Proteomics-based clustering of lung adenocarcinoma identifies three subtypes with significantly different clinical and molecular features.

BACKGROUND: Lung adenocarcinoma (LUAD) is a predominant subtype of lung cancer. Although molecular classification of LUAD has been widely explored, proteomics-based subtyping of LUAD remains scarce. METHODS: We proposed a subtyping method for LUAD based on the expression profiles of 500 proteins with the largest expression variability across LUAD. Furthermore, we comprehensively compared molecular and clinical features among the LUAD subtypes. RESULTS: Consensus clustering identified three subtypes of LUAD, namely MtE, DrE, and StE. We demonstrated this subtyping method to be reproducible by analyzing two independent LUAD cohorts. MtE was characterized by high enrichment of metabolic pathways, high EGFR mutation rate, low stemness, proliferation, invasion, metastasis and inflammation signatures, favorable prognosis; DrE was characterized by high enrichment of DNA repair pathways, high TP53 mutation rate, and high levels of genomic instability, stemness, proliferation, and intratumor heterogeneity (ITH); and StE was characterized by high enrichment of stroma-related pathways, high KRAS mutation rate, and low levels of genomic instability. CONCLUSIONS: The proteomics-based clustering analysis identified three LUAD subtypes with significantly different molecular and clinical properties. The novel subtyping method offers new perspectives on the cancer biology and holds promise in improving the clinical management of LUAD.

Complex mixtures of pesticides and metabolites modulate the malignant phenotype of murine melanoma B16-F1 cells.

Pesticides use increased worldwide with a record in Brazil. Although several works addressed the effects of pesticides on living organisms, only a few considered their mixture, and even fewer tried to unravel their role in tumoral progression. Due to the relevance of cancer, in the present study, the effects of the mixture of pesticides widely used in Brazil (Glyphosate, 2,4-dichlorophenoxyacetic acid, Mancozeb, Atrazine, Acephate, and Paraquat) and their main metabolites (Aminomethylphosphonic Acid, 2,4-diclorophenol, Ethylenethiourea, Desethylatrazine, Methamidophos, and Paraquat) were investigated on the malignancy phenotype of murine melanoma B16-F1 cells after acute (24 h) and chronic (15 days) exposures. The tested concentrations were based on the Acceptable Daily Intake (ADI) value established by Brazilian legislation. The set of results showed that these chemicals modulate important parameters of tumor progression, affecting the expression of genes related to tumor aggressiveness (Mmp14 and Cd44) and multidrug resistance (Abcb1, Abcc1, and Abcc4), as well as tissue inhibitors of metalloproteinases (Timp1, Timp2, and Timp3). These findings revealed an absence of cytotoxicity but showed modulation of migration, invasion, and colonization capacity of B16-F1 cells. Together, the results point to some negative ways that exposure to pesticides can affect the progression of melanoma and raise a concern related to the increasing trend in pesticide use in Brazil, as the country is one of the major world food suppliers.

Mexican Colorectal Cancer Research Consortium (MEX-CCRC): Etiology, Diagnosis/Prognosis, and Innovative Therapies.

In 2013, recognizing that Colorectal Cancer (CRC) is the second leading cause of death by cancer worldwide and that it was a neglected disease increasing rapidly in Mexico, the community of researchers at the Biomedicine Research Unit of the Facultad de Estudios Superiores Iztacala from the Universidad Nacional Autónoma de México (UNAM) established an intramural consortium that involves a multidisciplinary group of researchers, technicians, and postgraduate students to contribute to the understanding of this pathology in Mexico. This article is about the work developed by the Mexican Colorectal Cancer Research Consortium (MEX-CCRC): how the Consortium was created, its members, and its short- and long-term goals. Moreover, it is a narrative of the accomplishments of this project. Finally, we reflect on possible strategies against CRC in Mexico and contrast all the data presented with another international strategy to prevent and treat CRC. We believe that the Consortium's characteristics must be maintained to initiate a national strategy, and the reported data could be useful to establish future collaborations with other countries in Latin America and the world.

Downregulation of indolethylamine N-methyltransferase is an early event in the rat hepatocarcinogenesis and is associated with poor prognosis in hepatocellular carcinoma patients.

