Gene Summary

Gene:ITCH; itchy E3 ubiquitin protein ligase
Aliases: AIF4, AIP4, ADMFD, NAPP1
Summary:This gene encodes a member of the Nedd4 family of HECT domain E3 ubiquitin ligases. HECT domain E3 ubiquitin ligases transfer ubiquitin from E2 ubiquitin-conjugating enzymes to protein substrates, thus targeting specific proteins for lysosomal degradation. The encoded protein plays a role in multiple cellular processes including erythroid and lymphoid cell differentiation and the regulation of immune responses. Mutations in this gene are a cause of syndromic multisystem autoimmune disease. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Mar 2012]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:E3 ubiquitin-protein ligase Itchy homolog
Source:NCBIAccessed: 29 August, 2019


What does this gene/protein do?
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Pathways:What pathways are this gene/protein implicaed in?
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Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 29 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 29 August, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (6)

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: ITCH (cancer-related)

Wang S, Wu Y, Xu Y, Tang X
miR-10b promoted melanoma progression through Wnt/β-catenin pathway by repressing ITCH expression.
Gene. 2019; 710:39-47 [PubMed] Related Publications
Dysregulation of microRNAs (miRNAs) have been reported to contribute to malignant progression in melanoma. However, the roles and mechanisms of several miRNAs in melanoma remain poorly understood. In our study, we showed that miR-10b was significantly up-regulated in melanoma tissues and cell lines, and was associated with overall survival of melanoma patients. Inhibition of miR-10b dramatically suppressed melanoma cell proliferation, migration and invasion in vitro and inhibited tumor growth in vivo. Moreover, we defined ITCH as a direct and functional downstream target of miR-10b, and showed that there was an inverse correlation between the expression of ITCH and miR-10b on melanoma tissues. Down-regulation of ITCH partially attenuated the inhibitory effects of miR-10b inhibition on melanoma cell proliferation, migration and invasion. Furthermore,we found that miR-10b exerted its effects on melanoma by regulating the Wnt/β-catenin pathway. Taken together, our results demonstrated that miR-10b was an important epigenetic modifier, promoting melanoma progression through regulating ITCH/Wnt/β-catenin pathway. These results offer a new strategy for epigenetic cancer therapy.

Ghasemi S, Emadi-Baygi M, Nikpour P
Down-regulation of circular RNA ITCH and circHIPK3 in gastric cancer tissues
Turk J Med Sci. 2019; 49(2):687-695 [PubMed] Related Publications
Background/aim: Gastric cancer (GC) is one of the major causes of cancer mortality worldwide. As a novel type of endogenous noncoding RNAs, circular RNAs (circRNAs) are formed by a covalent link between 5’ and 3’ ends. They are very stable and abundant in eukaryotes. As there were no reported studies on the expression profiles of circular RNA ITCH (cir-ITCH) and circHIPK3 in GC, in the current study, we aimed to delineate the expression profiles and clinicopathological relevance of these two circRNAs in GC tissues compared to their paired adjacent noncancerous tissues.
Materials and methods: Quantitative real-time polymerase chain reaction was performed to evaluate cir_ITCH and circHIPK3 expression in 30 paired gastric cancer tissues. The clinicopathological relevance of these two circular RNAs’ expression levels with gastric cancer was further examined.
Results: Our results showed that the expression of cir_ITCH and circHIPK3 were significantly downregulated in GC tumoral tissues compared with their paired adjacent nonneoplastic counterparts. Further analyses showed that cir_ITCH and circHIPK3 expression levels were related with numerous clinicopathological features of tumoral tissues.
Conclusion: Cir_ITCH and circHIPK3 may have imperative roles in GC and serve in the future as potential prognostic biomarkers in GC.

Li M, An W, Xu L, et al.
The arginine methyltransferase PRMT5 and PRMT1 distinctly regulate the degradation of anti-apoptotic protein CFLAR
J Exp Clin Cancer Res. 2019; 38(1):64 [PubMed] Free Access to Full Article Related Publications
METHODS: Lung cancer cells were cultured following the standard protocol and the cell lysates were prepared to detect the given proteins by Western Blot analysis, and the protein interaction was assayed by co-immunoprecipitation (Co-IP) or GST pull-down assay. CFLAR
RESULTS: We show that PRMT5 up-regulated the protein levels of CFLAR
CONCLUSIONS: PRMT5 and PRMT1 mediate the distinct effects on CFLAR

Luo L, Gao Y, Sun X
Circ-ITCH correlates with small tumor size, decreased FIGO stage and prolonged overall survival, and it inhibits cells proliferation while promotes cells apoptosis in epithelial ovarian cancer.
Cancer Biomark. 2018; 23(4):505-513 [PubMed] Related Publications
OBJECTIVE: The aim of this study was to evaluate the correlation of circular RNA itchy E3 ubiquitin protein ligase (Circ-ITCH) expression with clinicopathological features and survival in patients with epithelial ovarian cancer (EOC), and to explore its effect on cells proliferation as well as apoptosis in EOC cells.
METHODS: Seventy-seven EOC patients underwent surgery were retrospectively reviewed. Tumor tissues and paired adjacent tissues samples were collected, and Circ-ITCH expression was evaluated by quantitative polymerase chain reaction (qPCR). Blank mimic, Circ-ITCH mimic, blank inhibitor and Circ-ITCH inhibitor plasmids were transfected into SKOV3 cells and OVCAR-3 cells, and Counting Kit-8 (CCK-8) was performed to assess cells proliferation and Annexin V (AV)/propidium iodide (PI) was conducted to detect cells apoptosis.
RESULTS: Median value of Circ-ITCH relative expression was 0.697 (0.367-1.106) in tumor tissues, which was lower compared with paired adjacent tissues (1.690 (0.867-2.813)) (P< 0.001), and it negatively correlated with tumor size (P= 0.005) as well as International Federation of Gynecology and Obstetrics (FIGO) stage (P< 0.001) in EOC patients. Multivariate Cox's analysis revealed that high Circ-ITCH expression was an independent predictive factor for favorable OS in EOC patients. Moreover, further in vitro experiments disclosed that Circ-ITCH expression was decreased in several EOC cell lines compared with normal ovarian epithelial cell line, and it inhibited cells proliferation while promoted cells apoptosis in SKOV3 and OVCAR-3 cells.
CONCLUSIONS: Circ-ITCH correlates with small tumor size, decreased FIGO stage and prolonged OS, and it inhibits cells proliferation while promotes cells apoptosis in EOC.

