Research IndicatorsGraph generated 01 September 2019 using data from PubMed using criteria.
Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic. Tag cloud generated 01 September, 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).
OMIM, Johns Hopkin University
Referenced article focusing on the relationship between phenotype and genotype.
International Cancer Genome Consortium.
Summary of gene and mutations by cancer type from ICGC
Cancer Genome Anatomy Project, NCI
COSMIC, Sanger Institute
Somatic mutation information and related details
GEO Profiles, NCBI
Search the gene expression profiles from curated DataSets in the Gene Expression Omnibus (GEO) repository.
Latest Publications: TUSC2 (cancer-related)
BACKGROUND: MicroRNAs (miRNAs) have emerged as the critical modulators of the tumorigenesis and tumor progression.
METHODS: The levels of miR-663 in ovarian cancer cell lines and clinical tissues were detected using qRT-PCR assays. The Transwell invasion and wound healing assay were conducted to assess the roles of miR-663 in the migration and invasion of ovarian cancer cell in vitro. Rescue assays were carried out to confirm the contribution of tumor suppressor candidate 2 (TUSC2) in the aggressiveness of cancer cell which was regulated by miR-663.
RESULTS: The levels of miR-663 were up-regulated in ovarian cancer tissues in comparison with the corresponding normal tissues. Up-regulation of miR-663 increased the proliferation, colony formation, migration and invasion of ovarian cancer SKOV3 cell. Additional, over-expression of miR-663 increased the tumor growth of SKOV3 in xenograft model. Bioinformatics analysis and luciferase reporter assay identified that miR-663 decreased the level of TUSC2 via binding to the 3'-UTR of TUSC2 gene. Finally, the expression of TUSC2 was inversely associated with the level of miR-663 in ovarian carcinoma tissue and over-expression of TUSC2 inhibited the migration and invasion abilities of SKOV3 that was promoted by miR-663.
CONCLUSION: Altogether, these results indicate that miR-663 acts as a potential tumor-promoting miRNA through targeting TUSC2 in ovarian cancer.
Chen J, Song B, Kong GMicroRNA‑663b downregulation inhibits proliferation and induces apoptosis in bladder cancer cells by targeting TUSC2.
Mol Med Rep. 2019; 19(5):3896-3902 [PubMed
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The present study aimed to explore the role and underlying molecular mechanism of microRNA‑663b (miR‑663b) in the tumorigenesis of bladder cancer. The miR‑663b expression in human bladder cancer tissues and cell lines was measured determined reverse transcription‑quantitative polymerase chain reaction. TargetScan was used to predict the potential targets of miR‑663b, and a dual‑luciferase reporter assay was performed to validate tumor suppressor candidate 2 (TUSC2) as a target of miR‑663b. Cell Counting Kit‑8 was used for cell viability analysis, and cell apoptosis was evaluated by flow cytometry. In addition, western blot analysis was performed to detect protein expression in current study. The findings suggested that miR‑663b was upregulated in bladder cancer tissues and cell lines compared with normal tissue and cells. TUSC2 was validated as a direct target of miR‑663b and was negatively regulated by miR‑663b. miR‑663b inhibition significantly reduced the viability of T24 cells, and T24 cell apoptosis was markedly induced. In addition, miR‑663b inhibition enhanced the expression levels of p53 and p21 in T24 cells. Furthermore, the changes caused by miR‑663b inhibitor in T24 cells were eliminated by TUSC2 gene silencing. In conclusion, inhibition of miR‑663b reduced viability and induced apoptosis in bladder cancer cells by targeting TUSC2. These findings provide a promising novel therapeutic target for bladder cancer treatment.
Cassani B, Soldano G, Finocchiaro D, et al.Detection and genotyping of HPV-DNA through different types of diagnostic platforms in liquid-based cervical-cytology samples.
Pathologica. 2018; 110(4):294-301 [PubMed
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Background: At present cervical cancer represents the second most common cancer in women worldwide and it reaches a global mortality rate of 52%. Only the early detection and the adequate treatment of pre-neoplastic lesions and early-stage cervical cancer decrease the mortality rate for this type of cancer. Cervical carcinoma screening, as a method of second prevention, is currently feasible through molecular research of high-risk HPV genotypes and in lots of organized screening programs the Pap-test is performed only in women with positive HPV-test. Currently, there are various diagnostic platforms detecting and molecular genotyping HPV, which are based on different procedures, determining uneven viral genotypes panels and using diverse type of vials to collect and store the samples. Previous studies have pointed out that DNA-HPV test can be negative in pre-neoplastic lesions, even of high grade, or in presence of cervical cancer. Therefore, it's important to assess the risk of false negative diagnoses using DNA-HPV molecular test, because in this circumstance women do not undergo immediately Pap-test, but they are submitted to second round screening with DNA-HPV test after 5 years: this protocol could increase the incidence of "interval cancers". The present study aims at comparing the results of HPV detection and genotyping on liquid based cervical cytology, using some of the most relevant diagnostic platforms in commerce.
