CLTC

Gene Summary

Gene:CLTC; clathrin heavy chain
Aliases: Hc, CHC, CHC17, MRD56, CLH-17, CLTCL2
Location:17q23.1
Summary: Clathrin is a major protein component of the cytoplasmic face of intracellular organelles, called coated vesicles and coated pits. These specialized organelles are involved in the intracellular trafficking of receptors and endocytosis of a variety of macromolecules. The basic subunit of the clathrin coat is composed of three heavy chains and three light chains. [provided by RefSeq, Jul 2008]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:clathrin heavy chain 1
Source:NCBIAccessed: 30 August, 2019

Ontology:

What does this gene/protein do?
Show (27)
Pathways:What pathways are this gene/protein implicaed in?
Show (1)

Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 30 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.

  • Soft Tissue Cancers
  • Xenograft Models
  • ALK
  • Receptor Protein-Tyrosine Kinases
  • Signal Transduction
  • Lymphoma, Large-Cell, Anaplastic
  • FISH
  • Amino Acid Sequence
  • RTPCR
  • Messenger RNA
  • Renal Cell Carcinoma
  • Clathrin Heavy Chains
  • Translocation
  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
  • Clathrin
  • Diffuse Large B-Cell Lymphoma
  • Immunohistochemistry
  • Karyotyping
  • B-Cell Lymphoma
  • Inflammation
  • Protein-Tyrosine Kinases
  • Chromosome 17
  • Gene Rearrangement
  • Kidney Cancer
  • DNA Sequence Analysis
  • Tandem Mass Spectrometry
  • Chromosome 2
  • Polymerase Chain Reaction
  • Oncogene Fusion Proteins
  • Base Sequence
  • Smoking
  • Infant
  • Molecular Sequence Data
  • Childhood Cancer
  • Adolescents
  • Spectral Karyotyping
  • Vincristine
  • Lung Cancer
  • Cancer Gene Expression Regulation
  • Gene Fusion
Tag cloud generated 30 August, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (4)

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: CLTC (cancer-related)

Liu K, Newbury PA, Glicksberg BS, et al.
Evaluating cell lines as models for metastatic breast cancer through integrative analysis of genomic data.
Nat Commun. 2019; 10(1):2138 [PubMed] Free Access to Full Article Related Publications
Cell lines are widely-used models to study metastatic cancer although the extent to which they recapitulate the disease in patients remains unknown. The recent accumulation of genomic data provides an unprecedented opportunity to evaluate the utility of them for metastatic cancer research. Here, we reveal substantial genomic differences between breast cancer cell lines and metastatic breast cancer patient samples. We also identify cell lines that more closely resemble the different subtypes of metastatic breast cancer seen in the clinic and show that surprisingly, MDA-MB-231 cells bear little genomic similarities to basal-like metastatic breast cancer patient samples. Further comparison suggests that organoids more closely resemble the transcriptome of metastatic breast cancer samples compared to cell lines. Our work provides a guide for cell line selection in the context of breast cancer metastasis and highlights the potential of organoids in these studies.

Zhang W, Liang X, Gong Y, et al.
The Signal Transducer and Activator of Transcription 5B (STAT5B) Gene Promotes Proliferation and Drug Resistance of Human Mantle Cell Lymphoma Cells by Activating the Akt Signaling Pathway.
Med Sci Monit. 2019; 25:2599-2608 [PubMed] Free Access to Full Article Related Publications
BACKGROUND Mantle cell lymphoma (MCL) is a high-grade B-cell lymphoma with poor prognosis. Fludarabine is used alone or in combination for relapsed and advanced-stage MCL. The expression of the signal transducer and activator of transcription 5B (STAT5B) gene is associated with tumorigenesis in solid tumors, but its role in MCL remains unknown. The aims of this study were to investigate the role of STAT5B in GRANTA-519 human mantle cell lymphoma cells and drug resistance. MATERIAL AND METHODS GRANTA-519 human mantle cell lymphoma cells were cultured with and without 10 μM fludarabine dephosphorylated 9-ß-D-arabinofuranosyl-2-fluoroadenine, (2-F-araA) or 10 μM 4-hydroperoxycyclophosphamide (4-HC). The MTT assay assessed cell proliferation. Flow cytometry was used to investigate the cell cycle in MCL cells treated with the specific inhibitor of the Akt pathway, LY294002, and assessed cell cycle and cell apoptosis. Western blot was used to detect the expression levels of p-Akt/Akt and STAT5B/p-STAT5B. The gene expression profiles of lymph node (LN)-derived MCL cells were compared with peripheral blood (PB)-derived lymphocytes using bioinformatics and hierarchical cluster analysis. Quantitative reverse transcription polymerase chain reaction (RT-qPCR) was performed to determine the expression of the marker of proliferation Ki-67 (MKI67) gene. RESULTS STAT5B was significantly upregulated in LN-derived MCL cells compared with PB lymphocytes. Increased expression of STAT5B was associated with increased MCL cell proliferation and reduced cell apoptosis and was associated with drug resistance and activation of Akt. CONCLUSIONS STAT5B promoted cell proliferation and drug resistance in human MCL cells by activating the Akt signaling pathway.

Barooah P, Saikia S, Bharadwaj R, et al.
Role of
Genet Test Mol Biomarkers. 2019; 23(5):325-331 [PubMed] Related Publications

Weis A, Marquart L, Calvopina DA, et al.
Serum MicroRNAs as Biomarkers in Hepatitis C: Preliminary Evidence of a MicroRNA Panel for the Diagnosis of Hepatocellular Carcinoma.
Int J Mol Sci. 2019; 20(4) [PubMed] Free Access to Full Article Related Publications
Early diagnosis of cirrhosis and hepatocellular carcinoma (HCC) due to chronic Hepatitis C (CHC) remain clinical priorities. In this pilot study, we assessed serum microRNA (miRNA) expression to distinguish cirrhosis and HCC, alone and in combination with the aminotransferase-to-platelet ratio (APRI), Fibrosis 4 (FIB-4), and alpha-fetoprotein (AFP). Sixty CHC patients were subdivided into 3 cohorts: Mild disease (fibrosis stage F0-2;