Hu J, Wang L, Chen J, et al.
The circular RNA circ-ITCH suppresses ovarian carcinoma progression through targeting miR-145/RASA1 signaling.
Biochem Biophys Res Commun. 2018; 505(1):222-228 [PubMed] Related Publications
As the leading cause of death for gynecological cancers, ovarian cancer (OC) ranks fifth overall for cancer-related death among women. Emerging evidence has indicated that circular RNA (circRNA), recognized as functional non-coding transcripts in eukaryotic cells, may be involved in many physiological or pathological processes. It was reported that circ-ITCH is downregulated in multi cancers and serves as a powerful tumor suppressor among through a competing endogenous RNA (ceRNA) pathway. However, the existence and the role of circ-ITCH in OC was not reported. Here, we found a broad down-regulation of circ-ITCH in OC tissues and cells, which correlates with a worse prognosis in OC patients. Functional studies suggest that circ-ITCH overexpression inhibits the cell viability and motility by CCK8, cell cycle, wound healing assay and invasion assay. It also inhibits the tumorigenesis ability in xenograft NOD mice in vivo. Mechanically, we demonstrated that circ-TCH acts as a ceRNA to sponge miR-145, increases the level of RASA1, and inhibits the malignant progression of OC cells via the circ-ITCH-miR-145-RASA1 axis in vitro and in vivo. Taken together, our findings provide a novel tumor suppressive role regarding circ-ITCH function in the malignant progression of OC.

Zhang C, Kang Y, Ma R, et al.
Expression of Numb and Gli1 in malignant pleural mesothelioma and their clinical significance.
J Cancer Res Ther. 2018 Jul-Sep; 14(5):970-976 [PubMed] Related Publications
Aim of Study: Malignant pleural mesothelioma (MPM) is a highly lethal and refractory to multimodal treatment tumor. Numb is considered as a tumor suppressor playing critical roles in determining cell fate and has been shown to target the oncogenic transcription factor Gli1 for Itch-dependent ubiquitination, resulting in suppression of the oncogenic sonic hedgehog signaling in medulloblastoma. This study was designed to analysis the role of Numb and Gli1 in MPM.
Materials and Methods: Tissues of 61 MPM patients and 22 normal pleura as control were investigated. Numb and Gli1 expression were evaluated by immunohistochemistry. The associations with clinical and pathological parameters of the two markers were statistically analyzed, and the correlation between them was also demonstrated.
Results: The expression levels of Numb with nuclear Gli1 exhibited a significant inverse correlation (r = -0.361 P < 0.05). In addition, Numb has an inverse correlation with ki-67 labeling index (P < 0.05), and nuclear Gli1 was found in associated with the tumor International Mesothelioma Interest Group-stage (P < 0.05). The overall survival was influenced by the expression of Numb (P < 0.05) and histological subtype (P < 0.05), further regression analysis showed that only histological subtype has a prognostic influence on survival (P < 0.05).
Conclusion: The results provide new evidence of Numb and Gli1 on the clinical characteristics of MPM, which may be helpful in clinical diagnosis and targeted therapy. Further research with larger sample size is needed.

Aung KL, El-Khoueiry AB, Gelmon K, et al.
A multi-arm phase I dose escalating study of an oral NOTCH inhibitor BMS-986115 in patients with advanced solid tumours.
Invest New Drugs. 2018; 36(6):1026-1036 [PubMed] Related Publications
Background Inhibiting Notch is a promising anti-cancer strategy as it plays a critical role in cancer stem cells maintenance and tumour angiogenesis. BMS-986115 is an orally active, selective inhibitor of gamma-secretase mediated Notch signalling. Method Two dose escalation schedules (Arm-A continuous daily schedule and Arm-B intermittent 2 times weekly schedule) of BMS-986115 were evaluated in advanced solid tumour patients. The primary objective was to establish the safety, tolerability and Maximum Tolerated Dose (MTD) of BMS-986115. Results Thirty six patients (24 in Arm A and 12 in Arm B) were treated. The most frequent treatment related adverse advents were diarrhoea (72%), hypophosphataemia (64%), and nausea (61%). The MTD was 1.5 mg daily in Arm A but not established in Arm B. Four patients in Arm A and 2 in Arm B experienced dose limiting toxicities (grade 3 nausea, diarrhoea, pruritus/urticaria and ileus). BMS-986115 showed dose related increase in exposure within the dose range tested. Target inhibition of Notch pathway related genes was observed. Three patients in Arm A and 2 in Arm B achieved stable disease for more than 6 months. Conclusion The daily oral dosing of BMS-986115 is safe and tolerable with biological activity demonstrated by continuous target engagement and Notch signalling inhibition.

Lacouture ME, Anadkat M, Jatoi A, et al.
Dermatologic Toxicity Occurring During Anti-EGFR Monoclonal Inhibitor Therapy in Patients With Metastatic Colorectal Cancer: A Systematic Review.
Clin Colorectal Cancer. 2018; 17(2):85-96 [PubMed] Related Publications
Monoclonal antibody inhibitors of the epidermal growth factor receptor (EGFR) have been shown to improve outcomes for patients with metastatic colorectal cancer (mCRC) without RAS gene mutations. However, treatment with anti-EGFR agents can be associated with toxicities of the skin, nails, hair, and eyes. Because these dermatologic toxicities can result in treatment discontinuation and affect patient quality of life, their management is an important focus when administering anti-EGFR monoclonal antibodies. The present systematic review describes the current data reporting the nature and incidence of, and management and treatment options for, dermatologic toxicities occurring during anti-EGFR treatment of mCRC. A search of the National Library of Medicine PubMed database from January 1, 2009, to August 18, 2016, identified relevant reports discussing dermatologic toxicity management among patients with mCRC receiving anti-EGFR therapy. The studies were grouped by type and rated by level of evidence using the GRADE approach developed by the Agency for Healthcare Research and Quality. Overall, 269 reports were reviewed (nonrandomized trials, n = 120; randomized trials, n = 31; retrospective studies, n = 15; reviews, n = 39). Dermatologic toxicity of any grade occurs in most patients who receive anti-EGFR therapy; approximately 10% to 20% of patients experienced grade 3/4 toxicity. The most common dermatologic toxicities include papulopustular/acneiform rash, xerosis, and pruritus; however, nail changes, hair abnormalities, and ocular conditions also occur. Guidance for managing these toxicities includes the use of inexpensive emollient ointments and moisturizers, avoidance of sun exposure, avoidance of irritants, and the use of short showers. Several studies also found that preemptive treatment was more effective than reactive treatment at limiting the incidence and severity of skin toxicity. With appropriate treatment, the dermatologic toxicities associated with anti-EGFR monoclonal antibody therapy can be managed, minimizing patient discomfort and the need for therapy interruption and/or discontinuation. Additionally, preemptive treatment can reduce dermatologic toxicity severity, ultimately yielding better quality of life.

