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1.
J Transl Med ; 19(1): 379, 2021 09 06.
Artigo em Inglês | MEDLINE | ID: mdl-34488791

RESUMO

BACKGROUND: Since interferon regulatory factor (IRF) family functions in immune response to viral infection, its role in colorectal cancer (CRC) has not been inspected before. This study tries to investigate members of IRF family using bioinformatics approaches in aspect of differential expressions, biological function, tumor immune infiltration and clinical prognostic value for patients with CRC. METHODS: Transcriptome profiles data, somatic mutations and clinical information of CRC were obtained from COAD/READ dataset of The Cancer Genome Atlas (TCGA) as a training set. Gene expression data (GSE17536 and GSE39582) were downloaded from the Gene Expression Omnibus as a validating set. A random forest algorithm was used to score the risk for every case. Analyzing gene and function enrichment, constructing protein-protein interaction and noncoding RNA network, identifying hub-gene, characterizing tumor immune infiltration, evaluating differences in tumor mutational burden (TMB) and sensitivity to chemotherapeutics or immunotherapy were performed by a series of online tools and R packages. Immunohistochemical (IHC) examinations were carried out validation in tissue samples. RESULTS: Principal-component analysis (PCA) suggested that the transcript expression levels of nine members of IRF family differed between normal colorectum and CRC. The risk score constructed by IRF family not only acted as an independent factor for predicting survival in CRC patients with different biological processes, signaling pathways and TMB, but also indicated different immunotherapy response with diverse immune and stromal cells infiltration. IRF3 and IRF7 were upregulated in CRC and suggested a shorter survival time in patients with CRC. Differentially expressed members of IRF family exhibited varying degrees of immune cell infiltration. IHC analysis showed a positive association between IRF3 and IRF7 expression and tumor-infiltrating immune cells, including CD4+ T cell and CD68+ macrophages. CONCLUSIONS: On account of differential expression, IRF family members can help to predict both response to immunotherapy and clinical prognosis of patients with CRC. Our bioinformatic investigation not only gives a preliminary picture of the genetic features as well as tumor microenvironment, but it may provide a clue for further experimental exploration and verification on IRF family members in CRC.


Assuntos
Neoplasias Colorretais , Fatores Reguladores de Interferon , Biomarcadores Tumorais , Neoplasias Colorretais/genética , Regulação Neoplásica da Expressão Gênica , Humanos , Fatores Reguladores de Interferon/genética , Prognóstico , Microambiente Tumoral
2.
Niger J Clin Pract ; 24(9): 1294-1299, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34531340

RESUMO

Background: Colorectal carcinoma (CRC) is a major cause of morbidity and mortality worldwide. Microsatellite instability pathway is important in the pathogenesis of CRC. Immunohistochemistry expression of mismatch repair (MMR) proteins serves as surrogate marker for MMR gene mutation. Aims: This study aimed to determine MSI status of a cohort of CRC cases using immunohistochemistry. Materials and Method: Surgical pathology blocks of resected colonic carcinoma (CC) between 2011 and 2015 were extracted from our departmental archives and The Specialist Laboratories in Lagos. Immunohistochemical expression profile of 4 MMR proteins was assessed in the representative blocks and this was correlated with the demographic and pathological characteristics. Results: There were 19 males and 16 females with CC, mean age of 51.6 years, and 40% of them were below 50 years of age. Twenty (57.1%) out of the 35 CC cases seen were mismatch repair proficient (pMMR) while the remaining 15 (42.9%) were mismatch repair deficient (dMMR). Seven dMMR cases were seen equally on the right and left colonic tumors respectively. Five (71.4%) out of the 7 mucinous tumors in this study were dMMR, right sided with 3 of them in patients who were below 50 years of age. Conclusion: The frequency of mismatch repair deficiency in CC among Nigerians is high, and presence of right-sided mucinous colon cancer in patients below 50 years is highly suggestive of dMMR status. Mutation studies of larger patient samples to determine the percentage with germline mutation will further our knowledge, and influence therapeutic options for CC.


Assuntos
Neoplasias Colorretais , Reparo de Erro de Pareamento de DNA , Neoplasias Colorretais/genética , Reparo de Erro de Pareamento de DNA/genética , Feminino , Humanos , Imuno-Histoquímica , Masculino , Instabilidade de Microssatélites , Pessoa de Meia-Idade , Nigéria
3.
Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi ; 37(9): 821-827, 2021 Sep.
Artigo em Chinês | MEDLINE | ID: mdl-34533130

