur J Obstet Gynecol Reprod Biol. 2018; 229:103-107 [PubMed] Related Publications
OBJECTIVE: Uterine myomas are benign uterine tumors that originate from smooth muscle cells of the myometrium. This common complication can be associated with irreversible complications, including infertility and malignancy. Better understanding of the genetic characteristics of myoma may effect on treatment. Epidermal growth factor receptor gene (EGFR) is one of the most important genes that has the major role in the pathogenesis of myoma, cell growth, differentiation, proliferation and mutagenesis. The aim of this study was to investigate EGFR common gene mutations in Iranian women with uterine fibroids.
METHODS: In this case-control study, Common EGFR gene mutations in exons 21 and exons 19 of 100 women with uterine leiomyoma as cases and 100 healthy women as controls were studied. To investigate deletion mutations of exon 19 (rs121913438) and point mutations of exon 21 (rs121434568), Tetra ARMS/PCR, ARMS and conventional PCR methods were used respectively and the results were analyzed using χ 2 test. Odds ratios (ORs) and 95% confidence intervals (CI) were estimated using logistic regression with control for age.
RESULT: Our results showed significant difference in genotypes frequency of (TT, TG, GG) for exon 21 and (WW, WD, DD) of exon 19 among cases and controls (P-Value = 5.672e-20) and (P-Value = 3.242e-15). There was a significant relationship between [G] allele and risk uterine myoma (P-Value = 3.018e-36) and the presence of [G] allele increased the chance of developing the disease OR = 0.004, 95% CI 0.001-0.013. The result also showed significant relationship between [D] allele and risk of uterine myoma (P-Value = 1.324e-15). In addition, presence of [D] allele, increased the chance of developing the disease (OR = 0.008, 95% C.I. = 0.002-0.033).
CONCLUSION: The results indicated a significant correlation between mutations in exon 19 (rs121913438) and exon 21(rs121434568) of EGFR gene and susceptibility of myoma in the study population.

Yeh CH, Bellon M, Nicot C
FBXW7: a critical tumor suppressor of human cancers.
Mol Cancer. 2018; 17(1):115 [PubMed] Article available free on PMC after 02/11/2019 Related Publications
The ubiquitin-proteasome system (UPS) is involved in multiple aspects of cellular processes, such as cell cycle progression, cellular differentiation, and survival (Davis RJ et al., Cancer Cell 26:455-64, 2014; Skaar JR et al., Nat Rev Drug Discov 13:889-903, 2014; Nakayama KI and Nakayama K, Nat Rev Cancer 6:369-81, 2006). F-box and WD repeat domain containing 7 (FBXW7), also known as Sel10, hCDC4 or hAgo, is a member of the F-box protein family, which functions as the substrate recognition component of the SCF E3 ubiquitin ligase. FBXW7 is a critical tumor suppressor and one of the most commonly deregulated ubiquitin-proteasome system proteins in human cancer. FBXW7 controls proteasome-mediated degradation of oncoproteins such as cyclin E, c-Myc, Mcl-1, mTOR, Jun, Notch and AURKA. Consistent with the tumor suppressor role of FBXW7, it is located at chromosome 4q32, a genomic region deleted in more than 30% of all human cancers (Spruck CH et al., Cancer Res 62:4535-9, 2002). Genetic profiles of human cancers based on high-throughput sequencing have revealed that FBXW7 is frequently mutated in human cancers. In addition to genetic mutations, other mechanisms involving microRNA, long non-coding RNA, and specific oncogenic signaling pathways can inactivate FBXW7 functions in cancer cells. In the following sections, we will discuss the regulation of FBXW7, its role in oncogenesis, and the clinical implications and prognostic value of loss of function of FBXW7 in human cancers.