Herr DR, Ong JH, Ong WY
Potential Therapeutic Applications for Inhibitors of Autotaxin, a Bioactive Lipid-Producing Lysophospholipase D, in Disorders Affecting the Nervous System.
ACS Chem Neurosci. 2018; 9(3):398-400 [PubMed] Related Publications
Autotaxin is a dual-function ecto-enzyme, encoded by the gene ENPP2, which is the primary source of the bioactive signaling lipid, lysophosphatidic acid. Aberrations in autotaxin/lysophosphatidic acid signaling have been associated with a number of neurological, psychiatric, neoplastic, and neurodevelopmental conditions, such as pain, pruritus, glioblastoma multiforme, multiple sclerosis, Alzheimer's disease, hydrocephalus, and schizophrenia. This Viewpoint offers a brief overview of the likely indications for therapeutic targeting of autotaxin, in disorders affecting the nervous system.

Yang C, Yuan W, Yang X, et al.
Circular RNA circ-ITCH inhibits bladder cancer progression by sponging miR-17/miR-224 and regulating p21, PTEN expression.
Mol Cancer. 2018; 17(1):19 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Circ-ITCH is a circRNA generated from several exons of itchy E3 ubiquitin protein ligase (ITCH) and tumor suppressor served as a sponge for certain miRNAs targeting their parental transcripts of ITCH. However, the role of circ-ITCH in bladder cancer (BCa) was not reported. In the present study, we investigated the role of circ-ITCH in BCa.
METHODS: Quantitative real-time PCR was used to detect the expression of circ-ITCH and survival analysis was adopted to explore the association between circ-ITCH expression and the prognosis of BCa. BCa cells were stably transfected with lentivirus approach and cell proliferation, migration, invasion, cell cycle and cell apoptosis, as well as tumorigenesis in nude mice were performed to assess the effect of circ-ITCH in BCa. Biotin-coupled probe pull down assay, Biotin-coupled miRNA capture, Fluorescence in situ hybridization and Luciferase reporter assay were conducted to confirm the relationship between the circ-ITCH and the microRNA.
RESULTS: In the present study, we found that circ-ITCH, is down-regulated in BCa tissues and cell lines. BCa patients with low circ-ITCH expression had shortened survival. Enforced- expression of circ-ITCH inhibited cells proliferation, migration, invasion and metastasis both in vitro and in vivo. Mechanistically, we demonstrated that circ-ITCH up-regulates the expression of miR-17 and miR-224 target gene p21 and PTEN through 'sponging' miR-17 and miR-224, which suppressed the aggressive biological behaviors of BCa.
CONCLUSIONS: circ-ITCH acts as a tumor suppressor by a novel circ-ITCH/miR-17, miR-224/p21, PTEN axis, which may provide a potential biomarker and therapeutic target for the management of BCa.

Pal A, Dziubinski M, Di Magliano MP, et al.
Usp9x Promotes Survival in Human Pancreatic Cancer and Its Inhibition Suppresses Pancreatic Ductal Adenocarcinoma In Vivo Tumor Growth.
Neoplasia. 2018; 20(2):152-164 [PubMed] Free Access to Full Article Related Publications
Usp9x has emerged as a potential therapeutic target in some hematologic malignancies and a broad range of solid tumors including brain, breast, and prostate. To examine Usp9x tumorigenicity and consequence of Usp9x inhibition in human pancreatic tumor models, we carried out gain- and loss-of-function studies using established human pancreatic tumor cell lines (PANC1 and MIAPACA2) and four spontaneously immortalized human pancreatic patient-derived tumor (PDX) cell lines. The effect of Usp9x activity inhibition by small molecule deubiquitinase inhibitor G9 was assessed in 2D and 3D culture, and its efficacy was tested in human tumor xenografts. Overexpression of Usp9x increased 3D growth and invasion in PANC1 cells and up-regulated the expression of known Usp9x substrates Mcl-1 and ITCH. Usp9x inhibition by shRNA-knockdown or by G9 treatment reduced 3D colony formation in PANC1 and PDX cell lines, induced rapid apoptosis in MIAPACA2 cells, and associated with reduced Mcl-1 and ITCH protein levels. Although G9 treatment reduced human MIAPACA2 tumor burden in vivo, in mouse pancreatic cancer cell lines established from constitutive (8041) and doxycycline-inducible (4668) KrasG12D/Tp53R172H mouse pancreatic tumors, Usp9x inhibition increased and sustained the 3D colony growth and showed no significant effect on tumor growth in 8041-xenografts. Thus, Usp9x inhibition may be therapeutically active in human PDAC, but this activity was not predicted from studies of genetically engineered mouse pancreatic tumor models.

