Gene Summary

Gene:TFF2; trefoil factor 2
Aliases: SP, SML1
Summary:Members of the trefoil family are characterized by having at least one copy of the trefoil motif, a 40-amino acid domain that contains three conserved disulfides. They are stable secretory proteins expressed in gastrointestinal mucosa. Their functions are not defined, but they may protect the mucosa from insults, stabilize the mucus layer and affect healing of the epithelium. The encoded protein inhibits gastric acid secretion. This gene and two other related trefoil family member genes are found in a cluster on chromosome 21. [provided by RefSeq, Jul 2008]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:trefoil factor 2
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.

  • Amino Acid Sequence
  • Gene Expression Profiling
  • Pancreatic Cancer
  • Young Adult
  • Adenoma
  • Promoter Regions
  • Gastric Mucosa
  • Immunohistochemistry
  • Transfection
  • Upstream Stimulatory Factors
  • Neuropeptides
  • Bile Duct Cancer
  • Disease Progression
  • Muscle Proteins
  • Stomach Cancer
  • Cancer Gene Expression Regulation
  • Mucins
  • Up-Regulation
  • Neoplasm Proteins
  • Case-Control Studies
  • DNA Methylation
  • Adenocarcinoma
  • Cancer RNA
  • Growth Substances
  • Trefoil Factor-1
  • Breast Cancer
  • Neoplastic Cell Transformation
  • Metaplasia
  • Proteins
  • Trefoil Factor-2
  • Polymerase Chain Reaction
  • Down-Regulation
  • Biomarkers, Tumor
  • Peptides
  • Molecular Sequence Data
  • Cell Proliferation
  • Gene Expression
  • Signal Transduction
  • Messenger RNA
  • Chromosome 21
Tag cloud generated 29 August, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (5)

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

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

Latest Publications: TFF2 (cancer-related)

Zhang GH, Chen MM, Kai JY, et al.
Molecular profiling of mucinous epithelial ovarian cancer by weighted gene co-expression network analysis.
Gene. 2019; 709:56-64 [PubMed] Related Publications
PURPOSE: In order to identify the molecular characteristics and improve the efficacy of early diagnosis of mucinous epithelial ovarian cancer (mEOC), here, the transcriptome profiling by weighted gene co-expression network analysis (WGCNA) has been proposed as an effective method.
METHODS: The gene expression dataset GSE26193 was reanalyzed with a systematical approach, WGCNA. mEOC-related gene co-expression modules were detected and the functional enrichments of these modules were performed at GO and KEGG terms. Ten hub genes in the mEOC-related modules were validated using two independent datasets GSE44104 and GSE30274.
RESULTS: 11 co-expressed gene modules were identified by WGCNA based on 4917 genes and 99 epithelial ovarian cancer samples. The turquoise module was found to be significantly associated with the subtype of mEOC. KEGG pathway enrichment analysis showed genes in the turquoise module significantly enriched in metabolism of xenobiotics by cytochrome P450 and steroid hormone biosynthesis. Ten hub genes (LIPH, BCAS1, FUT3, ZG16B, PTPRH, SLC4A4, MUC13, TFF1, HNF4G and TFF2) in the turquoise module were validated to be highly expressed in mEOC using two independent gene expression datasets GSE44104 and GSE30274.
CONCLUSION: Our work proposed an applicable framework of molecular characteristics for patients with mEOC, which may help us to obtain a precise and comprehensive understanding on the molecular complexities of mEOC. The hub genes identified in our study, as potential specific biomarkers of mEOC, may be applied in the early diagnosis of mEOC in the future.

Rodrigues-Junior DM, Tan SS, de Souza Viana L, et al.
A preliminary investigation of circulating extracellular vesicles and biomarker discovery associated with treatment response in head and neck squamous cell carcinoma.
BMC Cancer. 2019; 19(1):373 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: There is a paucity of plasma-based biomarkers that prospectively segregate the outcome of patients with head and neck squamous-cell carcinoma (HNSCC) treated with chemoradiation therapy (CRT). Plasma extracellular vesicles (EVs) might be an alternative source for discovery of new specific markers present in patients with HNSCC, which could help to re-direct patients to appropriate curative therapies without delay.
METHODS: In order to identify new markers in plasma compartments, Cholerae toxin B chain (CTB) and Annexin V (AV) were used to isolate EVs from pooled plasma samples from patients with locally advanced HNSCC who responded (CR, n = 6) or presented incomplete response (NR, n = 6) to CRT. The crude plasma and EVs cargo were screened by antibody array.
RESULTS: Of the 370 polypeptides detected, 119 proteins were specific to NR patients while 38 were exclusive of the CR subjects. The Gene Set Enrichment Analysis (GSEA) and Search Tool for the Retrieval of Interacting Genes (STRING) database analysis indicated that the content of circulating plasma EVs might have a relevant function for the tumor intercellular communication in the HNSCC patients.
CONCLUSION: This study provides a list of potential markers present in plasma compartments that might contribute to the development of tools for prediction and assessment of CRT response and potentially guide therapeutic decisions in this context.

Ji M, Liu L, Hou Y, Li B
1α,25‑Dihydroxyvitamin D3 restrains stem cell‑like properties of ovarian cancer cells by enhancing vitamin D receptor and suppressing CD44.
Oncol Rep. 2019; 41(6):3393-3403 [PubMed] Related Publications
Scientific evidence linking vitamin D with various cancer types is growing, but the effects of vitamin D on ovarian cancer stem cell‑like cells (CSCs) are largely unknown. The present study aimed to examine whether vitamin D was able to restrain the stemness of ovarian cancer. A side population (SP) from malignant ovarian surface epithelial cells was identified as CSCs, in vitro and in vivo. Furthermore, 1α,25‑dihydroxyvitamin D3 [1α,25(OH)2D3] treatment inhibited the self‑renewal capacity of SP cells by decreasing the sphere formation rate and by suppressing the mRNA expression levels of cluster of differentiation CD44, NANOG, OCT4, SOX2, Krüppel‑like factor 4 and adenosine triphosphate binding cassette subfamily G member 2. Additionally, 1α,25(OH)2D3 treatment decreased the expression of Cyclin D1, whereas it increased the expression of β‑catenin and vitamin D receptor (VDR). Notably, immunofluorescence staining verified that 1α,25(OH)2D3 promoted the expression of β‑catenin in the cytoplasm. Furthermore, vitamin D3 delayed the onset of tumor formation derived from injection of ovarian CSCs to nude mice, by reducing CD44 and enhancing β‑catenin expressions in vivo. In conclusion, 1α,25(OH)2D3 restrains the stem cell‑like properties of ovarian cancer cells by enhancing the expression of VDR, by promoting the expression of β‑catenin in the cytoplasm, and by suppressing the expression of CD44. These findings provide a novel insight into the functions of vitamin D in diminishing the stemness of cancer CSCs.