Donner I, Katainen R, Sipilä LJ, et al.
Germline mutations in young non-smoking women with lung adenocarcinoma.
Lung Cancer. 2018; 122:76-82 [PubMed] Related Publications
OBJECTIVES: Although the primary cause of lung cancer is smoking, a considerable proportion of all lung cancers occur in never smokers. Gender influences the risk and characteristics of lung cancer and women are overrepresented among never smokers with the disease. Young age at onset and lack of established environmental risk factors suggest genetic predisposition. In this study, we used population-based sampling of young patients to discover candidate predisposition variants for lung adenocarcinoma in never-smoking women.
MATERIALS AND METHODS: We employed archival normal tissue material from 21 never-smoker women who had been diagnosed with lung adenocarcinoma before the age of 45, and exome sequenced their germline DNA.
RESULTS AND CONCLUSION: Potentially pathogenic variants were found in eight Cancer Gene Census germline genes: BRCA1, BRCA2, ERCC4, EXT1, HNF1 A, PTCH1, SMARCB1 and TP53. The variants in TP53, BRCA1, and BRCA2 are likely to have contributed to the early onset lung cancer in the respective patients (3/21 or 14%). This supports the notion that lung adenocarcinoma can be a component of certain cancer predisposition syndromes. Fifteen genes displayed potentially pathogenic mutations in at least two patients: ABCC10, ATP7B, CACNA1S, CFTR, CLIP4, COL6A1, COL6A6, GCN1, GJB6, RYR1, SCN7A, SEC24A, SP100, TTN and USH2A. Four patients showed a mutation in COL6A1, three in CLIP4 and two in the rest of the genes. Some of these candidate genes may explain a subset of female lung adenocarcinoma.

Lv Z, Zhang Y, Yu X, et al.
The function of long non-coding RNA MT1JP in the development and progression of gastric cancer.
Pathol Res Pract. 2018; 214(8):1218-1223 [PubMed] Related Publications
Gastric cancer is one of the most common malignant tumors with the third mortality rate of cancer in world. A larger number of researches showed that genetic factors played an important role in the development of gastric cancer. More and more evidences have indicated that lncRNAs can regulate the gene expression through the transcription, post transcription and epigenetic levels including cancer invasion and metastasis, cell differentiation and apoptosis. However, the mechanisms of lncRNAs in the pathogenesis of gastric cancer remaining unclear. LncRNA MT1JP overexpression vector was constructed and then transfected into gastric cancer cells. Further CCK-8 and transwell detection showed that lncRNA MT1JP exerted an evident inhibition role on proliferation, migration and invasion. By combining molecular cell biology experiments of the reporter gene, cell overexpression or interference and Western blot, we found that lncRNA MT1JP may regulate FBXW7 expression involved in the occurrence and development of gastric cancer. The results of this study not only explain the role of lncRNA MT1JP in the development of gastric cancer, but also provide important ideas and clues for the study of genetic regulation mechanism in gastric cancer.

Yuan Y, Qi G, Shen H, et al.
Clinical significance and biological function of WD repeat domain 54 as an oncogene in colorectal cancer.
Int J Cancer. 2019; 144(7):1584-1595 [PubMed] Related Publications
In recent years, protein-protein interactions have become an attractive candidate for identifying biomarkers and drug targets for various diseases. However, WD40 repeat (WDR) domain proteins, some of the most abundant mediators of protein interactions, are largely unexplored. In our study, 57 of 361 known WDR proteins were identified as hub nodes, and a hub (WDR54) with elevated mRNA in colorectal cancer (CRC) was selected for further study. Immunohistochemistry of specimens from 945 patients confirmed the elevated expression of WDR54 in CRC, and we found that patients with WDR54-high tumors typically had a shorter disease-specific survival (DSS) than those with WDR54-low tumors, especially for the subgroup without well-differentiated tumors. Multivariate analysis showed that WDR54-high tumors were an independent risk factor for DSS, with a hazard ratio of 2.981 (95% confidence interval, 1.425-6.234; p = 0.004). Knockdown of WDR54 significantly inhibited the growth and aggressiveness of CRC cells and reduced tumor growth in a xenograft model. Each WDR54 isoform (a, b, and c) was found to reverse the inhibitory effect of WDR54 knockdown; however, only isoform c, which exhibited the highest expression, was increased in CRC cells. Sensitization of WDR54 knockdown to an SHP2 inhibitor was consistently found in CRC cells, and the underlying mechanism involved their common function in regulating AKT and ERK signaling. In conclusion, the present study is the first to investigate the significance of WDR54 in cancer and to conclude that WDR54 serves as an oncogene in CRC and may be a potential prognostic marker and therapeutic target.