Tian F, Yu CT, Ye WD, Wang Q
Cinnamaldehyde induces cell apoptosis mediated by a novel circular RNA hsa_circ_0043256 in non-small cell lung cancer.
Biochem Biophys Res Commun. 2017; 493(3):1260-1266 [PubMed] Related Publications
Cinnamaldehyde (CA), the primary chemical component of the Chinese traditional herb Cinnamomum cassia, is an effective cytotoxic agent against various human cancers. Our previous study indicated that CA could trigger apoptosis in three kinds of non-small cell lung cancer (NSCLC) cells. However, CA mechanism of action in NSCLC has not been unveiled completely. Herein, we showed that a novel circular RNA hsa_circ_0043256 was upregulated in NSCLC cells in response to CA treatment, as detected by microarray and real-time PCR. Hsa_circ_0043256 could inhibit cell proliferation and induce apoptosis, while hsa_circ_0043256 knock-down could promote cell proliferation and restrain apoptosis induced by CA. Bioinformatics analysis predicted that hsa_circ_0043256 could work as a miR-1252 sponge, which could in turn directly target a vital negative regulator of Canonical Wnt signaling, Itchy E3 ubiquitin protein ligase (ITCH), as validated by dual-luciferase assay. Western blot results further confirmed that hsa_circ_0043256 could upregulate ITCH expression, whereas miR-1252 could partially abolish this effect. Interestingly, hsa_circ_0043256 knock-down could weaken Wnt/β-catenin pathway inhibition induced by CA. Finally, we discovered that CA induced apoptosis and meanwhile upregulated hsa_circ_0043256 expression in vivo. Immunohistochemical analysis revealed that ITCH expression was positively association with hsa_circ_0043256 levels. Above all, we characterized a new mechanism mediated by hsa_circ_0043256/miR-1252/ITCH axis in CA function against NSCLC, providing a novel insight into lung cancer therapy.

Kim TM, Lee KW, Oh DY, et al.
Phase 1 Studies of Poziotinib, an Irreversible Pan-HER Tyrosine Kinase Inhibitor in Patients with Advanced Solid Tumors.
Cancer Res Treat. 2018; 50(3):835-842 [PubMed] Free Access to Full Article Related Publications
Purpose: Poziotinib, a pan-human epidermal growth factor receptor 2 (HER) tyrosine kinase inhibitor, has shown potent activity againstwild type of epidermal growth factorreceptor(EGFR) family kinases including EGFR, HER2, and HER4 and EGFR-mutant cells in vitro. Two phase I studies were conducted to determine the maximum tolerated dose (MTD), pharmacokinetics, safety, and antitumor activity against advanced solid tumors.
Materials and Methods: Standard 3+3 dose escalation scheme using two different dosing schedules were studied: once daily, 14-day on, and 7-day off (intermittent schedule); and once daily continuous dosing with food effect. Additional patients were enrolled in an expansion cohort.
Results: A total of 75 patients were enrolled in the two studies. The most common drug-related treatment-emergent adverse eventswere diarrhea,rash, stomatitis, pruritus, and anorexia. Doselimiting toxicities were grade 3 diarrhea in the intermittent schedule and grade 3 anorexia and diarrhea in the continuous dosing schedule. The MTDs were determined as 24 mg/day in the intermittent dosing schedule and 18 mg/day in the continuous dosing schedule. Eight (16%) and 24 (47%) of 51 evaluable patients in the intermittent schedule achieved partial response (PR) and stable disease (SD), respectively. Four (21%) and six (32%) of 19 evaluable patients in continuous dosing schedule achieved PR and SD, respectively. Patients with PR (n=7) or SD ≥ 12 weeks (n=7) had HER2 amplification (n=7; breast cancer, 5; and stomach cancer, 2) and EGFR amplification (n=1, squamous cell lung cancer).
Conclusion: Poziotinib was safe and well tolerated in patients with advanced solid tumors. It showed an encouraging activity against EGFR-mutant and HER2-amplified cancers.

Komi DEA, Rambasek T, Wöhrl S
Mastocytosis: from a Molecular Point of View.
Clin Rev Allergy Immunol. 2018; 54(3):397-411 [PubMed] Free Access to Full Article Related Publications
Mast cells (MCs) are physiologically activated by binding of stem cell factor (SCF) to the extracellular domains of the Kit receptor. This binding increases the proliferation and prolongs the survival of normal mature MCs, as well as intensifies the release of mediators. In mastocytosis, somatic mutations of the coding Kit gene cause autocrine dysregulation and lead to constitutive KIT activation even in the absence of its ligand SCF. Clinical symptoms are caused by MC-mediator release and/or infiltration of MCs into tissues. Aberrant KIT activation may result in increased production of MCs in the skin and extracutaneous organs. Depending on the affected organ(s), the disease can be divided into cutaneous mastocytosis (CM), systemic mastocytosis (SM), and localized MC tumors. The updated classification of WHO discriminates between several distinct subvariants of CM and SM. While the prognosis in CM and indolent SM (ISM) is excellent with (almost) normal life expectancy, the prognosis in aggressive SM (ASM) and MC leukemia (MCL) is dismal. The symptoms may comprise urticaria, angioedema, flush, pruritus, abdominal pain, diarrhea, hypotension, syncope, and musculoskeletal pain and are the results of MC infiltration and mediator release into target organs, i.e., the skin, gastrointestinal tract, liver, spleen, lymph nodes, and bone marrow. Mastocytosis differs from a lot of other hematological disorders because its pathology is not only based on the lack of normal function of a specific pathway or of a specific cell type but additionally is a proliferative disease. Currently available treatments of mastocytosis include symptomatic, antimediator and cytoreductive targeted therapies.

Guo W, Zhang J, Zhang D, et al.
Polymorphisms and expression pattern of circular RNA circ-ITCH contributes to the carcinogenesis of hepatocellular carcinoma.
Oncotarget. 2017; 8(29):48169-48177 [PubMed] Free Access to Full Article Related Publications
Hepatocellular carcinoma (HCC) ranks the sixth most common cancer and the third cause of cancer-related mortality worldwide. Recent studies identified that circ-ITCH Suppresses mutiple cancers proliferation via inhibiting the Wnt/beta-Catenin pathway. In current study, conducted a genetic association study together with epidemiological follow-up study to delineate the role of circ-ITCH in the development and progression of HCC. we found rs10485505 (adjusted OR =1.18; 95% CI=1.06-1.31; P value =3.1×10-3) and rs4911154 (adjusted OR =1.27; 95% CI=1.14-1.43; P value =3.7×10-5) were significantly associated with increased HCC risk. The expression level of circ-ITCH was significantly lower in HCC tissues, compared with that in adjacent tissues (P value < 0.001). Cox regression analysis indicated that high expression of circ-ITCH was associated with favorable survival of HCC (HR=0.45; 95% CI=0.29-0.68; P value < 0.001). These results indicate that circ-ITCH may have an inhibitory effect on HCC, and could serve as susceptibility and prognostic biomarkers for HCC patients.