Jahan R, Ganguly K, Smith LM, et al.
Trefoil factor(s) and CA19.9: A promising panel for early detection of pancreatic cancer.
EBioMedicine. 2019; 42:375-385 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Trefoil factors (TFF1, TFF2, and TFF3) are small secretory molecules that recently have gained significant attention in multiple studies as an integral component of pancreatic cancer (PC) subtype-specific gene signature. Here, we comprehensively investigated the diagnostic potential of all the member of trefoil family, i.e., TFF1, TFF2, and TFF3 in combination with CA19.9 for detection of PC.
METHODS: Trefoil factors (TFFs) gene expression was analyzed in publicly available cancer genome datasets, followed by assessment of their expression in genetically engineered spontaneous mouse model (GEM) of PC (KrasG12D; Pdx1-Cre (KC)) and in human tissue microarray consisting of normal pancreas adjacent to tumor (NAT), precursor lesions (PanIN), and various pathological grades of PC by immunohistochemistry (IHC). Serum TFFs and CA19.9 levels were evaluated via ELISA in comprehensive sample set (n = 362) comprised of independent training and validation sets each containing benign controls (BC), chronic pancreatitis (CP), and various stages of PC. Univariate and multivariate logistic regression and receiver operating characteristic curves (ROC) were used to examine their diagnostic potential both alone and in combination with CA19.9.
FINDINGS: The publicly available datasets and expression analysis revealed significant increased expression of TFF1, TFF2, and TFF3 in human PanINs and PC tissues. Assessment of KC mouse model also suggested upregulated expression of TFFs in PanIN lesions and early stage of PC. In serum analyses studies, TFF1 and TFF2 were significantly elevated in early stages of PC in comparison to benign and CP control group while significant elevation in TFF3 levels were observed in CP group with no further elevation in its level in early stage PC group. In receiver operating curve (ROC) analyses, combination of TFFs with CA19.9 emerged as promising panel for discriminating early stage of PC (EPC) from BC (AUC
INTERPRETATION: In silico, tissue and serum analyses validated significantly increased level of all TFFs in precursor lesions and early stages of PC. The combination of TFFs enhanced sensitivity and specificity of CA19.9 to discriminate early stage of PC from benign control and chronic pancreatitis groups.

Giorgenon TMV, Carrijo FT, Arruda MA, et al.
Preoperative detection of TERT promoter and BRAFV600E mutations in papillary thyroid carcinoma in high-risk thyroid nodules.
Arch Endocrinol Metab. 2019 Mar-Apr; 63(2):107-112 [PubMed] Related Publications
OBJECTIVES: This observational study analyzed telomerase reverse transcriptase (pTERT) mutations in 45 fine-needle aspiration (FNA) specimens obtained from thyroid nodules followed by postoperatively confirmation of papillary thyroid cancer (PTC) diagnosis, examining their relationship with clinicopathologic aspects and the BRAFV600E mutation.
SUBJECTS AND METHODS: Clinical information was collected from patients who presented to Ribeirao Preto University Hospital for surgical consultation regarding a thyroid nodule and who underwent molecular testing between January 2010 to October 2012. Tests included a DNA-based somatic detection of BRAFV600E and pTERT mutations.
RESULTS: We found coexistence of pTERTC228T and BRAFV600E mutations in 8.9% (4/45) of thyroid nodules. All nodules positive for pTERT mutations were BRAFV600E positives. There was a significant association between pTERTC228T/BRAFV600E with older age and advanced stage compared with the group negative for either mutation.
CONCLUSIONS: This series provides evidence that FNA is a reliable method for preoperative diagnosis of high-risk thyroid nodules. pTERTC228T/BRAFV600E mutations could be a marker of poor prognosis. Its use as a personalized molecular medicine tool to individualize treatment decisions and follow-up design needs to be further studied.

Silva TM, Moretto FCF, Sibio MT, et al.
Triiodothyronine (T3) upregulates the expression of proto-oncogene TGFA independent of MAPK/ERK pathway activation in the human breast adenocarcinoma cell line, MCF7.
Arch Endocrinol Metab. 2019 Mar-Apr; 63(2):142-147 [PubMed] Related Publications
OBJECTIVE: To verify the physiological action of triiodothyronine T3 on the expression of transforming growth factor α (TGFA) mRNA in MCF7 cells by inhibition of RNA Polymerase II and the MAPK/ERK pathway.
MATERIALS AND METHODS: The cell line was treated with T3 at a physiological dose (10-9M) for 10 minutes, 1 and 4 hour (h) in the presence or absence of the inhibitors, α-amanitin (RNA polymerase II inhibitor) and PD98059 (MAPK/ERK pathway inhibitor). TGFA mRNA expression was analyzed by RT-PCR. For data analysis, we used ANOVA, complemented with the Tukey test and Student t-test, with a minimum significance of 5%.
RESULTS: T3 increases the expression of TGFA mRNA in MCF7 cells in 4 h of treatment. Inhibition of RNA polymerase II modulates the effect of T3 treatment on the expression of TGFA in MCF7 cells. Activation of the MAPK/ERK pathway is not required for T3 to affect the expression of TGFA mRNA.
CONCLUSION: Treatment with a physiological concentration of T3 after RNA polymerase II inhibition altered the expression of TGFA. Inhibition of the MAPK/ERK pathway after T3 treatment does not interfere with the TGFA gene expression in a breast adenocarcinoma cell line.