Binh MT, Hoan NX, Van Tong H, et al.
NTCP S267F variant associates with decreased susceptibility to HBV and HDV infection and decelerated progression of related liver diseases.
Int J Infect Dis. 2019; 80:147-152 [PubMed] Related Publications
OBJECTIVES: To determine potential associations of the rs2296651 variant (c.800C>T, S267F) of NTCP with HBV and HBV plus concomitant HDV infection as well as with the progression of related liver diseases.
METHODS: The S267F variant was genotyped by DNA sequencing in 620 HBV-infected patients and 214 healthy controls (HCs). Among the patients, 450 individuals were tested for HDV by a nested PCR assay. Logistic regression was applied to examine the association.
RESULTS: The S267F variant was found more frequently among HCs (16%) compared to HBV-infected (6%) and HBV-HDV co-infected patients (3%) (HBV patients vs HC: OR=0.32, P=0.00002 and HDV patients vs. HC: OR=0.17, P=0.018). The frequency of S267F variant was inversely correlated with CHB, LC or HCC patients compared with HCs (OR=0.31, P=0.001; OR=0.32, P=0.013; OR=0.34, P=0.002, respectively). S267F variant was also associated with decreased risk of the development of advanced liver cirrhosis (LC) and hepatocellular carcinoma (HCC) (Child B and C vs. Child A, OR=0.26, adjusted P=0.016; BCLC B,C,D vs. BCLC A, OR=0.038, P=0.045, respectively). In addition, patients with the genotype CT had lower levels of AST, ALT, total and direct bilirubin as well as higher platelet counts, indicating an association with a more favorable clinical outcome.
CONCLUSION: The NTCP S267F variant of the SLC10A1 gene exhibits protective effects against HBV and HDV infection and is associated with a reduced risk of developing to advanced stages of LC and HCC.

Wang Z, Lv J, Zou X, et al.
A three plasma microRNA signature for papillary thyroid carcinoma diagnosis in Chinese patients.
Gene. 2019; 693:37-45 [PubMed] Related Publications
Whether plasma miRNAs could be used as novel non-invasive biomarkers in diagnosing papillary thyroid carcinoma (PTC) remains unknown. In this study, we designed a four-phase study to identify differentially expressed plasma miRNAs in Chinese PTC patients. Exiqon panel was initially utilized to conduct plasma miRNA profile (3 PTC pools VS. 1 healthy control (HC) pool; each 10 samples were pooled as 1 sample). The dysregulated miRNAs were then analyzed in the training (30 PTC VS. 30 HCs), testing (57 PTC VS. 54 HCs) and external validation phases (33 PTC VS. 30HCs). The identified miRNAs were further affirmed in benign nodules (2 nodular goiter (NG) pool VS. 1 HC pool). We also verified the expression of identified miRNAs in 17 matched malignant and normal tissue samples, NG plasma samples (29 PTC VS. 29 NG) and plasma exosomes (25 PTC VS. 25 HCs). Receiver operating characteristic (ROC) curves were constructed to evaluate the diagnostic value of the identified miRNAs. As a result, the screening phase demonstrated 30 dysregulated plasma miRNAs in PTC patients compared with HCs. After multiphase experiment processes, miR-346, miR-10a-5p and miR-34a-5p were found significantly elevated in PTC plasma samples relative to HCs. The areas under the ROC curve (AUC) of the three-miRNA panel for the training, testing and validation phases were 0.926, 0.811 and 0.816, separately. The panel could also differentiate PTC from NG with the AUC of 0.877. MiR-346 and miR-34a-5p but not miR-10a-5p were up-regulated in PTC tissues. And the three miRNAs showed consistently up-regulation in PTC plasma exosomes. In conclusion, our study established a three-miRNA panel in plasma with considerable clinical value in discriminating PTC from HC or NG.

Wang S, Yao Y, Rao C, et al.
25-HC decreases the sensitivity of human gastric cancer cells to 5-fluorouracil and promotes cells invasion via the TLR2/NF-κB signaling pathway.
Int J Oncol. 2019; 54(3):966-980 [PubMed] Free Access to Full Article Related Publications
Hyperlipidemia is associated with metastasis in patients with gastric cancer (GC). 25‑Hydroxycholesterol (25‑HC) is a type of oxysterol which is synthesized from cholesterol and is involved in a number of processes, including inflammation, immune responses and cancer development. However, the role of 25‑HC in gastric cancer remains unknown. In the present study, we demonstrated that 25‑HC had no effects on GC cell proliferation and apoptosis, whereas it decreased the sensitivity of GC cells to 5‑fluorouracil (5‑FU), as demonstrated by the increased cell proliferation and the decreased cell apoptosis. On the other hand, exposure to 2.5‑10 µM of 25‑HC significantly promoted GC invasion, both in vitro (using AGS and MGC‑803 GC cell lines) and in vivo (in an animal model), accompanied by the upregulation of the expression levels of matrix metalloproteinases (MMPs). Further investigations revealed that the promotion of GC invasion was, at least in part due to the activation of Toll‑like receptor 2 (TLR2)/nuclear factor (NF)‑κB signaling. Our results demonstrated that 25‑HC promoted GC cells invasion by upregulating TLR2/NF‑κB‑mediated MMP expression. Thus, on the whole, the findings of this study suggest a novel mechanism of hyperlipidemia‑induced GC progression.

Nezos A, Gkioka E, Koutsilieris M, et al.
TNFAIP3 F127C Coding Variation in Greek Primary Sjogren's Syndrome Patients.
J Immunol Res. 2018; 2018:6923213 [PubMed] Free Access to Full Article Related Publications
Tumor necrosis factor, alpha-induced protein 3 (

Díaz KP, Gondak R, Martins LL, et al.
Fatty acid synthase and Ki-67 immunoexpression can be useful for the identification of malignant component in carcinoma ex-pleomorphic adenoma.
J Oral Pathol Med. 2019; 48(3):232-238 [PubMed] Related Publications
BACKGROUND: Fatty acid synthase (FASN) is the key molecule for catalyzing fatty acid synthesis and have been associated with several malignant tumors.
METHODS: We analyzed the expression of FASN and Ki-67, by immunohistochemistry on 29 carcinomas ex-pleomorphic adenoma (CXPAs) and 25 pleomorphic adenomas (PAs).
RESULTS: Ki-67 proliferation index and FASN expression were significantly higher in patients with CXPA than patients with PA (P < 0.001). We found intense immunoreactivity for FASN in the malignant component of CXPAs, and these malignant areas also had intense nuclear immunoreactivity for Ki-67.
CONCLUSIONS: The present results suggest that overexpression of FASN in CXPAs might be associated with malignant transformation of ductal epithelial cells and/or myoepithelial cells from PA. FASN associated with Ki-67 may be useful diagnostic markers for CXPA.