Hepatocellular carcinoma (HCC) is one of the deadliest cancers worldwide, often preceded by cirrhosis and usually diagnosed at advanced stages; therefore, identifying molecular changes at early stages is an attractive strategy for detection and timely treatment. Here, we investigated the progressive transcriptomic changes during experimental hepatocarcinogenesis to identify novel early tumor markers in an HCC model induced by chronic administration of sublethal doses of diethylnitrosamine. An analysis of differentially expressed genes showed that four processes associated with oxidation-reduction and detoxification were significantly over-represented during hepatocarcinogenesis progression, of which the Nuclear Factor, Erythroid 2 Like 2 pathway showed several dysregulated genes. Interestingly, we also identified 91 genes dysregulated at early HCC stages, but the expression of the indolethylamine N-methyltransferase gene (INMT), as well as the level of its encoding protein, were strongly downregulated. INMT was increased in perivenular hepatocytes of normal livers but decreased in livers of experimental HCC. Furthermore, a gene expression and survival analysis performed using data from the liver hepatocellular carcinoma project of The Cancer Genome Atlas Program revealed that INMT is also significantly downregulated in human HCC and is associated with poor overall survival. In conclusion, by performing a transcriptome analysis of the HCC progression, we identified that INMT is early downregulated in the rat hepatocarcinogenesis and is associated with poor prognosis in human HCC, suggesting that INMT downregulation may be a promising prognostic marker for HCC in high-risk populations.

Prognostic value of TERF1 expression in prostate cancer.

BACKGROUND: Telomere dysfunction is one of the hallmarks of cancer and is crucial to prostate carcinogenesis. TERF1 is a gene essential to telomere maintenance, and its dysfunction has already been associates with several cancers. TERF1 is a target of miR-155, and this microRNA can inhibit its expression and promotes carcinogenesis in breast cancer. We aim to analyze TERF1, in gene and mRNA level, involvement in prostate cancer progression. RESULTS: Alterations in TERF1 DNA were evaluated using datasets of primary tumor and castration-resistant tumors (CRPC) deposited in cBioportal. The expression of TERF1 mRNA levels was assessed utilizing TCGA datasets, clinical specimens, and metastatic prostate cancer cell lines (LNCaP, DU145, and PC3). Six percent of localized prostate cancer presents alterations in TERF1 (the majority of that was amplifications). In the CRPC cohort, 26% of samples had TERF1 amplification. Patients with TERF1 alterations had the worst overall survival only on localized cancer cohort (p = 0.0027). In the TCGA cohort, mRNA levels of TERF1 were downregulated in comparison with normal tissue (p = 0.0013) and upregulated in tumors that invade lymph nodes (p = 0.0059). The upregulation of TERF1 is also associated with worst overall survival (p = 0.0028) and disease-free survival (p = 0.0023). There is a positive correlation between TERF1 and androgen receptor expression in cancer tissue (r = 0.53, p < 0.00001) but not on normal tissue (r = - 0.16, p = 0.12). In the clinical specimens, there is no detectable expression of TERF1 and upregulation of miR-155 (p = 0.0348). In cell lines, TERF1 expression was higher in LNCaP and was progressively lower in DU145 and PC3 (p = 0.0327) with no differences in miR-155 expression. CONCLUSION: Amplification/upregulation of TERF1 was associated with the worst prognostic in localized prostate cancer. Our results corroborate that miR-155 regulates TERF1 expression in prostate cancer. TERF1 has the potential to become a biomarker in prostate cancer.

Prognostic impact of microsatellite instability in gastric cancer.

Gastric cancer is a common and deadly cancer. Several factors are associated with its prognosis; however, controversy exists about the role of microsatellite instability (MSI). We aimed to determine the 5-year overall survival (OS) of MSI in gastric adenocarcinoma. A cross-sectional study was carried out on gastric adenocarcinoma in clinical stages I to III treated with D2 gastrectomy between 2010-2013. MSI was demonstrated by immunohistochemistry. We performed a survival analysis comparing cases with and without MSI. From 102 cases, 9.8% showed MSI. The median age was 63 years (range 33-91 years), and 57.8% were men. The more prevalent site of occurrence was the antrum (46.1%), 78.5% of the cases presented in stage III, 47.1% were of the diffuse type, 45.1% were of an intestinal type, and 7.8% were mixed. MSI cases were associated with lower clinical stages (stages I-II) and with better 5-year OS (100 vs. 47 months, p = 0.017). In a multivariate analysis, MSI was independently associated with better survival (HR = 0.209, 95% CI: 0.046-0.945, p = 0.042). MSI gastric cancers presented in early clinical stages and had favourable prognosis compared with non-MSI cancers.