Methods: The study is based on a group of patients which went to their private gynecologist in a contest of opportunistic screening. The vial used in the examined population has been EASYPREP
Results: We have examined 1284 samples of women aged 16 to 73 years: 1125 have been tested using HC2 procedure, 272 samples with Onclarity method, 159 with Xpert
Discussion: The present study highlights the following: 1) Positive results' percentage for high-risk HPV-DNA genotypes, deriving from the three diagnostic platforms used and with the same vial to collect and store samples, does not significantly vary on the basis of the type of equipment and it is congruent with the Italian percentage already detected during organized screening programs. 2) Even the molecular diagnostic approach could give false negative results, preventing the detection in the screened population of cervical HPV-related lesions and theoretically endangering women to develop "interval cancer". 3) In the population examined, genotype 16 has been the most expressed, whereas genotype 18 was among the less frequently detected. Other genotypes often noticed have been: 56-59-66 (Onclarity P3 group), 31, 51 and 35-39-68 (Onclarity P2 group). This remark emphasizes the importance of HPV infection and genotypes distribution's continuous monitoring, considering that HPV-vaccines planned in Italy in the "National vaccination prevention program 2017-2019" are not specific for the majority of these genotypes. 4) The necessity to improve the screening program to identify cervical carcinomas and pre-neoplastic cervical lesions is remarked by the detection during HPV-test of possible coinfection (present at least in 8,76% of our records). In fact, the risk of development of cervical cancer might be associated with type-specific interactions between genotypes in multiple infections and, in addition, other genotypes, not targeted by quadrivalent HPV-vaccine, can increase the risk of cervical carcinoma. 5) As there's a different combination of HPV-genotypes in diagnostic categories used by the HPV screening platforms, it's important that anyone who is in charge of this diagnostic analysis promotes among clinicians the adequate rendition of the laboratory's data in the patient records, reporting both the diagnostic result and the method through which it has been obtained.
Background & objectives: Human papillomavirus (HPV) infections play a crucial role in the aetiology of cervical cancer (CC), and HPV16 is the primary viral genotype associated with CC. A number of variants of the HPV16 E6 gene are involved in the progression of CC, differing in their prevalence and biological and biochemical properties. This study was designed to determine the frequency of HPV types 16/18 and to identify the presence of HPV16 E6-variants in asymptomatic Mexican women.
Methods: A total of 189 cervical Pap smears were collected from women attending public health services in three different cities in Sinaloa, Mexico. Viral DNA was identified by amplification of E6 viral gene fragments using polymerase chain reaction (PCR). Identification of variants was done by sequencing a DNA fragment (321bp) of the HPV16 E6 gene.
Results: More than half of the women tested were HPV-positive (52.38%), with HPV16 being the most frequent genotype (21.16%), followed by HPV18 (8.99%). Sequence analysis of the E6-HPV16 PCR products showed that in all cases, the viruses corresponded to European variants. It was further observed that the E350G intra-variant was the most common (>76%).
Interpretation & conclusions: This study showed a predominance of European lineage variants of HPV16 among asymptomatic women from Sinaloa, Mexico, predominantly with of the E350G variant. This variant has been shown to be associated with an increased risk of early development of CC. The use of molecular identification of carcinogenic HPV and Pap test screening may be a good strategy for monitoring women to prevent CC.
BACKGROUND: Gene fusions and fusion products have been proven to be ideal biomarkers and drug targets for cancer. Even though a comprehensive study of cervical cancer has been conducted as part of the Cancer Genome Atlas (TCGA) project, few recurrent gene fusions have been found, and none above 3% of frequency.
METHODS: We believe that chimeric fusion RNAs generated by intergenic splicing represent a new repertoire of biomarkers and/or therapeutic targets. However, they would be missed when only genome sequences and fusions at DNA level are considered. We performed extensive data mining for chimeric RNAs using both our and TCGA cervical cancer RNA-Seq datasets. Multiple criteria were applied. We analyzed the landscape of chimeric RNAs at various levels, and from different angles.
FINDINGS: The chimeric RNA landscape changed as different filters were applied. 15 highly frequent (>10%) chimeric RNAs were identified. LHX6-NDUFA8 was detected exclusively in cervical cancer tissues and Pap smears, but not in normal controls. Mechanistically, it is not due to interstitial deletion, but a product of cis-splicing between adjacent genes. Silencing of another recurrent chimera, SLC2A11-MIF, resulted in cell cycle arrest and reduced cellular proliferation. This effect is unique to the chimera, and not shared by the two parental genes.
INTERPRETATION: Highly frequent chimeric RNAs are present in cervical cancers. They can be formed by intergenic splicing. Some have clear implications as potential biomarkers, or for shedding new light on the biology of the disease. FUND: Stand Up To Cancer and the National Science Foundation of China.
INTRODUCTION: Anaplastic lymphoma kinase (ALK) rearrangement gene testing is used increasingly to identify patients with advanced non-small-cell lung cancer (NSCLC) who are most likely to benefit from crizotinib. This study was to evaluate the cost-effectiveness of the ALK tests followed by crizotinib compared to the standard chemotherapy in advanced NSCLC from the Chinese healthcare system perspective.
METHODS: A 10-year Markov model was constructed to compare the costs and quality-adjusted life-years (QALYs) of crizotinib with standard chemotherapy, guided by the ALK rearrangement tests: next-generation sequencing (NGS) panel tests and multiplex polymerase chain reaction (PCR) testing. The health states included progression-free survival (PFS), progressed survival, and death. The costs examined included cost of drugs (pemetrexed, standard chemotherapy, salvage chemotherapy, and crizotinib), follow-up, palliative care, supportive care, severe adverse events, and ALK rearrangement testing.
RESULTS: Under Patient Assistance Program (PAP), the model demonstrated that the patients using NGS panel tests spent US $31,388 and gained 0.780 QALYs, whereas patients using multiplex PCR spent US $31,362 and gained 0.780 QALYs, respectively. The incremental cost-effectiveness ratios of crizotinib with PAP compared to the control strategy were projected at $14,384 (NGS) and $13,740 (multiplex PCR) per QALY gained, respectively. Sensitivity analyses showed the utility of PFS and the costs of crizotinib and pemetrexed were the most impactful factors on the model outcomes. The results were robust to changes in all parameters.
CONCLUSION: ALK-rearrangement test positive followed by crizotinib may be cost-effective compared to standard chemotherapy from the Chinese healthcare system perspective when PAP was available.
BACKGROUND: Pseudogenes are RNA transcripts with high homology with its parent protein-coding genes. Although pseudogenes lost the ability to produce protein, it still exert import biological function, and play important role in the pathogenesis of a wide varity of tumors; However, the role of pseudogenes in esophageal squamous cell carcinoma (ESCC) is poorly understood.