Amorim PVGH, Grande IPP, Batista RL, et al.
Association between KISS1 rs5780218 promoter polymorphism and onset of growth hormone secreting pituitary adenoma.
Ann Endocrinol (Paris). 2019; 80(2):96-100 [PubMed] Related Publications
OBJECTIVES: This study analyzed the KISS1 c.-145delA (rs5780218) promoter polymorphism in a cohort of patients with growth hormone secreting pituitary adenoma (somatotropinoma) and controls, to investigate its role in the incidence of acromegaly and to assess patient/tumor characteristics. Material and methods rs5780218 allelic and genotypic distributions were compared between 49 somatotropinoma patients and 167 healthy controls. rs5780218 was also assessed in relation to patient characteristics and tumor aggressiveness, as characterized by tumor invasion and resistance to conventional therapy. The relationship between KISS1 mRNA expression and the rs5780218 genotype was also assessed in available pituitary tumor samples.
RESULTS: The homozygous -/- variant genotype was associated with high rates of somatotropinoma (P<0.01), but not with tumor invasiveness, patient characteristics or hormonal remission. KISS1 mRNA expression was much lower in somatotropinomas carrying the deleted allele than in homozygous wild type AA.
CONCLUSIONS: In this pilot study, the rs5780218 promoter polymorphism was evaluated in pituitary adenoma, and showed a possible association with the incidence of somatotropinoma but not with tumor progression.

Zeng B, Lai Z, Sun L, et al.
Structural and functional profiles of the gut microbial community in polycystic ovary syndrome with insulin resistance (IR-PCOS): a pilot study.
Res Microbiol. 2019 Jan - Feb; 170(1):43-52 [PubMed] Related Publications
Polycystic ovary syndrome (PCOS) is a complex endocrine and metabolic disorder that affects 9-21% of reproductive-aged women. Affected women frequently display obesity, insulin resistance, and inflammation. Altered gut microbial community has been reported in PCOS and obese PCOS patients. However, the profile of the gut microbial community in insulin resistant PCOS (IR-PCOS) patients still remains unknown. In this study, next-generation sequencing based on the 16S rRNA gene was used to compare the gut microbial composition of women with IR-PCOS (n = 9, PCOS with insulin resistance), NIR-PCOS (n = 8, PCOS alone) and healthy controls (n = 8, HC). We assessed that the composition of the gut microbial communities in NIR-PCOS and IR-PCOS patients were significantly altered. The family Bacteroidaceae was prolific in the NIR-PCOS group and reached its highest level in the IR-PCOS group, while the Prevotellaceae dramatically decreased in PCOS patients, especially in the IR-PCOS group. Subsequent correlation analysis revealed that the increased clinical parameter levels, including insulin resistance, sex-hormones and inflammation, were positively associated with the abundance of Bacteroidaceae, but negatively associated with that of Prevotellaceae. In addition, IR-PCOS patients also displayed a significant difference in their amounts of Ruminococcaceae and Lachnospiraceae when compared to the NIR-PCOS group. Moreover, the functional prediction from PICRUSt revealed that 73 pathways are significantly changed in the gut microbial communities of PCOS patients. Specifically, 21 metabolism-associated pathways, including the steroid hormone biosynthesis and lipopolysaccharide biosynthesis pathways, are obviously changed in IR-PCOS when compared to NIR-PCOS and HC groups. Taking this into consideration, our present study suggests that the dysbiosis of gut microbial communities occurred most notably in IR-PCOS patients, and the difference in gut dysbiosis profile between the IR-PCOS and NIR-PCOS should be considered in clinical treatment for PCOS patients and future drugs development.

Zhang Y, He J, Wang Y, et al.
Photothermal therapy with AuNRs and EGFRmAb-AuNRs inhibits subcutaneous transplantable hypopharyngeal tumors in nude mice.
Int J Oncol. 2018; 53(6):2647-2658 [PubMed] Related Publications
The present study aimed to investigate the effects of photothermal therapy with gold nanorods (AuNRs) or epidermal growth factor receptor monoclonal antibody‑conjugated AuNRs (EGFRmAb‑AuNRs) on hypopharyngeal carcinoma (HC) in nude mice. In addition, the associated signaling pathways were explored. Briefly, a subcutaneous transplantable hypopharyngeal tumor model was established in nude mice injected with FaDu human HC cells. A total of 70 nude mice were randomly divided into seven groups, each of which received a different treatment. Mice were treated with AuNRs, locally or through intravenous injection, whereas EGFRmAb or EGFRmAb‑AuNRs were only administered locally. Near infrared spectroscopy (NIR) was also applied for plasmonic photothermal therapy (PPTT). The growth curve and the inhibitory rate for tumor growth were used to evaluate the effects of each treatment. Flow cytometry and the terminal‑deoxynucleotidyl transferase dUTP nick end labeling assay were adopted to detect apoptosis of cells in the transplanted tumors. Reverse transcription‑quantitative polymerase chain reaction and western blotting were used to determine the mRNA and protein expression levels of target genes, respectively. Local treatment with AuNRs + NIR or EGFRmAb significantly inhibited tumor growth, and EGFRmAb conjugation further increased the inhibitory effects. Furthermore, there was a significant increase in apoptosis of tumor cells in the AuNRs + NIR, EGFRmAb and EGFRmAb‑AuNRs + NIR groups; treatment with EGFRmAb‑AuNRs + NIR induced the highest apoptotic effect. Mechanistic studies indicated that EGFRmAb‑AuNRs + NIR may inhibit tumors through the AKT serine/threonine kinase (Akt) and DNA damage signaling pathways. In the AKT pathway, the mRNA and protein expression levels of phosphatase and tensin homolog were increased, whereas the expression levels of Akt and glycogen synthase kinase 3β were decreased. In the DNA damage signaling pathway, the mRNA and protein expression levels of ATR serine/threonine kinase, checkpoint kinase 1 and p53 were enhanced, whereas phosphorylated‑p53 protein expression was reduced. The present findings indicated that AuNRs + NIR inhibited HC tumor growth, and conjugating EGFRmAb to AuNRs further enhanced the inhibitory effects. EGFRmAb conjugation may increase the antitumor effects of AuNRs‑induced PPTT by downregulating the phosphatidylinositol‑3‑kinase/Akt pathway and upregulating the DNA damage pathway. These findings may provide novel insights into tumor‑targeting PPTT in vivo.