Zięba S, Kowalik A, Zalewski K, et al.
Somatic mutation profiling of vulvar cancer: Exploring therapeutic targets.
Gynecol Oncol. 2018; 150(3):552-561 [PubMed] Related Publications
BACKGROUND: Vulvar squamous cell carcinoma (VSCC) constitutes over 90% of vulvar cancer. Its pathogenesis can follow two different pathways; high risk human papillomavirus (hrHPV)-dependent and HPV-independent. Due to the rarity of VSCC, molecular mechanisms underlying VSCC development remain largely unknown. The study aimed to identify pathogenic mutations implicated in the two pathways of VSCC development.
METHODS: Using next generation sequencing, 81 VSCC tumors, 52 hrHPV(+) and 29 hrHPV(-), were screened for hotspot mutations in 50 genes covered by the Ion AmpliSeq Cancer Hotspot Panel v2 Kit (Thermo Fisher Scientific).
RESULTS: Mutations of TP53 (46% and 41%, of hrHPV(+) and hrHPV(-) cases respectively) and CDKN2A (p16) (25% and 21%, of hrHPV(+) and hrHPV(-) cases respectively) were the most common genetic alterations identified in VSCC tumors. Further mutations were identified in PIK3CA, FBXW7, HRAS, FGFR3, STK11, AKT1, SMAD4, FLT3, JAK3, GNAQ, and PTEN, albeit at low frequencies. Some of the identified mutations may activate the PI3K/AKT/mTOR pathway. The activation of mTOR was confirmed in the vast majority of VSCC samples by immunohistochemical staining.
CONCLUSIONS: Detecting pathogenic mutations in 13/50 genes examined at comparable frequencies in hrHPV(+) and hrHPV(-) tumors suggest that genetic mechanisms of the two routes of VSCC pathogenesis may be similar, despite being initiated from different premalignant lesions. Importantly, our data provide a rationale for new anti-VSCC therapies targeting the PI3K/AKT/mTOR pathway.

Li YQ, Zhang XY, Chen J, et al.
J Cancer Res Ther. 2018; 14(4):881-886 [PubMed] Related Publications
Aims: Platinum-based chemotherapy is considered as the first-line treatment for nonsmall cell lung cancer (NSCLC) patients. However, platinum resistance and toxicity are major obstacles to its clinical applications. The two P-type ATPases ATP7A and ATP7B have been identified to play an essential role in the transport of platinum. Their genetic polymorphisms may affect the treatment outcome and toxicity of platinum. In this study, we aimed to investigate the association of ATP7A and ATP7B genetic polymorphisms with clinical outcome and toxicity of platinum-based chemotherapy in NSCLC patients.
Subjects and Methods: Four hundred and twenty-seven NSCLC patients were enrolled. All patients have accepted platinum-based chemotherapy for at least two cycles. ATP7A (rs2227291 and rs6622665) and ATP7B (rs1061472 and rs9535826) polymorphisms were genotyped by allele-specific matrix-assisted laser desorption ionization-time-of-flight mass spectrometry. Chemotherapeutic response, overall survival time, and hematological and gastrointestinal toxicity were recorded and their associations with genetic factors were evaluated.
Results: ATP7A rs2227291 and rs6622665 deviated from Hardy-Weinberg equilibrium. Therefore, the two single-nucleotide polymorphisms were not taken into consideration. For ATP7B polymorphism, ATP7B rs9535826 was associated with gastrointestinal toxicity, and the GG genotype showed lower gastrointestinal toxicity (odds ratio = 0.30; 95% confidence interval = 0.10-0.90; P = 0.031).
Conclusion: The genotypes of ATP7B gene may be novel and significant biomarkers for predicting the gastrointestinal toxicity of platinum-based chemotherapy in NSCLC patients.