Li YJ, Qing X, Tao QX, et al.
Vasculogenic Mimicry Formation Is Associated with Erythropoietin Expression but Not with Erythropoietin Receptor Expression in Cervical Squamous Cell Carcinoma.
Biomed Res Int. 2019; 2019:1934195 [PubMed] Free Access to Full Article Related Publications
Background: Vasculogenic mimicry (VM), as an endothelium-independent cancer microcirculation, has been observed in many malignancies including cervical cancer. Erythropoietin (EPO) and erythropoietin receptor (EPO-R) could produce an angiogenic effect to promote cervical squamous cell carcinoma (CSCC) progression. However, the association between VM formation and EPO/EPO-R expression in CSCC is poorly explored.
Methods: Seventy-six paraffin-embedded CSCC samples, 25 high-grade squamous intraepithelial lesion (HSIL) samples, 20 low-grade squamous intraepithelial lesion (LSIL) samples, and 20 normal cervix samples were collected. Immunohistochemistry SP method was performed to detect EPO/EPO-R expression and CD31/periodic acid-Schiff (PAS) double staining was performed to detect VM formation. The associations of EPO/EPO-R and VM with clinicopathological parameters of CSCC were analyzed. The associations between VM formation and EPO/EPO-R expression were also analyzed.
Results: The positive expression rates of EPO and EPO-R were gradually increasing along the progression of normal cervix-LSIL-HSIL-CSCC sequence (
Conclusion: These data suggest that increased EPO/EPO-R expression may play an important role in cervical carcinogenesis. EPO overexpression may promote VM formation in CSCC.

Murakami R, Matsumura N, Michimae H, et al.
The mesenchymal transition subtype more responsive to dose dense taxane chemotherapy combined with carboplatin than to conventional taxane and carboplatin chemotherapy in high grade serous ovarian carcinoma: A survey of Japanese Gynecologic Oncology Group study (JGOG3016A1).
Gynecol Oncol. 2019; 153(2):312-319 [PubMed] Related Publications
OBJECTIVE: Recently, we established new histopathological subtypes of high-grade serous ovarian cancer (HGSOC) that include the mesenchymal transition (MT) type, the immune reactive (IR) type, the solid and proliferative (SP) type and the papillo-glandular (PG) type. Furthermore, we identified that the mesenchymal transcriptome subtype might be sensitive to taxane. We investigated whether these different histopathological subtypes of HGSOC require individualized chemotherapy for optimal treatment.
METHODS: We conducted the Japanese Gynecologic Oncology Group (JGOG) 3016A1 study, wherein we collected hematoxylin and eosin slides (total n = 201) and performed a histopathological analysis of patients with HGSOC registered in the JGOG3016 study, which compared the efficacy of conventional paclitaxel and carboplatin (TC) and dose-dense TC (ddTC). We analyzed the differences in progression-free survival (PFS) and overall survival (OS) among the four histopathological subtypes. We then compared the PFS between the TC group and the ddTC group for each histopathological subtype.
RESULTS: There were significant differences in both PFS and OS among the four histopathological subtypes (p = 0.001 and p < 0.001, respectively). Overall, the MT subtype had the shortest PFS (median 1.4 y) and OS (median 3.6 y). In addition, the MT subtype had a longer PFS in the ddTC group (median 1.8 y) than in the TC group (median 1.2 y) (p = 0.01). Conversely, the other types had no significant difference in PFS when the two regimens were compared.
CONCLUSIONS: The MT type of HGSOC is sensitive to taxane; therefore, the ddTC regimen is recommended for this histopathological subtype.

Liu H, Wang J, Tao Y, et al.
Curcumol inhibits colorectal cancer proliferation by targeting miR-21 and modulated PTEN/PI3K/Akt pathways.
Life Sci. 2019; 221:354-361 [PubMed] Related Publications
AIMS: The purpose of this study was to demonstrate how curcumol affected the expression of miR-21 and whether its effects on miR-21 was associated with the activation of PTEN/PI3K/Akt pathways in CRC cells.
MAIN METHODS: MTT and xenograft assay were used to examine how curcumol inhibits colorectal cancer (CRC) cells' growth. Q-PCR and western blot analysis were employed to test the role of miR-21 in the inhibition of curcumol on proliferation and PTEN/PI3K/Akt pathways of CRC cells.
KEY FINDINGS: We found that curcumol effectively inhibited CRC cells from proliferating via the PTEN/PI3K/Akt pathways and reduced expression of miR-21 both in vitro and in vivo. miR-21 mimics were found to decrease the protein level of PTEN and increase the expression of PI3K, phospho-Akt (p-Akt) and NF-κB, while miR-21 sponge (miR-21-SP) enhanced the expression of PTEN and reduced the activity of PI3K, Akt and NF-κB. Furthermore, miR-21-SP strengthened the role of curcumol in up-regulating PTEN and inhibiting PI3K/Akt pathways, but miR-21 reversed the effect of curcumol on the PTEN/PI3K/Akt pathways.
SIGNIFICANCE: Our research demonstrated that curcumol reduced the proliferation of CRC cells through PTEN/PI3K/Akt by targeting miR-21 and miR-21 could be a target molecule of curcumol for CRC treatment.