Do MH, To PK, Cho YS, et al.
Targeting CD46 Enhances Anti-Tumoral Activity of Adenovirus Type 5 for Bladder Cancer.
Int J Mol Sci. 2018; 19(9) [PubMed] Free Access to Full Article Related Publications
CD46 is generally overexpressed in many human cancers, representing a prime target for CD46-binding adenoviruses (Ads). This could help to overcome low anti-tumoral activity by coxsackie-adenoviral receptor (CAR)-targeting cancer gene therapy viruses. However, because of scarce side-by-side information about CAR and CD46 expression levels in cancer cells, mixed observations of cancer therapeutic efficacy have been observed. This study evaluated Ad-mediated therapeutic efficacy using either CAR-targeting Ad5 or CD46-targeting Ad5/35 fiber chimera in bladder cancer cell lines. Compared with normal urothelia, bladder cancer tissue generally overexpressed both CAR and CD46. While CAR expression was not correlated with disease progression, CD46 expression was inversely correlated with tumor grade, stage, and risk grade. In bladder cancer cell lines, expression levels of CD46 and CAR were highly correlated with Ad5/35- and Ad5-mediated gene transduction and cytotoxicity, respectively. In a human EJ bladder cancer xenograft mouse model, with either overexpressed or suppressed CD46 expression levels, Ad5/35-tk followed by ganciclovir (GCV) treatment significantly affected tumor growth, whereas Ad5-tk/GCV had only minimal effects. Overall, our findings suggest that bladder cancer cells overexpress both CAR and CD46, and that adenoviral cancer gene therapy targeting CD46 represents a more suitable therapy option than a CAR-targeting therapy, especially in patients with low risk bladder cancers.

Bray MJ, Wellons MF, Jones SH, et al.
Transethnic and race-stratified genome-wide association study of fibroid characteristics in African American and European American women.
Fertil Steril. 2018; 110(4):737-745.e34 [PubMed] Article available free on PMC after 01/09/2019 Related Publications
OBJECTIVE: To identify, through genome-wide association studies, genetic loci that associate with differences in fibroid size and number in a population of African American and European American women.
DESIGN: Cross-sectional study.
SETTING: Not applicable.
PATIENT(S): Using BioVU, a clinical population from the Vanderbilt University Medical Center, and the Coronary Artery Risk Development in Young Adults cohort, a prospective cohort, we identified 1520 women (609 African American and 911 European American) with documented fibroid characteristics.
INTERVENTION(S): None.
MAIN OUTCOME MEASURE(S): Outcome measurements include volume of largest fibroid, largest fibroid dimension, and number of fibroids (single vs. multiple).
RESULT(S): In race-stratified analyses we achieved genome-wide significance at a variant located between MAT2B and TENM2 (rs57542984, β = 0.13; 95% confidence interval 0.09, 0.17) for analyses of largest fibroid dimension in African Americans. The strongest signal for transethnic analyses was at a variant on 1q31.1 located between PLA2G4A and BRINP3 (rs6605005, β = 0.24; 95% confidence interval 0.15, 0.33) for fibroid volume. Results from MetaXcan identified an association between predicted expression of the gene ER degradation enhancing alpha-mannosidase like protein 2 (EDEM2) in the thyroid and number of fibroids (Z score = -4.51).
CONCLUSION(S): This study identified many novel associations between genetic loci and fibroid size and number in both race-stratified and transethnic analyses. Future studies are necessary to further validate our study findings and to better understand the mechanisms underlying these associations.

Jadid FZ, Chihab H, Alj HS, et al.
Control of progression towards liver fibrosis and hepatocellular carcinoma by SOCS3 polymorphisms in chronic HCV-infected patients.
Infect Genet Evol. 2018; 66:1-8 [PubMed] Related Publications
BACKGROUND & AIMS: Chronic Hepatitis C is one of the most important risk factors of liver cirrhosis and hepatocellular carcinoma. Before reaching these ultimate steps, insulin resistance triggered by hepatitis C virus infection is known to participate in the progression of liver disease. The present study aims to investigate the influence of two functional polymorphisms on SOCS3 mRNA expression and on the outcomes of CHC progression in a North African context.
PATIENTS & METHODS: In this case-control study, 601 Moroccan subjects composed of 200 healthy controls, 101 resolvers and 300 patients with persistent HCV infection including 95 mild chronic hepatitis, 131 Advanced Liver Diseases and 74 HCC were enrolled. They were genotyped for the 4874 A/G (rs4969170) and A + 930- > G (rs4969168) SOCS3 variants using TaqMan SNPs assays. SOCS3 mRNA expression was assessed using Real Time PCR technique.
RESULTS: Logistic regression analysis showed that variation at rs4969168 was associated with spontaneous clearance of HCV (P < 0.05). In addition, minor allele frequencies were significantly higher in AdLD patients when compared to the mCHC group both for rs4969168 (P = 7.0 E-04) and rs4969170 (P = 4.0 E-05). A significant association between haplotype and liver disease progression was also found. Moreover, SOCS3 mRNA was significantly more expressed in peripheral leukocytes from patients with HCC than in those from mCHC. Finally, rs4969170 was significantly associated with LDL-lipoprotein (P = 0.04), total cholesterol (P = 5.0 E-04), and higher fasting glucose levels (P = 0.005) in patients with persistent HCV infection.
CONCLUSIONS: Our results underline the importance of the functional SOCS3 polymorphisms in the modulation of CHC progression and suggest their contribution to HCC development by affecting its mRNA expression and perturbing key metabolic parameters.