Urick ME, Bell DW
In vitro effects of FBXW7 mutation in serous endometrial cancer: Increased levels of potentially druggable proteins and sensitivity to SI-2 and dinaciclib.
Mol Carcinog. 2018; 57(11):1445-1457 [PubMed] Article available free on PMC after 01/11/2019 Related Publications
Serous endometrial cancers (ECs) are clinically aggressive tumors that frequently harbor somatic mutations in FBXW7 (F-box and WD repeat domain-containing 7). The FBXW7 tumor suppressor is part of a SCF (complex of SKP1, Cullin 1, F-box protein) ubiquitin ligase complex which controls the degradation of numerous substrates that, if not properly regulated, can contribute to the initiation or progression of tumorigenesis. Despite reports that up to 30% of serous ECs include somatic mutations in FBXW7, the molecular effects of mutated FBXW7 in ECs have not been determined. Here, we used transient transfection and Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) editing in serous EC cell lines to interrogate the molecular effects of six recurrent FBXW7 mutations. We show that FBXW7 mutations lead to increased Cyclin E1, steroid receptor coactivator 3 (SRC-3), c-MYC, Rictor, glycogen synthase kinase 3 (GSK3), P70S6 kinase, and protein kinase B (AKT) phosphorylated protein levels in serous EC cells. Furthermore, we demonstrate that CRISPR-edited FBXW7-mutant ARK1 serous EC cells exhibit increased sensitivity to SI-2 (a SRC inhibitor) and dinaciclib (a cyclin dependent kinase (CDK) inhibitor) compared to parental ARK1 cells. Collectively, our findings reveal biochemical effects of FBXW7 mutations in the context of EC and provide in vitro evidence of sensitivity to targeted inhibitors.

Bravo D, Salduz A, Shogren KL, et al.
Decreased local and systemic levels of sFRP3 protein in osteosarcoma patients.
Gene. 2018; 674:1-7 [PubMed] Article available free on PMC after 20/10/2019 Related Publications
Osteosarcoma is a malignant bone tumor that occurs mainly in children and adolescents. Because Wnt signaling has been implicated in the pathogenesis of osteosarcoma, we have investigated the circulating and local levels of the Wnt antagonist protein, Secreted Frizzled Related Protein (sFRP) 3, in osteosarcoma patients. Enzyme linked immunosorbent assay (ELISA) analysis of 67 osteosarcoma and age-matched non-diseased control sera showed that sFPR3 protein levels were significantly lower in osteosarcoma than in normal. Analysis of tumor and adjacent normal tissues (9 pairs) from osteosarcoma patients showed a decrease in sFRP3 expression in 5 out of 9 tumor samples compared to normal tissues. Furthermore, immunohistochemical analysis of tissue microarray revealed a significant decrease in sFRP3 levels in tumor compared to normal bone. RNA sequencing analysis in osteosarcoma cells shows suppression of sFRP3 and concomitant expression of multiple Wnt family members mediating canonical or non-canonical Wnt signaling. Taken together, our findings show that the systemic and local levels of sFRP3 protein are downregulated in osteosarcoma and sFRP3 levels could be explored further in the diagnosis and the care of osteosarcoma patients.

Li Q, Li Y, Li J, et al.
FBW7 suppresses metastasis of colorectal cancer by inhibiting HIF1α/CEACAM5 functional axis.
Int J Biol Sci. 2018; 14(7):726-735 [PubMed] Article available free on PMC after 20/10/2019 Related Publications
F-box and WD repeat domain-containing 7 (FBW7) functions as a major tumor suppressor by targeting oncoproteins for degradations. FBW7 has been reported to be one of the most frequently mutated genes in colorectal cancer (CRC). However, its roles and possible mechanisms in the development of CRC are still unclear. In the present study, we adopted immunohistochemistry staining in tissue microarray (TMA), consisting of 276 samples from stage I-IV CRC patients, and analyzed the correlation between FBW7 expression and clinicopathological parameters, as well as overall survival (OS) and disease-free survival (DFS). The impact of FBW7 on migration was further validated

Marimuthu M, Andiappan M, Wahab A, et al.
Canonical Wnt pathway gene expression and their clinical correlation in oral squamous cell carcinoma.
Indian J Dent Res. 2018 May-Jun; 29(3):291-297 [PubMed] Related Publications
Aim: The aim of this study is to explore the prognostic significance and clinicopathological correlations of the Wnt pathway genes in a cohort of surgically treated patients with oral squamous cell carcinoma (OSCC) patients.
Settings and Design: A prospective genetic study on patients with OSCC was carried out during the period from July 2014 to January 2016. Informed consent from patients and institutional ethical approval for the study was obtained and the guidelines were strictly followed for collection of samples.
Subjects and Methods: Clinical data and mRNA expression analysis of ten genes in the canonical Wnt pathway were evaluated and their relationships with clinical and demographic variables were studied in 58 tissue samples. Wnt-3a, β-catenin, secreted frizzled-related proteins sFRP-1, sFRP-2, sFRP-4, sFRP-5, Wnt inhibitory factor 1, dickkopf-1, c-MYC, and cyclin-D1 from cancer (n = 29) and normal (n = 29) tissue samples were investigated using quantitative reverse transcription-polymerase chain reaction.
Statistical Analysis: Descriptive statistics were used to summarize the sample characteristics and clinical variables. If the data were normal, then parametric tests were used; otherwise, nonparametric alternatives were used. All the analyses were carried out using SPSS version 23.0 (IBM SPSS Inc., USA).
Results: Expression of sFRP-1, sFRP-2, and sFRP-5 in control samples and expression of c-MYC and cyclin D1 in cancer samples showed statistical significance. Significant expression of Wnt3A was observed among patients who had recurrence and were deceased.
Conclusion: Wnt3A, β-catenin, and cyclin D1 are recognized as key components of Wnt/β-catenin signaling. However, in this study, there was no significant expression of all the three genes in OSCC. The proto-oncogene c-MYC showed statistically significant upregulation in cancer tissue samples suggesting that the OSCC among South Indian population is primarily not mediated by the canonical Wnt signaling pathway.