Golhar A, Ray S, Haugk B, Singhvi SK
Cytogenetically confirmed primary Ewing's sarcoma of the pancreas.
BMJ Case Rep. 2017; 2017 [PubMed] Free Access to Full Article Related Publications
Ewing's sarcoma is a highly aggressive malignant tumour most commonly affecting long bones in children and adolescents. It is part of the Ewing's sarcoma family of tumours (ESFTs) that also include peripheral primitive neuroectodermal tumour and Askin's tumours. ESFTs share common cytogenetic aberrations, antigenic profiles and proto-oncogene expression with an overall similar clinical course. In 99% of ESFTs, genetic translocation with molecular fusion involves the EWSR1 gene on 22q12. Approximately 30% of ESFTs are extraosseous, most commonly occurring in the soft tissues of extremities, pelvis, retroperitoneum and chest wall. Primary presentation in solid organs is very rare but has been described in multiple sites including the pancreas. Accurate diagnosis of a Ewing's sarcoma in a solid organ is critical in facilitating correct treatment. We report the case of a 17-year-old girl with cytogenetically confirmed primary pancreatic Ewing's sarcoma and provide a brief review of the published literature.

Tsui YM, Sze KM, Tung EK, et al.
Dishevelled-3 phosphorylation is governed by HIPK2/PP1Cα/ITCH axis and the non-phosphorylated form promotes cancer stemness via LGR5 in hepatocellular carcinoma.
Oncotarget. 2017; 8(24):39430-39442 [PubMed] Free Access to Full Article Related Publications
Dishevelled-3 (Dvl3) is regarded as a binding hub with many different interacting partners. However, its regulation and mechanism on cancer stemness remain to be explored. In this study, we showed that Dvl3 was significantly overexpressed in human hepatocellular carcinomas (HCCs) and promoted cancer stemness both in vitro and in vivo. We found that the non-phosphorylated (NP)-Dvl3 was more stable than the phosphorylated form, more active in activating β-catenin transcriptional activity, and more potent in enhancing self-renewal ability in HCC cells. Mechanistically, we confirmed that the homeodomain-interacting protein kinase-2 (HIPK2) and E3 ubiquitin ligase ITCH were able to physically bind to Dvl3 protein. Knockdown of HIPK2 and the protein phosphatase regulatory unit C-alpha (PP1Cα) resulted in sustained Dvl3 phosphorylation and hence decrease in the NP form of Dvl3. On the other hand, knockdown of E3 ubiquitin ligase ITCH reduced the phosphorylation-induced degradation and stabilized the phosphorylated Dvl3 protein. Furthermore, the NP-Dvl3 enhanced the LGR5 promoter activity to upregulate LGR5 expression, which was associated with increased cancer stemness in HCC. Our findings established that HIPK2/PP1Cα/ITCH axis sustains the de-phosphorylation of Dvl3. This post-translational modification of Dvl3 in turn maintains LGR5 expression and enhances the cancer stemness properties in HCC.

Kim Y, Kim W, Song Y, et al.
Deubiquitinase YOD1 potentiates YAP/TAZ activities through enhancing ITCH stability.
Proc Natl Acad Sci U S A. 2017; 114(18):4691-4696 [PubMed] Free Access to Full Article Related Publications
Hippo signaling controls the expression of genes regulating cell proliferation and survival and organ size. The regulation of core components in the Hippo pathway by phosphorylation has been extensively investigated, but the roles of ubiquitination-deubiquitination processes are largely unknown. To identify deubiquitinase(s) that regulates Hippo signaling, we performed unbiased siRNA screening and found that YOD1 controls biological responses mediated by YAP/TAZ. Mechanistically, YOD1 deubiquitinates ITCH, an E3 ligase of LATS, and enhances the stability of ITCH, which leads to reduced levels of LATS and a subsequent increase in the YAP/TAZ level. Furthermore, we show that the miR-21-mediated regulation of YOD1 is responsible for the cell-density-dependent changes in YAP/TAZ levels. Using a transgenic mouse model, we demonstrate that the inducible expression of YOD1 enhances the proliferation of hepatocytes and leads to hepatomegaly in a YAP/TAZ-activity-dependent manner. Moreover, we find a strong correlation between YOD1 and YAP expression in liver cancer patients. Overall, our data strongly suggest that YOD1 is a regulator of the Hippo pathway and would be a therapeutic target to treat liver cancer.

Fernández-Mateos J, Seijas-Tamayo R, Mesía R, et al.
Epidermal growth factor receptor (EGFR) pathway polymorphisms as predictive markers of cetuximab toxicity in locally advanced head and neck squamous cell carcinoma (HNSCC) in a Spanish population.
Oral Oncol. 2016; 63:38-43 [PubMed] Related Publications
OBJECTIVES: To examine the relationship between polymorphisms of the epidermal growth factor receptor (EGFR) pathway and toxicity in head and neck squamous cell carcinoma (HNSCC) patients treated with cetuximab.
MATERIAL AND METHODS: Multicenter, retrospective, observational pilot study which included 110 patients with histologically-confirmed human papillomavirus (HPV) negative HNSCC in locally advanced stages (III-IVA-B) and who were treated with chemotherapy and radiotherapy plus cetuximab between 2003 and 2013. Genetic analyses for single nucleotide polymorphisms (SNP) in genes EGFR, CCDN1, FCGR2A, FCGR3A and KRAS-LCS6 were performed though available allelic discrimination assay and/or polymerase chain reaction-restriction fragment length polymorphism methods.
RESULTS: Acneiform rash was observed in 55.5% of patients, dry skin in 45.5% and pruritus in 20.9%. A significant association with dry skin and global cetuximab-related toxicity was observed for the KRAS-LCS6 (rs61764370) variant (p<0.05); carriers of the G allele (genotypes TG+GG) in the dominant model were observed to have a decreased susceptibility of developing dry skin (OR=0.287 [95%CI=0.119-0.695]). Carriers of the A (GA+AA) allele for EGFR (rs2227983) showed a decreased risk of suffering from pruritus (OR=0.345 [0.124-0.958]). Similarly, KRAS (rs1801274) was related with lower global cetuximab-related toxicity (OR=0.266 [0.114-0.622]).
CONCLUSION: This pilot study provides preliminary evidence supporting genetic variation of EGFR (rs2227983), KRAS (rs61764370) and FCGR2A (rs180127) as useful biomarkers for predicting reduced skin toxicity in HNSCC patients treated with a cetuximab-based therapy. Alternative therapeutic options should be explored for these patients.