Chen M, Du D, Zheng W, et al.
Small hepatitis delta antigen selectively binds to target mRNA in hepatic cells: a potential mechanism by which hepatitis D virus downregulates glutathione S-transferase P1 and induces liver injury and hepatocarcinogenesis.
Biochem Cell Biol. 2019; 97(2):130-139 [PubMed] Related Publications
Liver coinfection by hepatitis B virus (HBV) and hepatitis D virus (HDV) can result in a severe form of hepatocellular carcinoma with poor prognosis. Coinfection with HDV and HBV causes more deleterious effects than infection with HBV alone. Clinical research has shown that glutathione S-transferase P1 (GSTP1), a tumor suppressor gene, is typically downregulated in liver samples from hepatitis-infected patients. In the present study, our data indicated that small HDV antigen (s-HDAg) could specifically bind to GSTP1 mRNA and significantly downregulate GSTP1 protein expression. For the human fetal hepatocyte cell line L-02, cells transfected with s-HDAg, along with decreased GSTP1 expression, there was a significant accumulation of reactive oxygen species (ROS) and increased apoptotic ratios. Restoring GSTP1 expression through silencing s-HDAg via RNAi or overexpressing exogenous GSTP1 could largely recover the abnormal cell status. Our results revealed a novel potential mechanism of HDV-induced liver injury and hepatocarcinogenesis: s-HDAg can inhibit GSTP1 expression by directly binding to GSTP1 mRNA, which leads to accumulation of cellular ROS, resulting in high cellular apoptotic ratios and increased selective pressure for malignant transformation. To our knowledge, this is the first study to examine s-HDAg-specific pathogenic mechanisms through potential protein-RNA interactions.

Abel EV, Goto M, Magnuson B, et al.
HNF1A is a novel oncogene that regulates human pancreatic cancer stem cell properties.
Elife. 2018; 7 [PubMed] Article available free on PMC after 01/09/2019 Related Publications
The biological properties of pancreatic cancer stem cells (PCSCs) remain incompletely defined and the central regulators are unknown. By bioinformatic analysis of a human PCSC-enriched gene signature, we identified the transcription factor HNF1A as a putative central regulator of PCSC function. Levels of HNF1A and its target genes were found to be elevated in PCSCs and tumorspheres, and depletion of HNF1A resulted in growth inhibition, apoptosis, impaired tumorsphere formation, decreased PCSC marker expression, and downregulation of

Yuan J, Levitin HM, Frattini V, et al.
Single-cell transcriptome analysis of lineage diversity in high-grade glioma.
Genome Med. 2018; 10(1):57 [PubMed] Article available free on PMC after 01/09/2019 Related Publications
BACKGROUND: Despite extensive molecular characterization, we lack a comprehensive understanding of lineage identity, differentiation, and proliferation in high-grade gliomas (HGGs).
METHODS: We sampled the cellular milieu of HGGs by profiling dissociated human surgical specimens with a high-density microwell system for massively parallel single-cell RNA-Seq. We analyzed the resulting profiles to identify subpopulations of both HGG and microenvironmental cells and applied graph-based methods to infer structural features of the malignantly transformed populations.
RESULTS: While HGG cells can resemble glia or even immature neurons and form branched lineage structures, mesenchymal transformation results in unstructured populations. Glioma cells in a subset of mesenchymal tumors lose their neural lineage identity, express inflammatory genes, and co-exist with marked myeloid infiltration, reminiscent of molecular interactions between glioma and immune cells established in animal models. Additionally, we discovered a tight coupling between lineage resemblance and proliferation among malignantly transformed cells. Glioma cells that resemble oligodendrocyte progenitors, which proliferate in the brain, are often found in the cell cycle. Conversely, glioma cells that resemble astrocytes, neuroblasts, and oligodendrocytes, which are non-proliferative in the brain, are generally non-cycling in tumors.
CONCLUSIONS: These studies reveal a relationship between cellular identity and proliferation in HGG and distinct population structures that reflects the extent of neural and non-neural lineage resemblance among malignantly transformed cells.

Mattar MM, Zekri AN, Hussein N, et al.
Polymorphisms of base-excision repair genes and the hepatocarcinogenesis.
Gene. 2018; 675:62-68 [PubMed] Related Publications
AIM: To determine the possible association between polymorphisms of DNA repair genes, including XRCC1 Arg194Tryp, Arg280His, and Arg399Glu, APE1 Asp148Glu, and NEIL2 Arg257Leu, and the risk of developing hepatitis C virus (HCV)-related hepatocellular carcinoma (HCC).
METHODS: A total of 264 subjects were recruited in this retrospective case-control study and were categorized into four groups: 88 control subjects (CR), 53 chronic hepatitis C patients (CHC), 36 liver cirrhotic patients (LC), and 87 HCC patients. The XRCC1 Arg194Tryp, Arg280His, and Arg399Glu polymorphisms were detected using PCR-RFLP, while real-time PCR was used to genotype APE1 Asp148Glu and NEIL2 Arg257Leu.
RESULTS: Our data revealed that, compared with the healthy controls, for those subjects with the XRCC1 Arg194Trp genotype, the risk of developing CHC, LC, and HCC was increased by 6.66- (odds ratio (OR) = 6.667; 95% confidence interval (CI) = 3.244-13.701; P > 0.01), 3.85- (OR = 3.852; 95% CI = 1.797-8.256; P > 0.01), and 2.14-fold (OR = 2.14; 95% CI = 1.13-4.06; P > 0.05), respectively. There was no association between the risk of HCC development and the XRCC1 Arg280His or XRCC1 Arg399Gln genotypes. Moreover, the analysis showed a lack of association between APE1 Asp148Glu and the risk of HCC development. The analysis of clinicopathological parameters showed that the HCC patients with the XRCC1 Arg280His polymorphism were 2.9 fold more likely to have hepatic lesions in both hepatic lobes (OR: 2.9; 95% CI: 1.15-7.29). Notably, in the HCC patients, the prevalence of the APE1 polymorphism in the males was four times higher than that in the females (OR = 4; 95% CI = 1.129-14.175; P > 0.05).
CONCLUSION: Our results indicate that the XRCC1 Arg194Trp polymorphism could be a risk factor for HCV-related HCC development in Egypt.