Phosphorylation of Endothelin-Converting Enzyme-1c at Serines 18 and 20 by CK2 Promotes Aggressiveness Traits in Colorectal Cancer Cells.

Endothelin-converting enzyme-1 (ECE1) activates the endothelin-1 peptide, which upregulates pathways that are related to diverse hallmarks of cancer. ECE1 is expressed as four isoforms differing in their N-terminal domains. Protein kinase CK2 phosphorylates the N-terminus of isoform ECE1c, enhancing its stability and promoting invasiveness of colorectal cancer cells. However, the specific residues in ECE1c that are phosphorylated by CK2 and how this phosphorylation promotes invasiveness was unknown. Here we demonstrate that Ser-18 and Ser-20 are the bona fide residues phosphorylated by CK2 in ECE1c. Thus, biphospho-mimetic ECE1cDD and biphospho-resistant ECE1cAA mutants were constructed and stably expressed in different colorectal cancer cells through lentiviral transduction. Biphospho-mimetic ECE1cDD displayed the highest stability in cells, even in the presence of the specific CK2 inhibitor silmitasertib. Concordantly, ECE1cDD-expressing cells showed enhanced hallmarks of cancer, such as proliferation, migration, invasiveness, and self-renewal capacities. Conversely, cells expressing the less-stable biphospho-resistant ECE1cAA showed a reduction in these features, but also displayed an important sensitization to 5-fluorouracil, an antineoplastic agent traditionally used as therapy in colorectal cancer patients. Altogether, these findings suggest that phosphorylation of ECE1c at Ser-18 and Ser-20 by CK2 promotes aggressiveness in colorectal cancer cells. Therefore, phospho-ECE1c may constitute a novel biomarker of poor prognosis and CK2 inhibition may be envisioned as a potential therapy for colorectal cancer patients.

Prognostic impact of micro-rna expression in breast cancer: systematic review / Impacto prognóstico da expressão de micrornas no câncer de mama: revisão sistemática

Breast cancer is an important health problem worldwide and the identification of new prognostic markers is important in establishing the best treatment for each patient. MicroRNAs (miRNAs) are non-coding RNAs that regulate gene expression and that can be useful biomarkers for prognosis in breast cancer. The objective of this systematic review was to investigate tumor miRNA expression potentially associated with the prognostic factors of breast carcinomas. The search was done in the PubMed database; 1457 articles were initially found and 20 studies were included in the review. MiRNA-21 and miRNA-200b were the most commonly investigated in breast cancer prognosis. Lymph node metastasis was associated with the hyperexpression of miRNA-211, miRNA-301a and miRNA-370 and also associated with the hypoexpression of miRNA-124, miRNA-127, miRNA-129-5p, miRNA199-5p, miRNA-206, miRNA-218 and miRNA-339-5p. Distant metastasis was associated with miRNA-204 hypoexpression. Tumor size was associated with hyperexpression of miRNA-21 and miRNA-301a and also to the hypoexpression of miRNA-29b and miRNA129-5p. Lower survival rates were associated with the hyperexpression of miRNA-21, miRNA-301a and microRNA-711, and hypoexpression of miRNA-15a, miRNA-29b, miRNA-124, miRNA-129-5p, miRNA 199b -5p, miRNA-200b, miRNA-204, miRNA-206 and miRNA-218. On the other hand, higher survival rates were associated with the hyperexpression of miRNA-339-5p and miRNA-127 and also to the hypoexpression of miRNA-210. The results of this review emphasize the need to validate these findings in additional studies