METHODS: TUSC2P function in ESCC were explored using both in vitro and in vivo experiments cell proliferation, invasion and apoptosis assay was performed to evaluated the effect of TUSC2P on the tumor biology of ESCC. Expression of relative genes was assessed by quantitative real-time PCR (qRT-PCR) and western blotting in EC109 and TE-1 cell, as well as ESCC patients. 3'UTR luciferase assay was used to confirm the direct binding of miRNAs with TUSC2 and TUSC2P 3'UTR. Relation betweenTUSC2P, TUSC2 and ESCC prognosis was predicted by survival analysis (n = 56).
RESULTS: Pseudogene TUSC2P was down regulated in ESCC tissues compared with paired normal adjacent tissues, and the expression of TUSC2P was significantly correlated with survivalof ESCC patients. Over expression of TUSC2P in EC109 and TE-1 cells resulted in altered expression of TUSC2, thus inhibited proliferation, invasion and promoted apoptosis. Dual luciferase assay demonstrated that TUSC2P 3'UTR decoyed miR-17-5p, miR-520a-3p, miR-608, miR-661 from binding to TUSC2.
CONCLUSIONS: TUSC2P can suppresses the tumor function of esophageal squamous cell carcinoma by regulating TUSC2 expression and may also serve as a prognostic factor for ESCC patients.
BACKGROUND: A low cost and accurate method for detecting high-risk (HR) human papillomavirus (HPV) is important to permit HPV testing for cervical cancer prevention. We used a commercially available HPV method (H13, Hybribio) which was documented to function accurately in a reduced volume of cervical specimen to determine the most prevalent HPV types and the distribution of HPV infections in over 1795 cancer-free women in Guatemala undergoing primary screening for cervical cancer by cytology.
METHODS: HR-HPV detection was attempted in cervical samples from 1795 cancer-free women receiving Pap smears using the Hybribio™ real-time PCR assay of 13 HR types. The test includes a globin gene internal control. HPV positive samples were sequenced to determine viral type. Age-specific prevalence of HPV was also assessed in the study population.
RESULTS: A total of 13% (226/1717) of women tested HPV+, with 78 samples (4.3%) failing to amplify the internal control. The highest prevalence was found in younger women (< 30 years, 22%) and older ones (≥60 years, 15%). The six most common HR-HPV types among the 148 HPV+ typed were HPV16 (22%), HPV18 (11%), HPV39 (11%), HPV58 (10%), HPV52 (8%), and HPV45 (8%).
CONCLUSIONS: In this sample of cancer free women in Guatemala, HPV16 was the most prevalent HR type in Guatemala and the age-specific prevalence curve peaked in younger ages. Women in the 30-59-year age groups had a prevalence of HR-HPV of 8%, however, larger studies to better describe the epidemiology of HPV in Guatemala are needed.
Zejnullahu VA, Zejnullahu VA, Josifovska S, et al.Correlation of hTERT Expression with Cervical Cytological Abnormalities and Human Papillomavirus Infection.
Pril (Makedon Akad Nauk Umet Odd Med Nauki). 2017; 38(3):143-151 [PubMed
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Telomerase Reverse Transcriptase (TERT) is the main catalytic sub-unit of telomerase, a reverse transcriptase enzyme. Telomerase expression is regulated at many levels, with numerous studies suggesting that up-regulation of human TERT gene (hTERT) at transcriptional level results in immortal cell phenotype associated with cancer. The aim of this study is to determine the correlation between hTERT expression and different cervical precursor lesions, as well as with cervical cancer in patients with confirmed Human papillomavirus (HPV) infection. The study included molecular analyzes on cervical samples from 214 women and matched Papanicolaou (Pap) test results. HPV detection and genotyping was performed by polymerase chain reaction (PCR) and genotyping. Quantitative real-time PCR (qRT-PCR) was performed using TaqMan probes and were calculated relative to the reference gene. Results showed significantly increased hTERT mRNA expression levels in high-grade and low-grade lesions compared to normal control samples (p<0.01) associated with 6.31 fold higher risk for developing ASC-US and 9.20 for LSIL. Strong correlation between HPV infection and hTERT expression in the high-grade lesions and cervical cancer was also observed. hTERT relative expression values showed 98% specificity and 100 % sensitivity as indicator of cervical lesions particularly for the ACS-H, HSIL and cervical cancer. In conclusion, hTERT expression correlate with the cytological grade of the cervical lesions and HPV infection and has a potential to be used as a diagnostic and prognostic marker.
Chmelarova M, Laco J, Kovarikova H, et al.Elevated DNA methylation in malignant tumors of the sinonasal tract and its association with patient survival.
Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub. 2018; 162(3):232-238 [PubMed
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BACKGROUND: Epigenetic modifications have been recognized as an important mechanism underlying carcinoma progression. DNA methylation plays an important role in cancer biology and represents potentially heritable changes in gene expression that do not involve DNA sequence. The aim of this study was to investigate promoter methylation of selected genes in sinonasal carcinoma by comparison with noncancerous sinonasal tissue.
METHODS: To search for epigenetic events (methylation in 25 tumor suppressor genes) we used MS-MLPA (Methylation-specific multiplex ligation-dependent probe amplification) to compare methylation status of 59 formalin fixed, paraffin embedded tissue samples of sinonasal carcinomas with 18 control samples. The most important changes in methylation were confirmed using MSP (Methylation specific PCR). Detected alterations in methylation were compared with clinicopathological characteristics.
RESULTS: Using a 20% cut-off for methylation (MS-MLPA), we found significantly higher methylation in GATA5 (P=0.0005), THSB1 (P=0.0002) and PAX5 (P=0.03) genes in the sinonasal cancer group compared to the control group. Methylation in five or more genes was associated with impaired overall survival (P=0.017).
CONCLUSION: These findings provide evidence that alterations in methylation profile may be one of the major mechanisms in sinonasal carcinogenesis. In addition, changes in methylation could potentially be used as prognostic factors of sinonasal carcinoma and may have implications for future individualized therapy based on epigenetic changes.