Velloso FJ, Campos AR, Sogayar MC, Correa RG
Proteome profiling of triple negative breast cancer cells overexpressing NOD1 and NOD2 receptors unveils molecular signatures of malignant cell proliferation.
BMC Genomics. 2019; 20(1):152 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Triple negative breast cancer (TNBC) is a malignancy with very poor prognosis, due to its aggressive clinical characteristics and lack of response to receptor-targeted drug therapy. In TNBC, immune-related pathways are typically upregulated and may be associated with a better prognosis of the disease, encouraging the pursuit for immunotherapeutic options. A number of immune-related molecules have already been associated to the onset and progression of breast cancer, including NOD1 and NOD2, innate immune receptors of bacterial-derived components which activate pro-inflammatory and survival pathways. In the context of TNBC, overexpression of either NOD1or NOD2 is shown to reduce cell proliferation and increase clonogenic potential in vitro. To further investigate the pathways linking NOD1 and NOD2 signaling to tumorigenesis in TNBC, we undertook a global proteome profiling of TNBC-derived cells ectopically expressing each one of these NOD receptors.
RESULTS: We have identified a total of 95 and 58 differentially regulated proteins in NOD1- and NOD2-overexpressing cells, respectively. We used bioinformatics analyses to identify enriched molecular signatures aiming to integrate the differentially regulated proteins into functional networks. These analyses suggest that overexpression of both NOD1 and NOD2 may disrupt immune-related pathways, particularly NF-κB and MAPK signaling cascades. Moreover, overexpression of either of these receptors may affect several stress response and protein degradation systems, such as autophagy and the ubiquitin-proteasome complex. Interestingly, the levels of several proteins associated to cellular adhesion and migration were also affected in these NOD-overexpressing cells.
CONCLUSIONS: Our proteomic analyses shed new light on the molecular pathways that may be modulating tumorigenesis via NOD1 and NOD2 signaling in TNBC. Up- and downregulation of several proteins associated to inflammation and stress response pathways may promote activation of protein degradation systems, as well as modulate cell-cycle and cellular adhesion proteins. Altogether, these signals seem to be modulating cellular proliferation and migration via NF-κB, PI3K/Akt/mTOR and MAPK signaling pathways. Further investigation of altered proteins in these pathways may provide more insights on relevant targets, possibly enabling the immunomodulation of tumorigenesis in the aggressive TNBC phenotype.

Laus AC, de Paula FE, de Lima MA, et al.
EGF+61 A>G polymorphism is not associated with lung cancer risk in the Brazilian population.
Mol Biol Rep. 2019; 46(2):2417-2425 [PubMed] Related Publications
Epidermal growth factor (EGF) and its receptor (EGFR) play an important role in lung carcinogenesis. A functional single nucleotide polymorphism (SNP) in EGF promoter region (EGF+61 A>G-rs4444903) has been associated with cancer susceptibility. Yet, in lung cancer, the EGF+61 A>G role is unclear. The aim of this study was to evaluate the risk of lung cancer associated with EGF+61 A>G SNP in the Brazilian population. For that, 669 lung cancer patients and 1104 controls were analyzed. EGF+61 A>G genotype was assessed by PCR-RFLP and TaqMan genotyping assay. Both patients and controls were in Hardy-Weinberg equilibrium. As expected, uni- and multivariate analyses showed that tobacco consumption and age were significant risk factors for lung cancer. The genotype frequencies in lung cancer patients were 27.3% of AA, 47.4% of AG and 25.3% of GG, and for controls were 25.3% of AA, 51.6% of AG and 23.1% of GG. The allele frequencies were 51.1% of A and 48.9% of G for both cases and controls. No significant differences for the three genotypes (AA, AG and GG-codominant model) were observed between cases and controls. We then grouped AG and GG (recessive model) genotypes, as well as AA and AG (dominant model), and again, no significant differences were also found. This is the largest study to explore EGF+61 A>G polymorphism association with lung cancer risk and suggests that this SNP is not a risk factor for lung cancer in the Brazilian population.

Cao Y, Huang HY, Chen LQ, et al.
Enhanced Lysosomal Escape of pH-Responsive Polyethylenimine-Betaine Functionalized Carbon Nanotube for the Codelivery of Survivin Small Interfering RNA and Doxorubicin.
ACS Appl Mater Interfaces. 2019; 11(10):9763-9776 [PubMed] Related Publications
The combination of gene therapy and chemotherapy has recently received considerable attention for cancer treatment. However, low transfection efficiency and poor endosomal escape of genes from nanocarriers strongly limit the success of the clinical use of small interfering RNA (siRNA). In this study, a novel pH-responsive, surface-modified single-walled carbon nanotube (SWCNT) was designed for the codelivery of doxorubicin (DOX) and survivin siRNA. Polyethylenimine (PEI) was covalently conjugated with betaine, and the resulting PEI-betaine (PB) was further synthesized with the oxidized SWCNT to form SWCNT-PB (SPB), which exhibits an excellent pH-responsive lysosomal escape of siRNA. SPB was modified with the targeting and penetrating peptide BR2 (SPBB), thereby achieving considerably higher uptake of siRNA than SWCNT-PEI (SP) or SPB. Furthermore, SPBB-siRNA presented substantially lower survivin expression and higher apoptotic index than Lipofectamine 2000. DOX and survivin siRNA were adsorbed onto SPB to form DOX-SPBB-siRNA, and siRNA/DOX was released into the cytoplasm and nuclei of adenocarcinomic human alveolar basal epithelial (A549) cells without lysosomal retention. Compared with SPBB-siRNA or DOX-SPBB treatment alone, DOX-SPBB-siRNA significantly reduced tumor volume in A549 cell-bearing nude mice, demonstrating the synergistic effects of DOX and survivin siRNA. Pathological analysis also indicated the potential therapeutic effects of DOX-SPBB-siRNA on tumors without distinct damages to normal tissues. In conclusion, the novel functionalized SWCNT loaded with DOX and survivin siRNA was successfully synthesized, and the nanocomplex exhibited effective antitumor effects both in vitro and in vivo, thereby providing an alternative strategy for the codelivery of antitumor drugs and genes.