Saei A, Palafox M, Benoukraf T, et al.
Loss of USP28-mediated BRAF degradation drives resistance to RAF cancer therapies.
J Exp Med. 2018; 215(7):1913-1928 [PubMed] Article available free on PMC after 20/10/2019 Related Publications
RAF kinase inhibitors are clinically active in patients with BRAF (V600E) mutant melanoma. However, rarely do tumors regress completely, with the majority of responses being short-lived. This is partially mediated through the loss of negative feedback loops after MAPK inhibition and reactivation of upstream signaling. Here, we demonstrate that the deubiquitinating enzyme USP28 functions through a feedback loop to destabilize RAF family members. Loss of USP28 stabilizes BRAF enhancing downstream MAPK activation and promotes resistance to RAF inhibitor therapy in culture and in vivo models. Importantly, we demonstrate that USP28 is deleted in a proportion of melanoma patients and may act as a biomarker for response to BRAF inhibitor therapy in patients. Furthermore, we identify Rigosertib as a possible therapeutic strategy for USP28-depleted tumors. Our results show that loss of USP28 enhances MAPK activity through the stabilization of RAF family members and is a key factor in BRAF inhibitor resistance.

Liu R, Gao J, Yang Y, et al.
PHD finger protein 1 (PHF1) is a novel reader for histone H4R3 symmetric dimethylation and coordinates with PRMT5-WDR77/CRL4B complex to promote tumorigenesis.
Nucleic Acids Res. 2018; 46(13):6608-6626 [PubMed] Article available free on PMC after 20/10/2019 Related Publications
Histone post-translational modifications regulate chromatin structure and function largely through interactions with effector proteins that often contain multiple histone-binding domains. PHF1 [plant homeodomain (PHD) finger protein 1], which contains two kinds of histone reader modules, a Tudor domain and two PHD fingers, is an essential factor for epigenetic regulation and genome maintenance. While significant progress has been made in characterizing the function of the Tudor domain, the roles of the two PHD fingers are poorly defined. Here, we demonstrated that the N-terminal PHD finger of PHF1 recognizes symmetric dimethylation of H4R3 (H4R3me2s) catalyzed by PRMT5-WDR77. However, the C-terminal PHD finger of PHF1, instead of binding to modified histones, directly interacts with DDB1, the main component of the CUL4B-Ring E3 ligase complex (CRL4B), which is responsible for H2AK119 mono-ubiquitination (H2AK119ub1). We showed that PHF1, PRMT5-WDR77, and CRL4B reciprocally interact with one another and collaborate as a functional unit. Genome-wide analysis of PHF1/PRMT5/CUL4B targets identified a cohort of genes including E-cadherin and FBXW7, which are critically involved in cell growth and migration. We demonstrated that PHF1 promotes cell proliferation, invasion, and tumorigenesis in vivo and in vitro and found that its expression is markedly upregulated in a variety of human cancers. Our data identified a new reader for H4R3me2s and provided a molecular basis for the functional interplay between histone arginine methylation and ubiquitination. The results also indicated that PHF1 is a key factor in cancer progression, supporting the pursuit of PHF1 as a target for cancer therapy.