Prigenzi KCK, Heinke T, Salim RC, Focchi GRADual p16 and Ki-67 Expression in Liquid-Based Cervical Cytological Samples Compared to Pap Cytology Findings, Biopsies, and HPV Testing in Cervical Cancer Screening: A Diagnostic Accuracy Study.
Acta Cytol. 2018; 62(2):104-114 [PubMed
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OBJECTIVE: Our objective was to verify the sensitivity and specificity of dual immunocytochemistry staining for p16 and Ki-67 in liquid-based samples (the "dual" assay) for cervical lesion screening, compared to biopsy findings and human papillomavirus (HPV) DNA molecular detection.
STUDY DESIGN: Sensitivity, specificity, and positive (PPV) and negative (NPV) predictive values for the "dual immunocytochemistry assay" were calculated and compared to histopathological results and to high-risk HPV DNA detection in adult women or teenagers submitted to cervical cancer screening.
RESULTS: A total of 151 women were included. The majority (96.2%) of those with negative dual assay results had lower biopsy grades (p < 0.001). Women with cytology results suggestive of cervical cancer had positive dual immunocytochemistry assay results more frequently (p < 0.001), and these positive results were also significantly associated with biopsy findings (p < 0.001) and with high-risk genotype HPV infection (p = 0.007). Specificity and PPV for the dual assay were 0.972 (0.855-0.999) and 0.800 (0.284-0.995), respectively, and 1.000 (0.590-1.000) and 1.000 (0.631-1.000) for HPV detection.
CONCLUSIONS: The dual immunocytochemistry assay had high specificity and PPV. It reveals a persistent HPV infection, avoiding the need for new tissue collections for biopsies or hybrid capture.
Volejnikova J, Zapletalova J, Jarosova M, et al.Acute lymphoblastic leukemia in a child with Leri-Weill syndrome and complete SHOX gene deletion: A Case Report.
Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub. 2018; 162(1):65-70 [PubMed
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BACKGROUND: Leri-Weill syndrome (LWS) ranks among conditions with short stature homeobox gene (SHOX) haploinsufficiency. Data on possible association of SHOX aberrations with malignant diseases are scarce.
METHODS AND RESULTS: We report a unique case of an 8-year-old girl who was successfully treated for acute lymphoblastic leukemia (pre-B ALL, intermediate risk) and was subsequently diagnosed with LWS due to characteristic clinical appearance (short disproportionate stature, Madelung deformity of the wrist) and molecular genetic examination (complete deletion of SHOX). An identical SHOX deletion was identified also in the patient's mother. Leukemic cells of the patient were retrospectively examined by array comparative genomic hybridization (aCGH), which revealed five regions of deletions at chromosome X, including the SHOX gene locus.
CONCLUSION: Growth retardation in children with hemato-oncologic malignancies cannot always be attributed to cytotoxic treatment and should be carefully evaluated, especially with regards to growth hormone therapy.
Yang XS, Xu ZW, Yi TL, et al.Ouabain suppresses the growth and migration abilities of glioma U‑87MG cells through inhibiting the Akt/mTOR signaling pathway and downregulating the expression of HIF‑1α.
Mol Med Rep. 2018; 17(4):5595-5600 [PubMed
] Free Access to Full Article Related Publications
Glioma is one of the most malignant forms of brain tumor, and has been of persistent concern due to its high recurrence and mortality rates, and limited therapeutic options. As a cardiac glycoside, ouabain has widespread applications in congestive heart diseases due to its positive cardiac inotropic effect by inhibiting Na+/K+‑ATPase. Previous studies have demonstrated that ouabain has antitumor activity in several types of human tumor, including glioma. However, the exact underlying mechanism remains to be elucidated. The purpose of present study was to elucidate the effect of ouabain on human glioma cell apoptosis and investigate the exact mechanism. U‑87MG cells were treated with various concentrations of ouabain for 24 h, following which cell viability and survival rate were assessed using a 3‑(4,5-dimethylthiazol-2‑yl)‑2,5‑diphenyltetrazolium bromide assay. The dynamic changes and cell motility were observed using digital holographic microscopy. Additionally, western blot analysis and high‑content screening assays were used to detect the protein expression levels of phosphorylated (p‑)Akt, mammalian target of rapamycin (mTOR), p‑mTOR and hypoxia‑inducible factor (HIF)‑1α, respectively. Compared with the control group, ouabain suppressed U‑87MG cell survival, and attenuated cell motility in a dose‑dependent manner (P<0.01). The downregulation of p‑Akt, mTOR, p‑mTOR and HIF‑1α were observed following treatment with 2.5 and 25 µmol/l of ouabain. These results suggested that ouabain exerted suppressive effects on tumor cell growth and motility, leading to cell death via regulating the intracellular Akt/mTOR signaling pathway and inhibiting the expression of HIF‑1α in glioma cells. The present study examined the mechanism underlying the antitumor property of ouabain, providing a novel potential therapeutic agent for glioma treatment.
Tang X, Zhou J, Zhang J, et al.Low Expression of FUS1 Is Negatively Correlated with miR-378 and May Predict Adverse Prognoses in Acute Myeloid Leukemia.
Acta Haematol. 2018; 139(2):89-95 [PubMed
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FUS1 is a tumor suppressor gene that has been found to be frequently lost in a variety of solid tumors. In this study, we aimed to investigate the expression status of the FUS1 gene in acute myeloid leukemia (AML), as well as its clinical significance. We further explored the correlation between the expression of FUS1 and miR-378 in AML. We detected expression of the FUS1 transcript in bone marrow mononuclear cells from 23 controls and 158 newly diagnosed AML patients by real-time quantitative polymerase chain reaction. Downregulated FUS1 expression was found in 139 out of 158 (87.97%) AML cases; this rate was significantly lower than that in all 23 controls (p = 0.012). Receiver operating characteristic curve analysis revealed that the FUS1 transcript level could discriminate AML patients from controls effectively (area under the ROC curve = 0.663). Kaplan-Meier analysis demonstrated that non-M3-AML patients with a low FUS1 expression had a shorter overall survival (p = 0.049) and leukemia-free survival (p = 0.051) than those with a high FUS1 expression. Furthermore, we studied the correlation between the expression of FUS1 and miR-378 in 53 newly diagnosed AML patients. We found that the correlation coefficient was -0.346, which showed that FUS1 and miR-378 were negatively correlated in AML patients (p = 0.011). These results indicate that the low expression of FUS1 is a common molecular event in AML.