Wan L, Zhang L, Fan K, et al.
Circular RNA-ITCH Suppresses Lung Cancer Proliferation via Inhibiting the Wnt/β-Catenin Pathway.
Biomed Res Int. 2016; 2016:1579490 [PubMed] Free Access to Full Article Related Publications
As a special form of noncoding RNAs, circular RNAs (circRNAs) played important roles in regulating cancer progression mainly by functioning as miRNA sponge. While the function of circular RNA-ITCH (cir-ITCH) in lung cancer is still less reported, in this study, we firstly detected the expression of cir-ITCH in tumor tissues and paired adjacent noncancer tissues of 78 patients with lung cancer using a TaqMan-based quantitative real-time PCR (qRT-PCR). The results showed that the expression of cir-ITCH was significantly decreased in lung cancer tissues. In cellular studies, cir-ITCH was also enhanced in different lung cancer cell lines, A549 and NIC-H460. Ectopic expression of cir-ITCH markedly elevated its parental cancer-suppressive gene, ITCH, expression and inhibited proliferation of lung cancer cells. Molecular analysis further revealed that cir-ITCH acted as sponge of oncogenic miR-7 and miR-214 to enhance ITCH expression and thus suppressed the activation of Wnt/β-catenin signaling. Altogether, our results suggested that cir-ITCH may play an inhibitory role in lung cancer progression by enhancing its parental gene, ITCH, expression.

Shah NN, Loeb DM, Khuu H, et al.
Induction of Immune Response after Allogeneic Wilms' Tumor 1 Dendritic Cell Vaccination and Donor Lymphocyte Infusion in Patients with Hematologic Malignancies and Post-Transplantation Relapse.
Biol Blood Marrow Transplant. 2016; 22(12):2149-2154 [PubMed] Related Publications
Relapse of hematologic malignancies is the primary cause of treatment failure after allogeneic hematopoietic stem cell transplantation (HCT). Treatment for post-HCT relapse using donor lymphocyte infusion (DLI) has limited utility, particularly in the setting of acute leukemia, and can result in the development of graft-versus-host disease (GVHD). The Wilms' tumor 1 (WT1) gene product is a tumor-associated antigen that is expressed in acute leukemia and other hematologic malignancies, with limited expression in normal tissues. In this pilot trial, we assessed safety and feasibility of a WT1 peptide-loaded donor-derived dendritic cell (DC) vaccine given with DLI designed to enhance and direct the graft-versus-leukemia effect. Secondary objectives were to evaluate immunologic and clinical responses. A total of 5 subjects, median age 17 years (range, 9 to 19 years), with post-HCT relapse were enrolled. Disease subtypes included acute lymphoblastic leukemia (n = 3), acute myelogenous leukemia (n = 1), and Hodgkin lymphoma (n = 1). Successful vaccine production was feasible from all donors. DC vaccination and DLI were well tolerated. One recipient developed grade 1 skin GVHD not requiring systemic therapy. The most common adverse events included grade 1 reversible pain and pruritus at the vaccine injection and delayed-type hypersensitivity (DTH) skin testing sites. There were no grade 3 or higher adverse events related to the research. Immune responses consisted of ELISpot response in 3 recipients and positive DTH tests to WT1 peptide cocktail in 2 subjects. Our study provides 1 of the first attempts to apply tumor-specific vaccine therapy to the allogeneic setting. Preliminary results show the DC-based vaccination is safe and feasible after allogeneic HCT, with a suggestion that this approach can be used to sensitize the repopulated allogeneic-donor immune system to WT1. Future directions may include testing of vaccination strategies in the early post-transplantation setting for relapse prevention.

Nikolaou V, Papadavid E, Patsatsi A, et al.
Prognostic indicators for mycosis fungoides in a Greek population.
Br J Dermatol. 2017; 176(5):1321-1330 [PubMed] Related Publications
BACKGROUND: Mycosis fungoides (MF) is an indolent cutaneous lymphoma with excellent prognosis at early stages and much poorer outcome during disease progression. Old age, male sex and folliculotropism have been proposed as relevant prognostic factors; however, their exact effect remains debatable.
OBJECTIVES: To evaluate MF prognostic indicators and survival rates in a Greek population.
METHODS: Prognostic variables affecting survival rates were studied in 473 patients with MF diagnosed and treated by two academic referral centres in Greece. Kaplan-Meier estimates were used to determine survival rates and progression. The Cox proportional hazards regression model was used to assess prognostic factors.
RESULTS: The mean age of diagnosis was 61·7 years (SD 16·33). Five-year disease-specific survival was 96% in patients with stage IA disease and 52% in patients with stage IIB disease. Univariate analysis certified that large-cell transformation, clonal rearrangements of the TCR gene, severe pruritus and presence of plaques were the most important prognostic factors. Folliculotropism altered disease progression only in patients with early-stage disease. The application of the Cutaneous Lymphoma International Prognostic Index (CLIPI) on our late-stage group failed to provide reliable evidence. The current Cutaneous Lymphoma International Consortium (CLIC) prognostic index can efficiently distinguish a low-risk from a high-risk group of patients. Tumour-Node-Metastasis-Blood (TNMB) staging was the most important prognostic factor for survival rates in multivariate analysis.
CONCLUSIONS: In our study we validated the current prognostic indicators for MF in a Greek population and identified new potential prognostic factors for survival outcome. Our findings contribute to the ongoing investigation of prognostic indicators of MF, further validation of which is highly needed through prospective studies and among different populations.