Liu Z, Liu X, Liu S, Cao Q
Cholesterol promotes the migration and invasion of renal carcinoma cells by regulating the KLF5/miR-27a/FBXW7 pathway.
Biochem Biophys Res Commun. 2018; 502(1):69-75 [PubMed] Related Publications
Clear cell renal cell carcinoma (ccRCC) is the most common and lethal subtype of renal cell carcinoma. Accumulation of cholesterol and cholesterol ester is a remarkable feature of ccRCC. However, the effect of cholesterol on ccRCC remains unknown. Out results showed that cholesterol treatment significantly promoted cells migration and invasion in ccRCC. Mechanism analysis indicated that cholesterol induced KLF5 expression. KLF5 positively regulated the transcription of miR-27a, increasing miR-27a expression. MiR-27a directly targeted FBXW7 by binding to its 3'UTR, reducing FBXW7 expression. FBXW7 silencing further increased the expression of KLF5 and miR-27a, and promoted cells migration and invasion. These results suggested that cholesterol accelerated ccRCC cells migration and invasion by regulating KLF5/miR-27a/FBXW7 axis.

Davis RJ, Gönen M, Margineantu DH, et al.
Pan-cancer transcriptional signatures predictive of oncogenic mutations reveal that Fbw7 regulates cancer cell oxidative metabolism.
Proc Natl Acad Sci U S A. 2018; 115(21):5462-5467 [PubMed] Related Publications
The Fbw7 (F-box/WD repeat-containing protein 7) ubiquitin ligase targets multiple oncoproteins for degradation and is commonly mutated in cancers. Like other pleiotropic tumor suppressors, Fbw7's complex biology has impeded our understanding of how Fbw7 mutations promote tumorigenesis and hindered the development of targeted therapies. To address these needs, we employed a transfer learning approach to derive gene-expression signatures from The Cancer Gene Atlas datasets that predict Fbw7 mutational status across tumor types and identified the pathways enriched within these signatures. Genes involved in mitochondrial function were highly enriched in pan-cancer signatures that predict Fbw7 mutations. Studies in isogenic colorectal cancer cell lines that differed in Fbw7 mutational status confirmed that Fbw7 mutations increase mitochondrial gene expression. Surprisingly, Fbw7 mutations shifted cellular metabolism toward oxidative phosphorylation and caused context-specific metabolic vulnerabilities. Our approach revealed unexpected metabolic reprogramming and possible therapeutic targets in Fbw7-mutant cancers and provides a framework to study other complex, oncogenic mutations.

Zhang G, Li S, Lu J, et al.
LncRNA MT1JP functions as a ceRNA in regulating FBXW7 through competitively binding to miR-92a-3p in gastric cancer.
Mol Cancer. 2018; 17(1):87 [PubMed] Article available free on PMC after 20/10/2019 Related Publications
BACKGROUND: Emerging evidence has shown that dysregulation function of long non-coding RNAs (lncRNAs) implicated in gastric cancer (GC). However, the role of the differentially expressed lncRNAs in GC has not fully explained.
METHODS: LncRNA expression profiles were determined by lncRNA microarray in five pairs of normal and GC tissues, further validated in another 75 paired tissues by quantitative real-time PCR (qRT-PCR). Overexpression of lncRNA MT1JP was conducted to assess the effect of MT1JP in vitro and in vivo. The biological functions were demonstrated by luciferase reporter assay, western blotting and rescue experiments.
RESULTS: LncRNA MT1JP was significantly lower in GC tissues than adjacent normal tissues, and higher MT1JP was remarkably related to lymph node metastasis and advance stage. Besides, GC patients with higher MT1JP expression had a well survival. Functionally, overexpression of lncRNA MT1JP inhibited cell proliferation, migration, invasion and promoted cell apoptosis in vitro, and inhibited tumor growth and metastasis in vivo. Functional analysis showed that lncRNA MT1JP regulated FBXW7 expression by competitively binding to miR-92a-3p. MiR-92a-3p and down-regulated FBXW7 reversed cell phenotypes caused by lncRNA MT1JP by rescue analysis.
CONCLUSION: MT1JP, a down-regulated lncRNA in GC, was associated with malignant tumor phenotypes and survival of GC. MT1JP regulated the progression of GC by functioning as a competing endogenous RNA (ceRNA) to competitively bind to miR-92a-3p and regulate FBXW7 expression. Our study provided new insight into the post-transcriptional regulation mechanism of lncRNA MT1JP, and suggested that MT1JP may act as a potential therapeutic target and prognosis biomarker for GC.

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