Meraz IM, Majidi M, Cao X, et al.TUSC2 Immunogene Therapy Synergizes with Anti-PD-1 through Enhanced Proliferation and Infiltration of Natural Killer Cells in Syngeneic
Cancer Immunol Res. 2018; 6(2):163-177 [PubMed
] Free Access to Full Article Related Publications
Expression of the multikinase inhibitor encoded by the tumor suppressor gene
Star-PAP, a nuclear phosphatidylinositol (PI) signal-regulated poly(A) polymerase (PAP), couples with type I PI phosphate kinase α (PIPKIα) and controls gene expression. We show that Star-PAP and PIPKIα together regulate 3'-end processing and expression of pre-mRNAs encoding key anti-invasive factors (
Hoza J, Salzman R, Bakaj T, et al.Comparison of lymphatic vessel density and expression of VEGF-C and VEGF-D lymphangiogenic factors in Warthin's tumours and oncocytic adenomas.
Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub. 2018; 162(1):47-53 [PubMed
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OBJECTIVES: To compare the density of lymphatic vessels and VEGF-C and VEGF-D expression in Warthin's tumours (WTs) and oncocytic adenomas (OCAs).
METHODS: Twenty three WTs and 13 OCAs of the parotid gland were analyzed. Lymphatic vessels were detected using the D2-40 antibody. For evaluation of the intratumour and peritumour lymphatic vessel density (iLVD and pLVD, respectively) the area of greatest vascularisation (hot spots) was chosen, using a ×40 field, and the number of vessels per square millimeter was counted in a ×200 field. The staining intensity for VEGF-C and VEGF-D immunoreaction in the tumour cells was graded from 0 to 3.
RESULTS: The mean iLVD and pLVD values in WTs was 4.7 (range 1-8) and 6.9 (range 3-10), those in the OCAs 1.0 (range 0-3) and 5.8 (range 2-8), respectively. The differences in the iLVD, but not pLVD between the two tumour groups were statistically significant. In both entities, the pLVD markedly outnumbered the iLVD. The intratumour vessels in the WTs were present exclusively in the lymphoid stroma. In the group of 23 WTs, 13 (56.6%), 17 (73.9%) and 10 (43.4%) samples revealed positive VEGF-C, VEGF-D and both immunoreactions, respectively. 10 of 13 (77%) cases revealed VEGF-D immunoreaction and in none of them was the VEGF-C reaction present.
CONCLUSION: The tumours had a comparable high density of peritumorous lymphatic network. However, WTs markedly differed from OCAs in the number of the intratumorous vessels. These were abundant solely in the stroma of WT, while practically lacking in the neoplastic epithelium of the WT and relatively rare in OCAs. We suggest that homeostasis in both entities is mediated mainly by peritumorous lymphatics. The lymphatic drainage in WTs is also fostered exclusively by stromal lymphatics, whereas in stroma poor OCAs by the vessels present in their neoplastic epithelium. We also believe that WTs stimulate proliferation of pre-existing lymphatic capillaries by means of the paracrine secretion of VEGF-C and VEGF-D in the neoplastic as well as reactive stromal cells, while in the OCAs only the latter factor takes part in their lymphangiogenesis.
Hidalgo-Tenorio C, Gil-Anguita C, Ramírez-Taboada J, et al.Risk factors for infection by oncogenic human papillomaviruses in HIV-positive MSM patients in the ART era (2010-2016).
Medicine (Baltimore). 2017; 96(39):e8109 [PubMed
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Squamous cell carcinoma of anus (SCCA) is one of the most frequent non-AIDS-defining diseases in HIV patients, mainly in men who have sex with men (MSM), and it is associated with human papillomavirus (HPV) infection.To determine the prevalence of high-risk HPV (HR-HPV) genotypes, premalignant lesions (HSIL) and SCCA in a cohort of HIV-positive MSM; to study the distribution of HPV genotypes according to anal histology results; and to analyze risk factors for this infection.This prospective single-center study was conducted between May 2010 and September 2016. At the study visit, cotton swabs were used to collect anal samples for cytology study in ThinPrep Pap Test liquid medium (Thin Prep Processor 2000, Hologic Corp, USA), and for HPV PCR (Linear Array HPV Genotyping Test). After, high-resolution anoscopy (HRA) (Zeiss 150 fc) was carried out. Logistic regression analysis was performed to identify risk factors for HR-HPV infection.The study included 319 patients, with mean age of 36.7 years; HR-HPV was detected in 81.3%. The prevalence of HSIL was 13.5% and SCCA was 0.3%. With regard to the distribution of HPV genotypes according to histology results, HPV 16 was the most frequent genotype in normal anal mucosa (26.7%), in LSILs (36.9%), and in HSILs (38%). In multivariate analysis, CD4 nadir < 200 cells/μL was the factor associated with infection by HR-HPV (OR 3.66, 95% CI 1.05%-12.75%).HIV-positive MSM showed a high prevalence of HSIL+ lesions and of infection by oncogenic HPV, which appears to be favored by a deficient immune system. HPV 16 was the most frequently isolated genotype in anal mucosa, regardless of lesion type.
Kiss M, Czimmerer Z, Nagy G, et al.Retinoid X receptor suppresses a metastasis-promoting transcriptional program in myeloid cells via a ligand-insensitive mechanism.