Feng E, Liang T, Wang X, et al.
Correlation of alteration of HLA-F expression and clinical characterization in 593 brain glioma samples.
J Neuroinflammation. 2019; 16(1):33 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Human gliomas are highly fatal tumors with a significant feature of immune suppression. The association of the immune system in gliomas is gradually revealed, and immunotherapy is expected to improve the survival of glioma patients. In-depth understanding of the immune microenvironment of gliomas and their associated immunotherapy was increased exponentially in recent years. Gliomas provide clinical targets for immunotherapy during the search of key regulators of immune response. Our study focused on the human leukocyte antigen (HLA) system that is responsible for regulating the immune system, and discovered the relationship between HLA-F expression and clinical prognosis in gliomas.
METHODS: A total of 593 patients with gliomas were included in our research. Of these, 325 patients were from the Chinese Glioma Genome Atlas (CGGA) and 268 were from the GSE 16011 set. Kaplan-Meier (KM) analysis was performed to explore the prognostic value of HLA-F. t test analysis was used to find the distribution difference in various groups. R language packages are used for other statistical computations and figure drawing.
RESULTS: HLA-F was negatively correlated with overall survival (OS) in all grades of glioma and glioblastoma (GBM). Moreover, HLA-F was enriched in GBM and isocitrate dehydrogenase 1 wild-type (IDH1 wt) group and considered HLA-F as a mesenchymal subtype marker. Pearson correlation test showed that HLA-F was correlated with other HLA-I molecules.
CONCLUSION: HLA-F expression was positively correlated with malignant phenotype and negatively correlated with OS, indicating that HLA-F could predict the immune state of gliomas and might be a clinical target of glioma immunotherapy.

Lira MLA, Almeida MA, Reis-Feroldi MM, Rocha JA
Follicular thyroid carcinoma metastatic to skin: a small papule and a big diagnostic change.
An Bras Dermatol. 2019 Jan-Feb; 94(1):76-78 [PubMed] Free Access to Full Article Related Publications
Cutaneous metastases are uncommon in daily practice, although very important, since they may be the first manifestation of an undiscovered primary neoplasm or the first indication of recurrence. Cutaneous metastases from the breast are the most frequent in women and cutaneous metastases from the lung are the most frequent in men. Thyroid carcinoma, despite representing the most frequent endocrine neoplasm, is considered a rare neoplasm, corresponding to 1% of malignant neoplasms diagnosed. Cutaneous metastases from follicular carcinoma are rare and occur mainly in the head and neck area. We report a case of cutaneous metastasis in a patient with follicular thyroid carcinoma and breast carcinoma. Because of the association of these two neoplasms, the possibility of Cowden Syndrome - multiple hamartoma syndrome - was raised, but was excluded by genetic analysis of PTEN gene.

Jiang X, Finucane HK, Schumacher FR, et al.
Shared heritability and functional enrichment across six solid cancers.
Nat Commun. 2019; 10(1):431 [PubMed] Free Access to Full Article Related Publications
Quantifying the genetic correlation between cancers can provide important insights into the mechanisms driving cancer etiology. Using genome-wide association study summary statistics across six cancer types based on a total of 296,215 cases and 301,319 controls of European ancestry, here we estimate the pair-wise genetic correlations between breast, colorectal, head/neck, lung, ovary and prostate cancer, and between cancers and 38 other diseases. We observed statistically significant genetic correlations between lung and head/neck cancer (r

Coa LL, Abreu TF, Tashima AK, et al.
AKT/protein kinase B associates with β-actin in the nucleus of melanoma cells.
Biosci Rep. 2019; 39(1) [PubMed] Free Access to Full Article Related Publications
The serine-threonine kinase AKT/PKB is a critical regulator of various essential cellular processes, and dysregulation of AKT has been implicated in many diseases, including cancer. Despite AKT action is known to function mainly in the cytoplasm, AKT has been reported to translocate to the nucleus. However, very little is known about the mechanism required for the nuclear import of AKT as well as its function in this cellular compartment. In the present study, we characterized the presence of endogenous nuclear AKT in human melanoma cells and addressed the possible role of AKT by exploring its potential association with key interaction nuclear partners. Confocal and Western blot analyses showed that both phosphorylated and non-phosphorylated forms of AKT are present in melanoma cells nuclei. Using mass spectrometry in combination with protein-crosslinking and co-immunoprecipitation, we identified a series of putative protein partners of nuclear AKT, including heterogeneous nuclear ribonucleoprotein (hnRNP), cytoskeleton proteins β-actin, γ-actin, β-actin-like 2 and vimentin. Confocal microscopy and biochemical analyses validated β-actin as a new nuclear AKT-interacting partner. Cofilin and active RNA Polymerase II, two proteins that have been described to interact and work in concert with nuclear actin in transcription regulation, were also found associated with nuclear AKT. Overall, the present study uncovered a yet unrecognized nuclear coupling of AKT and provides insights into the involvement of AKT in the interaction network of nuclear actin.

Martins-Costa MC, Lindsey SC, Cunha LL, et al.
A pioneering RET genetic screening study in the State of Ceará, Brazil, evaluating patients with medullary thyroid cancer and at-risk relatives: experience with 247 individuals.
Arch Endocrinol Metab. 2018; 62(6):623-635 [PubMed] Related Publications
OBJECTIVE: Initial diagnosis of medullary thyroid carcinoma (MTC) is frequently associated with advanced stages and a poor prognosis. Thus, the need for earlier diagnoses and detection in relatives at risk for the disease has led to increased use of RET genetic screening.
SUBJECTS AND METHODS: We performed RET screening in 247 subjects who were referred to the Brazilian Research Consortium for Multiple Endocrine Neoplasia (BRASMEN) Center in the State of Ceará. Direct genetic sequencing was used to analyze exons 8, 10, 11, and 13-16 in MTC index cases and specific exons in at risk relatives. Afterward, clinical follow-up was offered to all the patients with MTC and their affected relatives.
RESULTS: RET screening was performed in 60 MTC index patients and 187 at-risk family members. At the initial clinical assessment of the index patients, 54 (90%) were diagnosed with apparently sporadic disease and 6 (10%) diagnosed with hereditary disease. After RET screening, we found that 31 (52%) index patients had sporadic disease, and 29 (48%) had hereditary disease. Regarding at-risk relatives, 73/187 were mutation carriers. Mutations in RET codon 804 and the rare p.M918V mutation were the most prevalent.
CONCLUSIONS: Performing RET screening in Ceará allowed us to identify a different mutation profile in this region compared with other areas. RET screening also enabled the diagnosis of a significant number of hereditary MTC patients who were initially classified as sporadic disease patients and benefited their relatives, who were unaware of the risks and the consequences of bearing a RET mutation.