O câncer de mama é um importante problema de saúde em todo o mundo e a identificação de novos marcadores prognósticos é necessária para estabelecer o melhor tratamento para cada paciente. MicroRNAs (miRNAs) são RNAs não codificadores reguladores da expressão gênica que têm sido evidenciados como biomarcadores úteis no prognóstico do câncer de mama. O objetivo desta revisão sistemática foi verificar o papel da expressão de miRNAs tumorais associados aos fatores prognósticos dos carcinomas de mama. A busca de estudos foi feita no banco de dados PubMed; 1.457 artigos foram inicialmente encontrados e 20 estudos foram incluídos na revisão. MiRNA-21 e miRNA-200b foram os mais comumente investigados em relação aoprognóstico do câncer de mama. A presença de metástase linfonodal foi significativamente associada à hiperexpressão de miRNA-211, miRNA-301a e miRNA-370 e também associada à hipoexpressão de miRNA-124, miRNA-127, miRNA-129-5p, miRNA199-5p, miRNA-206, miRNA-218 e miRNA- 339-5p. Metástase a distância foi associada à hipoexpressão de miRNA-204. O tamanho do tumor foi associado à hiperexpressão de miRNA-21 e miRNA-301a e também à hipoexpressão de miRNA-29b e miRNA129-5p. Em relação à sobrevida global, menores taxas de sobrevida foram associadas à hiperexpressão de miRNA-21, miRNA-301a e microRNA-711 e à hipoexpressão de miRNA- 15a, miRNA-29b, miRNA-124, miRNA-129-5p, miRNA 199b-5p, miRNA-200b, miRNA-204, miRNA-206 e miRNA-218. Por outro lado, maiores taxas de sobrevida foram associadas à hiperexpressão de miRNA-339-5p e miRNA-127 e também à hipoexpressão de miRNA-210. Os resultados desta revisão enfatizam a necessidade de validar esses achados em estudos adicionais

The Role of Chromosomal Instability in Cancer and Therapeutic Responses.

Cancer is one of the leading causes of death, and despite increased research in recent years, control of advanced-stage disease and optimal therapeutic responses remain elusive. Recent technological improvements have increased our understanding of human cancer as a heterogeneous disease. For instance, four hallmarks of cancer have recently been included, which in addition to being involved in cancer development, could be involved in therapeutic responses and resistance. One of these hallmarks is chromosome instability (CIN), a source of genetic variation in either altered chromosome number or structure. CIN has become a hot topic in recent years, not only for its implications in cancer diagnostics and prognostics, but also for its role in therapeutic responses. Chromosomal alterations are mainly used to determine genetic heterogeneity in tumors, but CIN could also reveal treatment efficacy, as many therapies are based on increasing CIN, which causes aberrant cells to undergo apoptosis. However, it should be noted that contradictory findings on the implications of CIN for the therapeutic response have been reported, with some studies associating high CIN with a better therapeutic response and others associating it with therapeutic resistance. Considering these observations, it is necessary to increase our understanding of the role CIN plays not only in tumor development, but also in therapeutic responses. This review focuses on recent studies that suggest possible mechanisms and consequences of CIN in different disease types, with a primary focus on cancer outcomes and therapeutic responses.

Education, tobacco smoking, alcohol consumption, and IL-2 and IL-6 gene polymorphisms in the survival of head and neck cancer

The association of education, tobacco smoking, alcohol consumption, and interleukin-2 (IL-2 +114 and -384) and -6 (IL-6 -174) DNA polymorphisms with head and neck squamous cell carcinoma (HNSCC) was investigated in a cohort study of 445 subjects. IL-2 and IL-6 genotypes were determined by real-time PCR. Cox regression was used to estimate hazard ratios (HR) and 95 percent confidence intervals (95 percentCI) of disease-specific survival according to anatomical sites of the head and neck. Mean age was 56 years and most patients were males (87.6 percent). Subjects with 5 or more years of schooling had better survival in larynx cancer. Smoking had no effect on HNSCC survival, but alcohol consumption had a statistically significant effect on larynx cancer. IL-2 gene +114 G/T (HR = 0.52; 95 percentCI = 0.15-1.81) and T/T (HR = 0.22; 95 percentCI = 0.02-3.19) genotypes were associated with better survival in hypopharynx cancer. IL-2 +114 G/T was a predictor of poor survival in oral cavity/oropharynx cancer and larynx cancer (HR = 1.32; 95 percentCI = 0.61-2.85). IL-2 -384 G/T was associated with better survival in oral cavity/oropharynx cancer (HR = 0.80; 95 percentCI = 0.45-1.42) and hypopharynx cancer (HR = 0.68; 95 percentCI = 0.21-2.20), but an inverse relationship was observed for larynx cancer. IL-6 -174 G/C was associated with better survival in hypopharynx cancer (HR = 0.68; 95 percentCI = 0.26-1.78) and larynx cancer (HR = 0.93; 95 percentCI = 0.42-2.07), and C/C reduced mortality in larynx cancer. In general, our results are similar to previous reports on the value of education, smoking, alcohol consumption, and IL-2 and IL-6 genetic polymorphisms for the prognosis of HNSCC, but the risks due to these variables are small and estimates imprecise.