Lin Z, Chen X, Li Z, et al.
PD-1 Antibody Monotherapy for Malignant Melanoma: A Systematic Review and Meta-Analysis.
PLoS One. 2016; 11(8):e0160485 [PubMed] Free Access to Full Article Related Publications
Antibodies targeting programmed death 1 (PD-1) help prevent tumor cells from escaping immune-mediated destruction. We conducted this systematic review and meta-analysis to gain insight into the efficacy of PD-1 antibodies for the treatment of melanoma. Five trials involving 2,828 adult patients were included in this meta-analysis. In patients with previously untreated or refractory melanoma, treatment with PD-1 antibodies significantly improved the six-month progression-free survival (PFS) (HR 0.55, 95% CI 0.50-0.60, P<0.00001) and the overall response rate (OR 3.89, 95% CI 3.12-4.83, P<0.00001). This meta-analysis indicated that anti-PD-1 treatment might provide a significant survival benefit in patients with melanoma. In addition, we found that patients treated with nivolumab reported significantly fewer treatment-related adverse events (OR 0.74, 95% CI 0.57-0.97, P = 0.03) than those treated with other agents, but there was a dose-dependent increase in the frequency of adverse events in patients treated with pembrolizumab.

Pefani DE, Pankova D, Abraham AG, et al.
TGF-β Targets the Hippo Pathway Scaffold RASSF1A to Facilitate YAP/SMAD2 Nuclear Translocation.
Mol Cell. 2016; 63(1):156-66 [PubMed] Related Publications
Epigenetic inactivation of the Hippo pathway scaffold RASSF1A is associated with poor prognosis in a wide range of sporadic human cancers. Loss of expression reduces tumor suppressor activity and promotes genomic instability, but how this pleiotropic biomarker is regulated at the protein level is unknown. Here we show that TGF-β is the physiological signal that stimulates RASSF1A degradation by the ubiquitin-proteasome pathway. In response to TGF-β, RASSF1A is recruited to TGF-β receptor I and targeted for degradation by the co-recruited E3 ubiquitin ligase ITCH. RASSF1A degradation is necessary to permit Hippo pathway effector YAP1 association with SMADs and subsequent nuclear translocation of receptor-activated SMAD2. We find that RASSF1A expression regulates TGF-β-induced YAP1/SMAD2 interaction and leads to SMAD2 cytoplasmic retention and inefficient transcription of TGF-β targets genes. Moreover, RASSF1A limits TGF-β induced invasion, offering a new framework on how RASSF1A affects YAP1 transcriptional output and elicits its tumor-suppressive function.

Lange M, Gleń J, Zabłotna M, et al.
Interleukin-31 Polymorphisms and Serum IL-31 Level in Patients with Mastocytosis: Correlation with Clinical Presen-tation and Pruritus.
Acta Derm Venereol. 2017; 97(1):47-53 [PubMed] Related Publications
Data on interleukin-31 (IL-31) involvement in the patho-genesis of mastocytosis, and its impact on pruritus development in the disease, are limited. The aim of this study was to analyse distinct IL-31 gene polymorphisms in 127 patients (age 0.5-76 years) with mastocytosis and their correlation with clinical presentation, pruritus and serum IL-31 levels. In patients with mastocytosis, the frequency of IL-31 IVS2+12AA genotype and IVS2+12A allele was higher than in control subjects and they were linked to an increased risk of development of mastocytosis. In adult patients, but not in children, -2057AA genotype was also associated with an increased risk of occurrence of mastocytosis. Pruritus affected 83.3% of 78 adult patients with mastocytosis, and a positive correlation between serum IL-31 levels and pruritus was found in these patients. In conclusion, distinct polymorphic variants of the IL-31 gene may be involved in the patho-genesis of mastocytosis, and IL-31 may be involved in the induction of pruritus in patients with mastocytosis.

Wang R, Xu A, Zhang X, et al.
Novel exosome-targeted T-cell-based vaccine counteracts T-cell anergy and converts CTL exhaustion in chronic infection via CD40L signaling through the mTORC1 pathway.
Cell Mol Immunol. 2017; 14(6):529-545 [PubMed] Free Access to Full Article Related Publications

Ogawa M, Anan T, Suzuki T, et al.
Initial Report of Phase II Study on Bi-weekly SOX plus Cetuximab Treatment for Wild-type K-RAS Advanced and Recurrent Colorectal Cancer.
Anticancer Res. 2016; 36(5):2505-11 [PubMed] Related Publications
AIM: This prospective study was designed to evaluate the tolerability and the efficacy of bi-weekly SOX (S-1 and oxaliplatin)+cetuximab as first-line chemotherapy for wild-type K-RAS metastatic colorectal cancer.
PATIENTS AND METHODS: We studied patients with previously untreated, unresectable, advanced or recurrent colorectal cancer who were treated in our hospital between October 2010 and March 2013. Their performance status (PS) was 0 to 1. Cetuximab was combined with S-1 and oxaliplatin (SOX+cetuximab). S-1 was given orally at a dose of 40 mg/m(2) (40-60 mg, calculated according to body surface area) twice daily after meals for 2 weeks, followed by a 2-week rest (course 1). Oxaliplatin (85 mg/m(2)) was given on days 1 and 15 of each course. Cetuximab was administered on days 1 (400 mg/m(2)), 8 (250 mg/m(2)) and 15 (500 mg/m(2)) of course 1, followed by every 2 weeks (500 mg/m(2)) thereafter.
RESULTS: The study group comprised of 18 patients. The mean age was 61 (range=32-72) years, the male:female ratio was 10:8 and the PS was 0 in 12 patients and 1 in 6 patients. The median number of administered courses was 6 (range=2-12). The treatment response was complete response (CR) in 2 and partial response (PR) in 10 (response rate=67% (12/18 patients)). The minimum number of treatment courses until a PR was 2, indicating an early response. Liver resection was performed in 4 patients (22.2%). The incidence of any adverse events (Grade 3/4) was 28% (5/18), including skin disorder (16.7%) as dry skin, cutaneous pruritus, contusion and paronychia, as well as peripheral sensory neuropathy (11.1%). The any-grade events of skin disorders and peripheral sensory neuropathy were mostly observed in all patients. These events were controllable by preventive skin care and by withdrawal and dose reduction, respectively. Death due to adverse events was not observed. Adverse events did not require the withdrawal of this regimen.
CONCLUSION: Based on the 18 patients studied, combined therapy with SOX+cetuximab was free of serious adverse events and could be safely administered by reducing the dose or temporarily suspending treatment, as required. These regimens seem to be promising for conversion therapy (4 out of 18 patients) because of good outcomes and an early response.