Ferraz C
Can current molecular tests help in the diagnosis of indeterminate thyroid nodule FNAB?
Arch Endocrinol Metab. 2018; 62(6):576-584 [PubMed] Related Publications
Approximately 15-30% of all thyroid nodules evaluated with fine-needle aspiration biopsy (FNAB) are classified as cytologically indeterminate. The stepwise unraveling of the molecular etiology of thyroid nodules has provided the basis for a better understanding of indeterminate samples and an opportunity to decrease diagnostic surgery in this group of patients. Over the last 15 years, several studies have tested different methodologies to detect somatic mutations (by polymerase chain reaction and next-generation sequencing, for example), and to identify differentially expressed genes or microRNA, aiming at developing molecular tests to improve the presurgical diagnosis of cytologically indeterminate nodules. In this review, we will provide an overview of the currently available molecular tests and the impact of mutation testing on the diagnosis of thyroid cancer. We will also review current published data and future perspectives in molecular testing of thyroid nodule FNAB and describe the current Brazilian experience with this diagnostic approach. Based on currently available data, especially for countries outside the US-Europe axis, a rational use of these tests must be made to avoid errors with regard to test indication and interpretation of test outcomes. In addition to clinical, radiological, and cytological features, we still need to determine local malignancy rates and conduct more independent validation and comparative performance studies of these tests before including them into our routine approach to indeterminate FNAB.

Zhang M, Wang T, Sirianni R, et al.
Identifying genes with tri-modal association with survival and tumor grade in cancer patients.
BMC Bioinformatics. 2019; 20(1):13 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Previous cancer genomics studies focused on searching for novel oncogenes and tumor suppressor genes whose abundance is positively or negatively correlated with end-point observation, such as survival or tumor grade. This approach may potentially miss some truly functional genes if both its low and high modes have associations with end-point observation. Such genes act as both oncogenes and tumor suppressor genes, a scenario that is unlikely but theoretically possible.
RESULTS: We invented an Expectation-Maximization (EM) algorithm to divide patients into low-, middle- and high-expressing groups according to the expression level of a certain gene in both tumor and normal patients. We found one gene, ORMDL3, whose low and high modes were both associated with worse survival and higher tumor grade in breast cancer patients in multiple patient cohorts. We speculate that its tumor suppressor gene role may be real, while its high expression correlating with worse end-point outcome is probably due to the passenger event of the nearby ERBB2's amplification.
CONCLUSIONS: The proposed EM algorithm can effectively detect genes having tri-modal distributed expression in patient groups compared to normal genes, thus rendering a new perspective on dissecting the association between genomic features and end-point observations. Our analysis of breast cancer datasets suggest that the gene ORMDL3 may have an unexploited tumor suppressive function.

Kim KH, Cheong HJ, Lee MY, et al.
Bortezomib Is More Effective to Side Population of RPMI8226 Myeloma Cells than Classical Anti-myeloma Agents.
Anticancer Res. 2019; 39(1):127-133 [PubMed] Related Publications
AIM: Cytotoxic chemotherapy-based treatment of multiple myeloma (MM) is not curative, and the disease eventually recurs. This is partially because although currently available anti-MM strategies are effective in targeting the bulk of tumor cells, they do not target the tumor-initiating subpopulation of cancer stem cells. This study investigated the prevalence and biological functions of side population (SP) cells in MM cell lines including RPMI8226, ARH77, MM.1R and IM 9.
MATERIALS AND METHODS: Flow cytometry-based Hoechst 33342 staining was used to evaluate the existence of SP cells. In addition, the ability of SP cells to regenerate the original population was determined.
RESULTS: The frequency of SP cells was heterogeneous. Most cell lines (ARH77, IM9, and MM.1R) contained fewer than 1% SP cells; however, RPMI8226 contained approximately 10% SP cells. Sorted SP cells showed a higher proliferative ability and clonogenicity than the MP in the RPMI8226 myeloma cell line. The activity of ATP-binding cassette subfamily G member 2 (ABCG2), which is associated with high rates of proliferation, was higher in SP cells. However, the expression of specific surface markers such as cluster of differentiation (CD)138, CD34, CD38, CD19, CD20, and CD27 did not differ between SP and MP cells. Bortezomib was the only agent that significantly affected proliferation of both SP and MP cells.
CONCLUSION: Our studies demonstrated that the SP fraction of myeloma cells possessed clonogenic tumor-initiating potential and revealed new mechanisms of action for bortezomib on SP cells.

Kim J, Luo W, Wang M, et al.
Prevalence of pathogenic/likely pathogenic variants in the 24 cancer genes of the ACMG Secondary Findings v2.0 list in a large cancer cohort and ethnicity-matched controls.
Genome Med. 2018; 10(1):99 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Prior research has established that the prevalence of pathogenic/likely pathogenic (P/LP) variants across all of the American College of Medical Genetics (ACMG) Secondary Findings (SF) genes is approximately 0.8-5%. We investigated the prevalence of P/LP variants in the 24 ACMG SF v2.0 cancer genes in a family-based cancer research cohort (n = 1173) and in cancer-free ethnicity-matched controls (n = 982).
METHODS: We used InterVar to classify variants and subsequently conducted a manual review to further examine variants of unknown significance (VUS).
RESULTS: In the 24 genes on the ACMG SF v2.0 list associated with a cancer phenotype, we observed 8 P/LP unique variants (8 individuals; 0.8%) in controls and 11 P/LP unique variants (14 individuals; 1.2%) in cases, a non-significant difference. We reviewed 115 VUS. The median estimated per-variant review time required was 30 min; the first variant within a gene took significantly (p = 0.0009) longer to review (median = 60 min) compared with subsequent variants (median = 30 min). The concordance rate was 83.3% for the variants examined by two reviewers.
CONCLUSION: The 115 VUS required database and literature review, a time- and labor-intensive process hampered by the difficulty in interpreting conflicting P/LP determinations. By rigorously investigating the 24 ACMG SF v2.0 cancer genes, our work establishes a benchmark P/LP variant prevalence rate in a familial cancer cohort and controls.