Proc Natl Acad Sci U S A. 2017; 114(40):10725-10730 [PubMed
] Free Access to Full Article Related Publications
Retinoid X receptor (RXR) regulates several key functions in myeloid cells, including inflammatory responses, phagocytosis, chemokine secretion, and proangiogenic activity. Its importance, however, in tumor-associated myeloid cells is unknown. In this study, we demonstrate that deletion of RXR in myeloid cells enhances lung metastasis formation while not affecting primary tumor growth. We show that RXR deficiency leads to transcriptomic changes in the lung myeloid compartment characterized by increased expression of prometastatic genes, including important determinants of premetastatic niche formation. Accordingly, RXR-deficient myeloid cells are more efficient in promoting cancer cell migration and invasion. Our results suggest that the repressive activity of RXR on prometastatic genes is mediated primarily through direct DNA binding of the receptor along with nuclear receptor corepressor (NCoR) and silencing mediator of retinoic acid and thyroid hormone receptor (SMRT) corepressors and is largely unresponsive to ligand activation. In addition, we found that expression and transcriptional activity of RXRα is down-modulated in peripheral blood mononuclear cells of patients with lung cancer, particularly in advanced and metastatic disease. Overall, our results identify RXR as a regulator in the myeloid cell-assisted metastatic process and establish lipid-sensing nuclear receptors in the microenvironmental regulation of tumor progression.
Liu X, Wei W, Li X, et al.BMI1 and MEL18 Promote Colitis-Associated Cancer in Mice via REG3B and STAT3.
Gastroenterology. 2017; 153(6):1607-1620 [PubMed
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BACKGROUND & AIMS: Polycomb group proteins are epigenetic factors that silence gene expression; they are dysregulated in cancer cells and contribute to carcinogenesis by unclear mechanisms. We investigated whether BMI1 proto-oncogene, polycomb ring finger (BMI1), and polycomb group ring finger 2 (PCGF2, also called MEL18) are involved in the initiation and progression of colitis-associated cancer (CAC) in mice.
METHODS: We generated mice containing floxed alleles of Bmi1 and/or Mel18 and/or Reg3b using the villin-Cre promoter (called Bmi1
RESULTS: Following administration of AOM and DSS, DKO mice developed significantly fewer polyps than control, Bmi1
CONCLUSIONS: BMI1 and MEL18 contribute to the development of CAC in mice by promoting proliferation and reducing apoptosis via suppressing expression of Reg3b. REG3B negatively regulates cytokine-induced activation of STAT3 in colon epithelial cells. This pathway might be targeted in patients with colitis to reduce carcinogenesis.
Tumor suppressor candidate 2 (TUSC2, also known as FUS1) was identified in 2000 as a candidate tumor suppressor gene located in a region on chromosome 3p21.3 that is homozygously deleted in some lung and breast cancers. The deletion is rare in lung and breast cancers, but is frequent in malignant pleural mesothelioma. Evidence to date indicates that TUSC2 behaves as a tumor suppressor in lung cancer; however, its role as a tumor suppressor for other tumor types has not been fully established. Loss of TUSC2 expression at the mRNA and protein levels has been reported in various cancers. While the mechanisms underlying the loss are still not well understood, several microRNAs have been reported to downregulate TUSC2 expression. TUSC2 elicits its anti-tumor effects through regulating G1 cell cycle progression, apoptosis, calcium homeostasis, gene expression, and the activity of various protein tyrosine kinases and Ser/Thr kinases, albeit the precise mechanisms that TUSC2 utilizes to regulate these cellular processes and signaling molecules are still elusive. TUSC2 restoration has been exploited as an anti-cancer therapy in various cancers in preclinical models, and clinically in patients with lung cancer. The first-in-human phase I trial demonstrated desirable safety outcomes. Phase I/II trials are being conducted to evaluate the efficacy of combining TUSC2-nanoparticles with erlotinib, an FDA-approved EGFR inhibitor. This review summarizes recent findings that advanced our understanding of TUSC2 as a novel tumor suppressor and a therapeutic opportunity for treating TUSC2-deficient cancers.
There is no available blood marker for the preoperative diagnosis of adrenocortical malignancy. The objective of this study was to investigate the expression of extracellular vesicle-associated microRNAs and their diagnostic potential in plasma samples of patients suffering from adrenocortical tumors. Extracellular vesicles were isolated either by using Total Exosome Isolation Kit or by differential centrifugation/ultracentrifugation. Preoperative plasma extracellular vesicle samples of 6 adrenocortical adenomas (ACA) and 6 histologically verified adrenocortical cancer (ACC) were first screened by Taqman Human Microarray A-cards. Based on the results of screening, two miRNAs were selected and validated by targeted quantitative real-time PCR. The validation cohort included 18 ACAs and 16 ACCs. Beside RNA analysis, extracellular vesicle preparations were also assessed by transmission electron microscopy, flow cytometry and dynamic light scattering. Significant overexpression of hsa-miR-101 and hsa-miR-483-5p in ACC relative to ACA samples has been validated. Receiver operator characteristics of data revealed dCT
Saito H, Kitagawa K, Yoneda T, et al.Combination of p53-DC vaccine and rAd-p53 gene therapy induced CTLs cytotoxic against p53-deleted human prostate cancer cells in vitro.