Chi KN, Yu EY, Jacobs C, et al.
A phase I dose-escalation study of apatorsen (OGX-427), an antisense inhibitor targeting heat shock protein 27 (Hsp27), in patients with castration-resistant prostate cancer and other advanced cancers.
Ann Oncol. 2016; 27(6):1116-22 [PubMed] Related Publications
BACKGROUND: Heat shock protein 27 (Hsp27) is a chaperone protein that regulates cell survival via androgen receptor and other signaling pathways, thereby mediating cancer progression. Apatorsen (OGX-427) is a 2'-methoxyethyl-modified antisense oligonucleotide that inhibits Hsp27 expression. This study evaluated the safety profile and recommended phase II dosing of apatorsen in patients with advanced cancer.
PATIENTS AND METHODS: Patients with castration-resistant prostate (CRPC), breast, ovary, lung, or bladder cancer were enrolled to this phase I dose-escalation study. Apatorsen was administered i.v. weekly in 21-day cycles following 3 loading doses and over 5 dose levels (200-1000 mg). Apatorsen plasma concentrations, circulating tumor cells (CTCs) and CTC Hsp27 expression, and serum Hsp27 levels were evaluated.
RESULTS: Forty-two patients were accrued, of which 52% had CRPC. Patients were heavily pretreated, with 57% having had ≥3 prior chemotherapy regimens. During the loading dose/cycle 1 and overall study period, 93% and 100% of patients (N = 42) experienced treatment-related adverse events, respectively; most were grade 1-2 and included chills, pruritus, flushing, prolonged aPTT, lymphopenia, and anemia. One patient experienced a dose-limiting toxicity at the 600 mg dose level (intracranial hemorrhage in a previously undiagnosed brain metastasis). A maximum tolerated dose was not defined. Apatorsen Cmax increased proportionally with dose. Decreases in tumor markers and declines in CTCs were observed, with a prostate-specific antigen decline >%50% occurring in 10% of patients with CRPC; 29/39 assessable patients (74%) had reductions from ≥5 CTC/7.5 ml at baseline to <5 CTC/7.5 ml post-treatment. Twelve patients had stable measurable disease as best response.
CONCLUSIONS: Apatorsen was tolerated at the highest dose evaluated (1000 mg). Single-agent activity was suggested by changes in tumor markers, CTC, and stable measurable disease. Phase II studies evaluating apatorsen are underway.

Maximov G, Chokoeva A, Philipov S, et al.
Georgian Med News. 2016; (251):58-64 [PubMed] Related Publications
We describe a rare case of a 28 year-old male patient presenting with pruritus and increased sensitivity of the prepuce accompanied by erythematous confluent papules, unilateral nevus flammeus (NF) along almost the whole length of the right lower limb and two dysplastic nevi (DN), one located on the mid back and the other on the medial border of the right fifth toe, the latter coinciding with the NF. A biopsy of the prepuce revealed lichen sclerosus et atrophicus (LSA). Mental health assessment revealed anxiety disorder and predisposition to panic attacks. Several clinical, paraclinical and histopathological examinations were undertaken to evaluate potential underlying factors for such unusual combination of findings. Both dysplastic nevi were surgically removed. A topical calcineurin inhibitor treatment of the LSA was prescribed. For the first time in medical literature, we report an extremely rare association of NF, DN (including DN over NF) and LSA, and we are focusing our discussion on a potentially common genetic background which could explain this unusual combination of different diseases, which could in turn be caused by different mutations in common genes and/or different genes with close location in the genome.

Goldinger SM, Stieger P, Meier B, et al.
Cytotoxic Cutaneous Adverse Drug Reactions during Anti-PD-1 Therapy.
Clin Cancer Res. 2016; 22(16):4023-9 [PubMed] Related Publications
PURPOSE: Immunotherapy has experienced impressive progress in cancer treatment. Antibodies against PD-1 improved survival in different types of cancer including melanoma. They are generally well tolerated. However, skin toxicities including pruritus, rashes, and vitiligo are reported. Although frequent, they have not been characterized further yet. In this analysis, we aimed to systematically assess and characterize the adverse cutaneous reactions observed in patients with melanoma treated with anti-PD-1 antibodies.
EXPERIMENTAL DESIGN: Patients with melanoma were treated with anti-PD-1 antibodies within clinical trials and an early-access program. Adverse cutaneous eruptions that emerged in our melanoma patient cohort were systematically investigated and classified using histology and gene expression profiling in comparison with maculopapular drug rash, cutaneous GVHD, and the severe drug eruption toxic epidermal necrolysis (TEN).
RESULTS: Between February 2013 and September 2015, 68 patients with stage IV melanoma were treated at the University Hospital Zurich (Zurich, Switzerland); 15 patients (22%) developed cutaneous reactions and 10 (15%) vitiligo. The cutaneous reactions ranged from small erythematous papules with mild pruritus to disseminated erythematous maculopapular rashes (MPR) without signs of epidermal involvement to severe MPRs, including epidermal detachment and mucosal involvement. Although skin involvement varied from mild rash to bullous drug eruptions, gene expression profiling pathogenically classified all investigated cases as TEN-like reactions.
CONCLUSIONS: As predicted by the PD-1 knockout mouse, anti-PD-1 antibodies frequently cause adverse cutaneous reactions. Gene expression profiling reminds in all cases of a TEN-like pattern, suggesting that PD-1/PD-L1 interaction is required to preserve epidermal integrity during inflammatory skin reactions. Clin Cancer Res; 22(16); 4023-9. ©2016 AACR.

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