Darrigo Júnior LG, Lira RCP, Fedatto PF, et al.
MicroRNA profile of pediatric pilocytic astrocytomas identifies two tumor-specific signatures when compared to non-neoplastic white matter.
J Neurooncol. 2019; 141(2):373-382 [PubMed] Related Publications
PURPOSES: Pilocytic astrocytoma (PA) is a low-grade neoplasm frequently found in childhood. PA is characterized by slow growth and a relatively good prognosis. Genetic mechanisms such as activation of MAPK, BRAF gene deregulation and neurofibromatosis type 1 (NF1) syndrome have been associated with PA development. Epigenetic signature and miRNA expression profile are providing new insights about different types of tumor, including PAs.
METHODS: In the present study we evaluated global miRNA expression in 16 microdissected pediatric PA specimens, three NF1-associated PAs and 11 cerebral white matter (WM) samples by the microarray method. An additional cohort of 20 PAs was used to validate by qRT-PCR the expression of six miRNAs differentially expressed in the microarray data.
RESULTS: Unsupervised hierarchical clustering analysis distinguished one cluster with nine PAs, including all NF1 cases and a second group consisting of the WM samples and seven PAs. Among 88 differentially expressed miRNAs between PAs and WM samples, the most underexpressed ones regulate classical pathways of tumorigenesis, while the most overexpressed miRNAs are related to pathways such as focal adhesion, P53 signaling pathway and gliomagenesis. The PAs/NF1 presented a subset of underexpressed miRNAs, which was also associated with known deregulated pathways in cancer such as cell cycle and hippo pathway.
CONCLUSIONS: In summary, our data demonstrate that PA harbors at least two distinct miRNA signatures, including a subgroup of patients with NF1/PA lesions.

Ryu TY, Kim K, Son MY, et al.
Downregulation of PRMT1, a histone arginine methyltransferase, by sodium propionate induces cell apoptosis in colon cancer.
Oncol Rep. 2019; 41(3):1691-1699 [PubMed] Free Access to Full Article Related Publications
The microbiota and bacterial metabolites in the colon are regarded as alternative targets for colon cancer prevention and therapy. Among these metabolites, short-chain fatty acids (SCFAs) exhibit anticancer effects and suppress inflammation in the colon. However, the molecular mechanisms and target development of SCFAs require additional study. In the present study, using RNA-seq results from colon cancer samples derived from the Cancer Genome Atlas (TCGA) portal, overexpressed epigenetic modifiers were identified and RT-PCR and qRT-PCR analysis was performed to select target genes that responded to treatment with propionate in HCT116 cells. Downregulation of protein arginine methyltransferase 1 (PRMT1), a histone arginine methyltransferase, was observed after sodium propionate (SP) treatment. Moreover, phospho-array analysis demonstrated that the mTOR pathway was involved in propionate and siPRMT1 treatment, and regulation of this pathway was associated with apoptosis in HCT116 cells. The present study, to the best of our knowledge, was the first to demonstrate that PRMT1 levels were reduced by propionate treatment in HCT116 cells and that downregulation of PRMT1 induced cell apoptosis. Thus, this novel mechanism of sodium propionate treatment for colon cancer therapy may indicate more effective approaches, such as dietary therapy, for CRC patients.

Hotfilder M, Mallela N, Seggewiß J, et al.
Defining a Characteristic Gene Expression Set Responsible for Cancer Stem Cell-Like Features in a Sub-Population of Ewing Sarcoma Cells CADO-ES1.
Int J Mol Sci. 2018; 19(12) [PubMed] Free Access to Full Article Related Publications
One of the still open questions in Ewing sarcoma, a rare bone tumor with weak therapeutic options, is to identify the tumor-driving cell (sub) population and to understand the specifics in the biological network of these cells. This basic scientific insight might foster the development of more specific therapeutic target patterns. The experimental approach is based on a side population (SP) of Ewing cells, based on the model cell line CADO-ES1. The SP is established by flow cytometry and defined by the idea that tumor stem-like cells can be identified by the time-course in clearing a given artificial dye. The SP was characterized by a higher colony forming activity, by a higher differentiation potential, by higher resistance to cytotoxic drugs, and by morphology. Several SP and non-SP cell fractions and bone marrow-derived mesenchymal stem cell reference were analyzed by short read sequencing of the full transcriptome. The double-differential analysis leads to an altered expression structure of SP cells centered around the AP-1 and APC/c complex. The SP cells share only a limited proportion of the full mesenchymal stem cell stemness set of genes. This is in line with the expectation that tumor stem-like cells share only a limited subset of stemness features which are relevant for tumor survival.

Tange R, Tomatsu T, Sato T
Transcription of human β4-galactosyltransferase 3 is regulated by differential DNA binding of Sp1/Sp3 in SH-SY5Y human neuroblastoma and A549 human lung cancer cell lines.
Glycobiology. 2019; 29(3):211-221 [PubMed] Related Publications
Poor prognosis of neuroblastoma patients has been shown to be associated with increased expression of β4-galactosyltransferase (β4GalT) 3. To address the underlying mechanism of the increased expression of β4GalT3, the transcriptional regulation of the human β4GalT3 gene was investigated in SH-SY5Y human neuroblastoma cell line comparing with A549 human lung cancer cell line, in which the β4GalT3 gene expression was the lowest among four cancer cell lines examined. The core promoter region was identified between nucleotides -69 and -6 relative to the transcriptional start site, and the same region was utilized in both cell lines. The promoter region contained two Specificity protein (Sp)1/3-binding sites at nucleotide positions -39/-30 and -19/-10, and the sites were crucial for the promoter activity. Although the gene expression of Sp family transcription factors Sp1 and Sp3 was comparable in each cell line, Sp3 bound to the promoter region in SH-SY5Y cells whereas Sp1 bound to the region in A549 cells. The promoter activities were enhanced by Sp1 and Sp3 in SH-SY5Y cells. In contrast, the promoter activities were enhanced by Sp1 but reduced by Sp3 in A549 cells. Furthermore, the function of each Sp1/3-binding site differed between SH-SY5Y and A549 cells due to the differential binding of Sp1/Sp3. These findings suggest that the transcription of the β4GalT3 gene is regulated by differential DNA binding of Sp3 and Sp1 in neuroblastoma and lung cancer. The increased expression of β4GalT3 in neuroblastoma may be ascribed to the enhanced expression of Sp3, which is observed for various cancers.