Huang CF, Wang SC, Yeh ML, et al.
Association of serial serum major histocompatibility complex class I chain-related A measurements with hepatocellular carcinoma in chronic hepatitis C patients after viral eradication.
J Gastroenterol Hepatol. 2019; 34(1):249-255 [PubMed] Related Publications
BACKGROUND AND AIM: Major histocompatibility complex class I chain-related A (MICA) genetic variants and their serum levels (sMICA) were associated with the development of hepatitis C virus-related hepatocellular carcinoma (HCC) in untreated cohorts. The dynamic changes in serial sMICA levels and their association with HCC in the post-curative status are elusive.
METHODS: Single nucleotide polymorphism rs2596542 of MICA and serial sMICA levels were analyzed in chronic hepatitis C patients with a sustained virologic response after antivirals. Forty-two patients who developed HCC and 84 age-matched, gender-matched, and cirrhosis propensity score-matched non-HCC controls were compared. Serial sMICA levels were measured within 6 months before treatment initiation (pre-sMICA), 6 months after the end of treatment (post-sMICA), and on the last visit before the development (or not) of HCC (last-sMICA).
RESULTS: Cox regression analysis revealed that last-sMICA was the only predictive factor of HCC development (hazard ratio/95% confidence interval: 2.27 (per 1 log pg/mL increase)/1.672-3.082, P < 0.001). Patients without HCC development showed a significantly reduced trend of sMICA levels during follow-up (trend P = 0.001), which was observed only in GG genotype (trend P < 0.001) but not A allele carriers (P = 0.88). In contrast, patients with HCC showed an increased trend of sMICA levels (trend P = 0.024). However, only the GG genotype "high expressors" (trend P = 0.06) but not A allele carriers (P = 0.18) showed a correlation of substantially increased trend of sMICA levels and HCC development.
CONCLUSIONS: Serial sMICA levels were associated with HCC development in SVR patients. The clinical utility of this finding is restricted to MICA rs2596542 GG genotype carriers.

Parker BM, Parker JV, Lymperopoulos A, Konda V
A case report: Pharmacology and resistance patterns of three generations of ALK inhibitors in metastatic inflammatory myofibroblastic sarcoma.
J Oncol Pharm Pract. 2019; 25(5):1226-1230 [PubMed] Related Publications
BACKGROUND: Little exists currently in research about the mechanisms of resistance of ALK inhibitors in inflammatory myofibroblastic sarcoma. It is known, however, that ALK gene rearrangements are common in inflammatory myofibroblastic tumors, similar to non-small cell lung cancer. In roughly 50% of inflammatory myofibroblastic tumors, gene rearrangement has been found to occur on chromosome 2 at band 2p23. In non-small cell lung cancer, it has been shown that about a third of patients who progress on the first generation ALK inhibitor, crizotinib develops mutations in the ALK kinase domain. The remaining two-thirds of patients tend to develop amplification of ALK or activation of alternative signaling pathways. Chromoplexy has also been described as a mechanism of resistance, where multiple closed chain rearrangements cause loss-of-function of tumor suppressor genes and gain-in-function of oncogenic fusions. Partner genes that have been identified in IMTs are tropomyosin 3 (TPM3), tropomyosin 4 (TPM4), clathrin heavy chain (CLTC), Ran-binding protein 2 (RANBP2), cysteinyl-tRNA synthetase (CARS), 5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase/IMP cyclohydrolase (ATIC), and SEC31L1. All are active promoters for the fusion gene, in response to NPM binding. Several inflammatory myofibroblastic tumor case reports indicated that fusion of ALK and RANBP2 led to a more aggressive clinical course. Although the majority of inflammatory myofibroblastic tumor case reports have utilized first and second generation ALK inhibitors, all generations of ALK inhibitors have demonstrated some ability to impair disease progression and extend life expectancy. However, at some point in the course of therapy with each generation of ALK inhibitor, resistance ultimately developed. In order to better understand the pharmacology and resistance patterns behind three generations of ALK inhibitors, we sought to examine a patient with metastatic anaplastic lymphoma kinase-1-rearranged inflammatory myofibroblastic sarcoma to the brain. We also explored the similarities and differences of this clinical case to other inflammatory myofibroblastic sarcoma case reports involving the use of ALK inhibitors.
CASE REPORT: A rare case of pulmonary IMS with ALK-1 gene rearrangement and multiple brain metastases responded to three generations of ALK inhibitors. However, similar to other case reports, due to the development of resistance and recurrence, the patient eventually succumbed to the disease.
CONCLUSIONS: ALK inhibitors are beneficial in the temporary prevention of progression of disease in patients with inflammatory myofibroblastic tumors. In this case, due to the inability to reveal the fusion partner in this patient via DNA sequencing, it is unknown exactly if that partner was RANBP2 or another ALK partner gene. Brain biopsy tissue was also unobtainable during sequence of ALK due to risk versus benefit, which would have provided insight as which type of ALK resistance mutations the patient was developing. It is likely that this patient had some form of chromoplexy occurring.