Cancer Gene Ther. 2017; 24(7):289-296 [PubMed
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Recently, the US FDA approved sipuleucel-T, which is composed of autologous DCs stimulated with a recombinant fusion protein of prostatic acid phosphatase (PAP) and granulocyte-macrophage colony-stimulating factor (GM-CSF), as the first immunotherapeutic agent for metastatic castration resistant prostate cancer (mCRPC). However, sipuleucel-T demonstrated only modest efficacy in mCPRC patients. Researchers are now investigating the potential of p53 protein as a tumor-associated antigen (TAA) loaded in DC-based cancer vaccine. Approximately half of all tumors overexpress p53, and up to 20% of prostate cancer cells overexpresses p53. In this study, we evaluated the feasibility of combining p53-DC vaccine and rAd-p53 gene therapy, using the p53-overexpressing and non-expressing prostate cancer cells in vitro. We successfully generated the p53-DC vaccine by culturing autologous DCs infected with rAd-p53. This p53-DC vaccine can differentiate CTLs specifically cytotoxic to p53-overexpressing prostate cancer cells. In addition, rAd-p53 infection can induce overexpression of p53 and thus the cytotoxicity of CTLs differentiated by the p53-DC vaccine in p53 non-expressing prostate cancer cells. These findings suggest that this combination therapy using p53-DC vaccine and rAd-p53 gene therapy together may represent a new paradigm for the treatment of mCRPC.
Skerenova M, Mikulova V, Capoun O, et al.Circulating tumor cells and serum levels of MMP-2, MMP-9 and VEGF as markers of the metastatic process in patients with high risk of metastatic progression.
Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub. 2017; 161(3):272-280 [PubMed
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BACKGROUND AND AIMS: Metastases are a severe complication in cancer patients and biomarkers predicting their progression are still lacking for specific groups of patients. HER2 positive breast cancer (HER2 BC) patients on trastuzumab therapy are at risk of the development of unpredictable and often fatal central nervous system (CNS) metastases and castration resistant prostate cancer (CRPC) patients urgently need a marker of disease progression during therapy. Proposed metastatic markers: circulating tumor cells (CTC), serum levels of matrix metalloproteinase 2 (MMP-2), 9 (MMP-9) and vascular endothelial growth factor (VEGF) were prospectively studied to confirm their utility in these two narrowly defined groups of cancer patients.
PATIENTS AND METHODS: The groups comprised 44 advanced HER2 BC, 24 CRPC patients and 42 healthy controls. An immunomagnetic separation method followed by PCR and electrophoretic detection (AdnaGen, Germany) were used for CTC determination. Serum marker levels were determined by the ELISAs (R&D System, USA).
RESULTS: MMP-2 serum level was significantly higher in HER2 BC patients who developed CNS metastases, especially if there were also bone metastases. CTCs were a negative predictive marker for overall survival in HER2 BC patients. MMP-9 serum level was significantly higher in CRPC patients in whom disease progression occurred. CTC vanished from the blood of most of the CRPC patients (from 88% to 37%) during chemotherapy.
CONCLUSION: MMP-2 serum level and CTCs show the potential to predict CNS metastases and overall survival in BC patients. CTCs and MMP-9 serum level could be a promising therapy response marker in CRPC patients.
Narsia N, Ramagiri P, Ehrmann J, Kolar ZTranscriptome analysis reveals distinct gene expression profiles in astrocytoma grades II-IV.
Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub. 2017; 161(3):261-271 [PubMed
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BACKGROUND: Astrocytoma is the most prevalent form of primary brain cancer categorized into four histological grades by the World Health Organization. Investigation into individual grades of astrocytoma by previous studies has provided some insight into dysregulation of regulatory networks associated with increasing astrocytoma grades. However, further understanding of key mechanisms that distinguish different astrocytoma grades is required to facilitate targeted therapies.
METHODS: In this study, we utilized a large cohort of publicly available RNA sequencing data from patients with diffuse astrocytoma (grade II), anaplastic astrocytoma (grade III), primary glioblastoma (grade IV), secondary glioblastoma (grade IV), recurrent glioblastoma (grade IV), and normal brain samples to identify genetic similarities and differences between these grades using bioinformatics applications.
RESULTS: Our analysis revealed a distinct gene expression pattern between grade II astrocytoma and grade IV glioblastoma (GBM). We also identified genes that were exclusively expressed in each of the astrocytoma grades. Furthermore, we identified known and novel genes involved in key pathways in our study. Gene set enrichment analysis revealed a distinct expression pattern of transcriptional regulators in primary GBM. Further investigation into molecular processes showed that the genes involved in cell proliferation and invasion were shared across all subtypes of astrocytoma. Also, the number of genes involved in metastasis, regulation of cell proliferation, and apoptosis increased with tumor grade.
CONCLUSIONS: We confirmed existing findings and shed light on some important genes and molecular processes that will improve our understanding of glioma biology.
He J, Zhang F, Tay LWR, et al.Lipin-1 regulation of phospholipid synthesis maintains endoplasmic reticulum homeostasis and is critical for triple-negative breast cancer cell survival.
FASEB J. 2017; 31(7):2893-2904 [PubMed
] Free Access to Full Article Related Publications
Cancer cells reprogram their metabolism to increase the synthesis of macromolecules for rapid proliferation. Compared to fatty acids, much less is known about the synthesis of phospholipids, which is essential for membrane biogenesis in cancer cells. We found that
Husek P, Pacovsky J, Chmelarova M, et al.Methylation status as a predictor of intravesical Bacillus Calmette-Guérin (BCG) immunotherapy response of high grade non-muscle invasive bladder tumor.
Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub. 2017; 161(2):210-216 [PubMed
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BACKGROUND AND AIMS: Genetic and epigenetic alterations play an important role in urothelial cancer pathogenesis. Deeper understanding of these processes could help us achieve better diagnosis and management of this life-threatening disease. The aim of this research was to evaluate the methylation status of selected tumor suppressor genes for predicting BCG response in patients with high grade non-muscle-invasive bladder tumor (NMIBC).
MATERIALS AND METHODS: We retrospectively evaluated 82 patients with high grade non-muscle-invasive bladder tumor (stage Ta, T1, CIS) who had undergone BCG instillation therapy. We compared epigenetic methylation status in BCG-responsive and BCG-failure groups. We used the MS-MLPA (Methylation-Specific Multiplex Ligation-Dependent Probe Amplification probe sets ME001 and ME004. The control group was 13 specimens of normal urotel (bladder tissue)).