Brassesco MS, Valera ET, Meyer C, et al.
A new complex rearrangement in infant ALL: t(X;11;17)(p11.2;q23;q12).
Cancer Genet. 2018; 228-229:110-114 [PubMed] Related Publications
We present a case of an infant who developed pro-B acute lymphoblastic leukemia with a rare and complex MLL-translocation. Cytogenetic analysis of bone marrow cells at diagnosis showed a 46,XY,t(X;11)(p11.2;q23)[13]/46,XY[7] karyotype. Fluorescence in situ hybridization analysis using a break apart specific probes showed a split in the MLL gene. Long distance inverse-PCR and next generation sequencing analysis depicted a complex rearrangement t(X;11;17)(p11.2;q23;q12) involving MLL, MLLT6 and the genomic region Xp11.23, 41 bases upstream of the WDR45 gene. WDR45 encodes a beta-propeller protein essential for autophagocytosis. MLL rearrangements with involvement of Xp have not been previously described.

Petruk G, Roxo M, De Lise F, et al.
The marine Gram-negative bacterium Novosphingobium sp. PP1Y as a potential source of novel metabolites with antioxidant activity.
Biotechnol Lett. 2019; 41(2):273-281 [PubMed] Related Publications
OBJECTIVE: The antioxidant activity and protective effect of a methanolic extract obtained from the marine Gram-negative bacterium Novosphingobium sp. PP1Y, isolated from the surface water of a polluted area in the harbour of Pozzuoli (Naples, Italy), was evaluated.
RESULTS: The extract was tested in vitro on epithelial colorectal adenocarcinoma cells and in vivo on Caenorhabditis elegans. It showed strong protective activity against oxidative stress, in both experimental systems, by preventing ROS accumulation. In the case of the cells, pre-treatment with methanolic extract was also able to maintain unaltered intracellular GSH levels and phosphorylation levels of mitogen-activated protein kinases p38. Instead, in the case of the worms, the extract was able to modulate the expression levels of stress response genes, by activating the transcription factor skn-1.
CONCLUSIONS: From a biotechnological and economical point of view, antioxidants from microorganisms are convenient as they provide a valid alternative to chemical synthesis and respond to the ever-growing market demand for natural antioxidants.

Bezerra LS, Santos-Veloso MAO, Bezerra Junior NDS, et al.
Impacts of Cytochrome P450 2D6 (CYP2D6) Genetic Polymorphism in Tamoxifen Therapy for Breast Cancer.
Rev Bras Ginecol Obstet. 2018; 40(12):794-799 [PubMed] Related Publications
Tamoxifen (TMX) is the main drug used both in pre and postmenopausal women as adjuvant treatment for hormone receptor-positive breast cancer. An important barrier to the use of TMX is the development of drug resistance caused by molecular processes related to genetic and epigenetic mechanisms, such as the actions of cytochrome P450 2D6 (

da Silva WC, Reis EC, Oshiro TM, Pontillo A
Genetics of Inflammasomes.
Exp Suppl. 2018; 108:321-341 [PubMed] Related Publications
Mutations in inflammasome genes are responsible for rare monogenic and polygenic autoinflammatory diseases. On the other side, genetic polymorphisms in the same molecules contribute to the development of common multifactorial diseases (i.e., autoimmune diseases, cardiovascular pathologies, cancer). In this chapter we depicted the current knowledge about inflammasome genetics.

Khan M, Muzumdar D, Shiras A
Attenuation of Tumor Suppressive Function of FBXO16 Ubiquitin Ligase Activates Wnt Signaling In Glioblastoma.
Neoplasia. 2019; 21(1):106-116 [PubMed] Free Access to Full Article Related Publications
Glioblastoma (GBM) is one of the most aggressive and lethal types of brain tumor. Despite the advancements in conventional or targeted therapies, median survival of GBM patients is less than 12 months. Amongst various signaling pathways aberrantly activated in glioma, active Wnt/β-catenin signaling pathway is one of the crucial oncogenic players. β-catenin, an important mediator of Wnt signaling pathway, gets phosphorylated by GSK3β complex. Phosphorylated β-catenin is specifically recognized by β-Trcp1, a F-box/WD40-repeat protein and with the help of Skp1 it plays a central role in recruiting phosphorylated β-catenin for degradation. In GBM, expression of β-TrCP1 and its affinity for β catenin is reported to be very low. Hence, we investigated whether any other members of the E3 ubiquitin ligase family could be involved in degradation of nuclear β-catenin. We here report that FBXO16, a component of SCF E3 ubiquitin ligase complex, is an interacting protein partner for β-catenin and mediates its degradation. Next, we show that FBXO16 functions as a tumor suppressor in GBM. Under normal growth conditions, FBXO16 proteasomally degrades β-catenin in a GSK-3β independent manner. Specifically, the C-terminal region of FBXO16 targets the nuclear β-catenin for degradation and inhibits TCF4/LEF1 dependent Wnt signaling pathway. The nuclear fraction of β-catenin undergoes K-48 linked poly-ubiquitination in presence of FBXO16. In summary, we show that due to low expression of FBXO16, the β-catenin is not targeted in glioma cells leading to its nuclear accumulation resulting in active Wnt signaling. Activated Wnt signaling potentiates the glioma cells toward a highly proliferative and malignant state.

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