Moussa MM, Helal NS, Youssef MM
Significance of pSmad2/3 and Smad4 in hepatitis C virus-related liver fibrosis and hepatocellular carcinoma.
APMIS. 2018; 126(6):477-485 [PubMed] Related Publications
Chronic hepatitis C (CHC) is a major public health problem, especially in Egypt. Risk of hepatocellular carcinoma (HCC) development increases as hepatitis C virus (HCV)-related liver diseases progress. Smads act as substrates for the transforming growth factor-beta (TGF-β) family of receptors. This study aims to assess hepatic expression of pSmad2/3 and Smad4 in CHC with different stages of fibrosis and grades of necro-inflammation as well as in HCC on top of CHC. This study was done on 33 core liver biopsies from patients with CHC (15 with early fibrosis and 18 with late fibrosis), 15 liver specimens from HCC cases on top of CHC, as well as five normal controls. pSmad2/3 and Smad4 show more immunopositivity, higher percentage of positive hepatocytes and stronger staining intensity in CHC with late fibrosis compared to early fibrosis. pSmad2/3 shows increase of the previous parameters in CHC with high grade activity than those with low activity. Smad4 shows increase of the previous parameters in HCC compared to CHC cases. pSmad2/3 and Smad4 can be used as diagnostic and/or prognostic markers for progression of HCV-related fibrosis to cirrhosis and further progression to HCC.

Tran TD, Kwon YK
Hierarchical closeness-based properties reveal cancer survivability and biomarker genes in molecular signaling networks.
PLoS One. 2018; 13(6):e0199109 [PubMed] Article available free on PMC after 01/09/2019 Related Publications
Specific molecular signaling networks underlie different cancer types and quantitative analyses on those cancer networks can provide useful information about cancer treatments. Their structural metrics can reveal survivability of cancer patients and be used to identify biomarker genes for early cancer detection. In this study, we devised a novel structural metric called hierarchical closeness (HC) entropy and found that it was negatively correlated with 5-year survival rates. We also made an interesting observation that a network of higher HC entropy was likely to be more robust against mutations. This finding suggested that cancers of high HC entropy tend to be incurable because their signaling networks are robust to perturbations caused by treatment. We also proposed a novel core identification method based on the reachability factor in the HC measure. The cores were permitted to decompose such that the negative relationship between HC entropy and cancer survival rate was consistently conserved in every core level. Interestingly, we observed that many promising biomarker genes for early cancer detection reside in the innermost core of a signaling network. Taken together, the proposed analyses of the hierarchical structure of cancer signaling networks may be useful in developing future novel cancer treatments.

Yoo JY, Kang HB, Broaddus RR, et al.
MIG-6 suppresses endometrial epithelial cell proliferation by inhibiting phospho-AKT.
BMC Cancer. 2018; 18(1):605 [PubMed] Article available free on PMC after 01/09/2019 Related Publications
BACKGROUND: Aberrant hyperactivation of epithelial proliferation, AKT signaling, and association with unopposed estrogen (E2) exposure is the most common endometrial cancer dysfunction. In the normal uterus, progesterone (P4) inhibits proliferation by coordinating stromal-epithelial cross-talk, which we previously showed is mediated by the function of Mitogen-inducible gene 6 (Mig-6). Despite their attractive characteristics, non-surgical conservative therapies based on progesterone alone have not been universally successful. One barrier to this success has been the lack of understanding of the P4 effect on endometrial cells.
METHOD: To further understand the role of Mig-6 and P4 in controlling uterine proliferation, we developed a Sprr2f-cre driven mouse model where Mig-6 is specifically ablated only in the epithelial cells of the uterus (Sprr2f
RESULTS: Sprr2f
CONCLUSIONS: These data suggest that endometrial epithelial cell proliferation is regulated by P4 mediated Mig-6 inhibition of AKT phosphorylation, uncovering new mechanisms of P4 action. This information may help guide more effective non-surgical interventions in the future.

Wu Q, Li Z, Liu Q
An important role of SREBP-1 in HBV and HCV co-replication inhibition by PTEN.
Virology. 2018; 520:94-102 [PubMed] Related Publications
HBV HCV co-infection leads to more severe liver diseases including liver cancer than mono-infections. Phosphatase and tensin homolog deleted on chromosome 10 (PTEN), a tumor suppressor, inhibits sterol regulatory element binding protein-1 (SREBP-1). In this study, we characterized the effect of the PTEN - SREBP-1 pathway on HBV HCV co-replication in a cellular model. We found that HBV and HCV can co-replicate in Huh-7 cells with no interference. Overexpression of PTEN inhibits, whereas PTEN knockdown enhances, HBV replication as well as HBV and HCV co-replication. Knocking down SREBP-1 decreases HBV replication in an HBx-dependent manner. SREBP-1 knockdown also decreases HCV replication. PTEN knockdown is concomitant with increased nuclear SREBP-1 levels. PTEN and SREBP-1 double knockdown results in intermediate levels of HBV and HCV replication in mono- and co-replication scenarios. Taken together, we demonstrated, for the first time, that the PTEN - SREBP-1 pathway can regulate HBV HCV co-replication.

Jiao X, Yu W, Qian J, et al.
ADAM-17 is a poor prognostic indicator for patients with hilar cholangiocarcinoma and is regulated by FoxM1.
BMC Cancer. 2018; 18(1):570 [PubMed] Article available free on PMC after 01/09/2019 Related Publications
BACKGROUND: A-disintegrin and metalloproteinases (ADAMs) are members of a family of multidomain transmembrane and secreted proteins. Specific ADAMs are upregulated in human cancers and correlated with tumor progression and poor outcome, but rarely studied in human hilar cholangiocarcinoma (HC). This study aimed to explore the expression profiles of ADAMs and their potential underlying mechanisms promoting cancer progression.
METHODS: mRNA expression of ADAM-9, - 10, - 11, - 12, - 15, - 17, - 28, and - 33 was analyzed in human hilar cholangiocarcinoma (HC) samples. Immunohistochemical (IHC) analysis was used to detect the expression of ADAM-10, - 17, - 28, and FoxM1 in HC. The regulation of ADAM-17 by FoxM1 and their functional study was investigated in vivo and in vitro.
RESULTS: ADAM-10, - 17, and - 28 were upregulated in tumors compared with matched non-cancerous tissues. IHC analysis revealed increased expression of ADAM-10, - 17, and - 28 in HC cells, and ADAM17 seems to be an independent prognostic factor. ADAM-17 is regulated by FoxM1. A decrease in the expression of ADAM-17 by silencing FoxM1 led to an inhibition of cell proliferation, tumor growth, and the production of tumor necrosis factor α. IHC analysis showed co-expression of FoxM1 and ADAM-17 in HC specimens.
CONCLUSIONS: The findings of the present study show an important role of the cross-talk among FoxM1, ADAM-17, and TNFa in HC development and progression.