RESULTS: Newly identified methylations in high grade NMIBC were found in MUS81a, NTRK1 and PCCA. The methylation status of CDKN2B (P=0.00312
CONCLUSION: The results show that the methylation status of selected tumor suppressor genes (TSGs) has the potential for predicting BCG response in patients with NMIBC high grade tumors. Tumor suppressor genes such as CDKN2b, MUS81a, PFM-1, MSH6 and THBS1 are very promising for future research.
Micenková L, Beňová A, Frankovičová L, et al.Human Escherichia coli isolates from hemocultures: Septicemia linked to urogenital tract infections is caused by isolates harboring more virulence genes than bacteraemia linked to other conditions.
Int J Med Microbiol. 2017; 307(3):182-189 [PubMed
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Escherichia coli is the most common cause of bloodstream infections and community-acquired sepsis. The main aim of this study was to determine virulence characteristics of E. coli isolates from hemocultures of patients with a primary disease of urogenital tract, digestive system, a neoplastic blood disease, or other conditions. Results from a set of 314 E. coli isolates from hemocultures were compared to data from a previously published analysis of 1283 fecal commensal E. coli isolates. Genetic profiling of the 314 E. coli isolates involved determination of phylogenetic group (A, B1, B2, D, C, E, and F), identification of 21 virulence factors, as well as 30 bacteriocin-encoding determinants. Pulsed-field gel electrophoresis was used to analyze clonal character of the hemoculture-derived isolates. The E. coli isolates from hemocultures belonged mainly to phylogenetic groups B2 (59.9%) and D (21.0%), and less frequently to phylogroups A (10.2%) and B1 (5.7%). Commonly detected virulence factors included adhesins (fimA 92.0%, pap 47.1%, and sfa 26.8%), and iron-uptake encoding genes (fyuA 87.9%, fepC 79.6%, aer 70.7%, iucC 68.2%, and ireA 13.7%), followed by colibactin (pks island 31.5%), and cytotoxic necrotizing factor (cnf1 11.1%). A higher frequency of microcin producers (and microcin M determinant) and a lower frequency of colicin Ib and microcin B17 was found in hemoculture-derived isolates compared to commensal fecal isolates. E. coli isolates from hemocultures harbored more virulence genes compared to fecal E. coli isolates. In addition, hemoculture E. coli isolates from patients with primary diagnosis related to urogenital tract were clearly different and more virulence genes were detected in these isolates compared to both fecal isolates and hemoculture-derived isolates from patients with blood and gastrointestinal diseases.
BACKGROUND: Prostate cancer (CP) cells differ from their normal counterpart in gene expression. Genes encoding secreted or extracellular proteins with increased expression in CP may serve as potential biomarkers. For their detection and quantification, assays based on monoclonal antibodies are best suited for development in the clinical setting. One approach to obtain antibodies is to use recombinant proteins as immunogen. However, the synthesis of recombinant protein for each identified candidate is time-consuming and expensive. It is also not practical to generate high quality antibodies to all identified candidates individually. Furthermore, non-native forms (e.g., recombinant) of proteins may not always lead to useful antibodies. Our approach was to purify a subset of proteins from CP tissue specimens for use as immunogen.
METHODS: In the present investigation, ten cancer specimens obtained from cases scored Gleason 3+3, 3+4 and 4+3 were digested by collagenase to single cells in serum-free tissue culture media. Cells were pelleted after collagenase digestion, and the cell-free supernatant from each specimen were pooled and used for isolation of proteins in the 10-30 kDa molecular weight range using a combination of sonication, dialysis and Amicon ultrafiltration. Western blotting and mass spectrometry (MS) proteomics were performed to identify the proteins in the selected size fraction.
RESULTS: The presence of cancer-specific anterior gradient 2 (AGR2) and absence of prostate-specific antigen (PSA)/KLK3 were confirmed by Western blotting. Proteomics also detected AGR2 among many other proteins, some outside the selected molecular weight range, as well.
CONCLUSIONS: Using this approach, the potentially harmful (to the mouse host) exogenously added collagenase was removed as well as other abundant prostatic proteins like ACPP/PAP and AZGP1 to preclude the generation of antibodies against these species. The paper presents an optimized scheme for convenient and rapid isolation of native proteins in any desired size range with minor modifications.
Machalek DA, Wark JD, Tabrizi SN, et al.Genetic and Environmental Factors in Invasive Cervical Cancer: Design and Methods of a Classical Twin Study.
Twin Res Hum Genet. 2017; 20(1):10-18 [PubMed
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BACKGROUND: Persistent high-risk human papillomavirus (HPV) infection is a necessary prerequisite for development of cervical cancer and its precursor lesion, high-grade squamous intraepithelial lesion (HSIL). However, HPV infection is not sufficient to drive this process, and genetic and environmental factors may also play a role.
METHODS/DESIGN: The Cervical Cancer, Genetics and Environment Twin Study was established to investigate the environmental and genetic influences on variation in susceptibility to cervical pre-cancer in 25- to 69-year-old monozygotic (MZ) and dizygotic (DZ) twins recruited through the Australian Twin Registry. Reviews of Papanicolaou (Pap) screening histories were undertaken to identify individual women with a history of an abnormal Pap test. This was followed by detection of HPV in archival Pap smears of selected twin pairs to determine HPV persistence. Selected twin pairs also completed a detailed questionnaire on socio-demographic characteristics, sexual behavior, and HPV knowledge. In future analyses, under the assumptions of the classical twin design, case-wise concordance for persistent HPV infection and HSIL will be calculated for MZ and DZ twin pairs, and twin pairs (both MZ and DZ) who are discordant for the above outcomes will be used to assess the contributions of measured environmental risk factors.
DISCUSSION: The study examines factors related to HPV persistence and development of HSIL among female MZ and DZ twins. The results will contribute to our understanding of the natural history of cervical HPV infection and the relative contributions of genetic and environmental factors in disease progression.