Bond MJ, Bleiler M, Harrison LE, et al.
Spindle Assembly Disruption and Cancer Cell Apoptosis with a CLTC-Binding Compound.
Mol Cancer Res. 2018; 16(9):1361-1372 [PubMed] Article available free on PMC after 01/09/2019 Related Publications
AK3 compounds are mitotic arrest agents that induce high levels of γH2AX during mitosis and apoptosis following release from arrest. We synthesized a potent AK3 derivative, AK306, that induced arrest and apoptosis of the HCT116 colon cancer cell line with an EC

Zhang J, Zhu Z, Wu H, et al.
PODXL, negatively regulated by KLF4, promotes the EMT and metastasis and serves as a novel prognostic indicator of gastric cancer.
Gastric Cancer. 2019; 22(1):48-59 [PubMed] Article available free on PMC after 01/09/2019 Related Publications
BACKGROUND: Podocalyxin-like 1 (PODXL) was reported to be closely associated with the development of various cancers, yet its functional roles and molecular mechanisms remain vague. The aim of our study was to investigate the clinical significance, biological function and molecular mechanism of PODXL in gastric cancer (GC).
METHODS: The level of PODXL in GC tissues was detected applying GC tissues microarray, fresh GC tissues and public database (Oncomine). The invasion, metastasis and tumorigenesis role of PODXL were performed in vitro and in vivo. The correlations between KLF4 and PODXL was determined in GC tissues microarray and fresh GC tissues, and the molecular regulatory mechanism between KLF4 and PODXL was explored in vitro.
RESULTS: The high level of PODXL was detected in GC tissues with advanced T stage, lymph node metastasis, Union for International Cancer Control stage and poor differentiation. And Cox proportional hazards model revealed that PODXL can serve as an independent prognostic indicator for disease-free survival and overall survival of GC patients. Moreover, downregulation of PODXL could inhibit EMT and reduce invasion and metastasis in vitro as well as tumorigenesis in vivo. Additionally, our findings showed that PODXL may be a significant downstream target of KLF4.
CONCLUSIONS: KLF4/PODXL signaling pathway assumes an irreplaceable role in tumorigenesis, invasion and metastasis of human GC and PODXL serves as an independent prognostic indicator for GC patients.

Tat Trung N, Duong DC, Tong HV, et al.
Optimisation of quantitative miRNA panels to consolidate the diagnostic surveillance of HBV-related hepatocellular carcinoma.
PLoS One. 2018; 13(4):e0196081 [PubMed] Article available free on PMC after 01/09/2019 Related Publications
BACKGROUND: Circulating microRNAs (miRNA) are biomarkers for several neoplastic diseases, including hepatocellular carcinoma (HCC). We performed a literature search, followed by experimental screening and validation in order to establish a miRNA panel in combination with the assessment of alpha-fetoprotein (AFP) levels and to evaluate its performance in HCC diagnostics.
METHODS: Expression of miRNAs was quantified by quantitative PCR (qPCR) in 406 serum samples from 118 Vietnamese patients with hepatitis B (HBV)-related HCC, 69 patients with HBV-related liver cirrhosis (LC), 100 chronic hepatitis B (CHB) patients and 119 healthy controls (HC).
RESULTS: Three miRNAs (mir-21, mir-122, mir-192) were expressed differentially among the studied subgroups and positively correlated with AFP levels. The individual miRNAs mir-21, mir-122, mir192 or the triplex miRNA panel showed high diagnostic accuracy for HCC (HCC vs. CHB, AUC = 0.906; HCC vs. CHB+LC, AUC = 0.81; HCC vs. CHB+LC+HC, AUC = 0.854). When AFP levels were ≤20ng/ml, the triplex miRNA panel still was accurate in distinguishing HCC from the other conditions (CHB, AUC = 0.922; CHB+LC, AUC = 0.836; CHB+LC+HC, AUC = 0.862). When AFP levels were used in combination with the triplex miRNA panel, the diagnostic performance was significantly improved in discriminating HCC from the other groups (LC, AUC = 0.887; CHB, AUC = 0.948; CHB+LC, AUC = 0.887).
CONCLUSIONS: The three miRNAs mir-21, mir-122, mir-192, together with AFP, are biomarkers that may be applied to improve diagnostics of HCC in HBV patients, especially in HBV-related LC patients with normal AFP levels or HCC patients with small tumor sizes.

Grande IPP, Amorim PVGH, Freire ACTB, et al.
Differential gene expression of sirtuins between somatotropinomas and nonfunctioning pituitary adenomas.
Pituitary. 2018; 21(4):355-361 [PubMed] Related Publications
Sirtuins 1-7 (SIRT) are a highly conserved family of histone deacetylases involved in the regulation of longevity that have a considerable impact in transcription, DNA repair regulation, telomeric stability, cell senescence and apoptosis. In the present study, SIRT1-7 mRNA levels were evaluated in 37 somatotropinomas and 31 nonfunctioning pituitary adenomas (NFPAs) using qPCR and relation to tumor size, invasiveness and Ki-67 proliferative index was made. Overexpression of SIRT1 was observed in 86.5% of somatotropinomas versus 41.9% of NFPAs (P < 0.01). SIRT3 was more underexpressed in NFPAs than somatotropinomas (77.4 and 40.5%, respectively, P < 0.01) as well as SIRT4 and SIRT7. Despite the lack of association between sirtuins and invasiveness or Ki-67 index, SIRT1 and SIRT3 expressions were related to tumor size. Mean of the largest diameter was smaller in adenomas with SIRT1 overexpression than with normal expression (P < 0.01) and SIRT3 underexpression was associated with larger tumors (P < 0.01). In conclusion, a pronounced difference in sirtuins expression was identified between pituitary adenomas, suggesting that these genes are potential markers of pituitary adenomas and could be employed in the characterization of somatotropinomas and NFPAs. The role of sirtuins in pathogenesis of pituitary tumors merits further investigation and possibly will provide new molecular insight about their progression.

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