RESUMO

Objective To investigate the inflammatory induction effect of HCT-116 colorectal cancer cells on normal fibroblasts (NFs) extracted from para-cancerous tissues and the effect of cancer associated fibroblasts (CAFs) on cancer cell migration and its potential mechanism. Methods The enzyme digestive method was used to extract NFs and CAFs from tissues. Spatial Gene Expression Dataset was downloaded to analyze transcriptional expression levels of inflammatory factors including transforming growth factor ß (TGF-ß), tumor necrosis factor-α (TNF-α), C-X-C motif chemokine ligand 2 (CXCL2), interleukin-1ß (IL-1ß), and stromal cell-derived factor-1 (SDF-1). In vitro direct and indirect co-culture models were used to study the interaction between fibroblasts and cancer cells. Flow cytometry was used to detect expressions of fibroblast activated protein (FAP) and α-smooth muscle actin (α-SMA). Inflammatory factors TGF-ß, TNF-α, CXCL2, IL-1ß, and SDF-1 secreted in medium were measured by ELISA. Three co-culture groups were set up in which HCT-116 cells were co-cultured respectively with NFs, CAFs, and CAFs pretreated with AMD3100, an inhibitor of SDF-1. Cell migration ability was evaluated by the cell scratch-wound assay and the TranswellTM migration assay. Results CAFs expressed higher levels of FAP and α-SMA than NFs, and HCT-116 cancer cells induced the transformation of NFs to CAFs. Compared to NFs, CAFs secreted higher levels of inflammatory factors TGF-ß, TNF-α, CXCL2, IL-1ß, and SDF-1, while in the in vitro co-culture models cancer cells induced the secretion of SDF-1 but had no effect on secretions of TGF-ß, TNF-α, CXCL2, and IL-1ß from NFs. CAFs significantly stimulated cancer cell migration compared to NFs, which was weakened by AMD3100, an inhibitor of SDF-1. Conclusion Colorectal cancer cells induce the transformation of NFs to CAFs, and CAFs stimulated cancer cell migration with the SDF-1 secreted.


Assuntos
Fibroblastos Associados a Câncer , Neoplasias Colorretais , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Quimiocina CXCL12/genética , Neoplasias Colorretais/genética , Fibroblastos , Humanos
4.
Anticancer Res ; 41(9): 4489-4495, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34475074

RESUMO

BACKGROUND/AIM: The chemokine receptors C-X-C chemokine receptor type 4 (CXCR4) and C-C chemokine receptor type 7 (CCR7) play an important role in the invasion and metastasis of cancer. This study investigated the relationship between relative expression of CXCR4 and CCR7 mRNA, clinicopathological factors, and outcomes in patients with colorectal cancer (CRC). PATIENTS AND METHODS: We studied 202 patients who underwent surgery for CRC. The expression levels of CXCR4 and CCR7 mRNA in cancerous tissue were measured using quantitative real-time reverse-transcriptase polymerase chain reaction. RESULTS: High CCR7 mRNA expression levels in CRC tissues were positively associated with tumour size and were more frequently associated with cancer of the rectum than of the colon. Moreover, outcomes were significantly poorer in patients with high CCR7 mRNA expression than in those with low expression. On multivariate Cox regression analysis, a higher CCR7 mRNA expression level was a significant independent predictor of poorer overall survival in patients with CRC. CONCLUSION: Overexpression of CCR7 mRNA may be a useful independent prognostic factor in patients with CRC.


Assuntos
Neoplasias Colorretais/cirurgia , Perfilação da Expressão Gênica/métodos , Receptores CCR7/genética , Receptores CXCR4/genética , Regulação para Cima , Idoso , Biomarcadores Tumorais/genética , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Análise de Sobrevida , Resultado do Tratamento , Carga Tumoral
6.
World J Surg Oncol ; 19(1): 265, 2021 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-34479583

RESUMO

INTRODUCTION: Colorectal cancer (CRC) is one of the most frequent neoplasms in the world. Based on the emerging role of noncoding RNAs, particularly circular RNAs in pathogenesis of cancers, we designed this study to inspect the expression levels of a circ0009910-mediated regulatory pathway in colorectal cancer. METHODS: After bioinformatics analyses and construction of putative circ0009910/ miR-145-5p/PEAK1 pathway, the expression levels of these components were evaluated in 50 CRC tissues and adjacent specimens by quantitative real-time PCR. Moreover, we appraised the correlation coefficients between these transcripts and calculated the correlation between circ0009910 expression levels with clinicopathological features of patients. RESULTS: Circ0009910 and PEAK1 were significantly upregulated, while miR-145-5p was decreased in CRC samples compared with adjacent tissues (p < 0.05). Moreover, statistically significant correlations were observed between expression levels of circ0009910, miR-145-5p, and PEAK1. We also reported considerable correlations between circ0009910 expression and clinicopathological parameters including sex and perineural invasion. Finally, ROC curve analysis showed circ0009910 level as a discriminative biomarker for CRC. CONCLUSION: For the first time, we could introduce circ0009910 as an important biomarker in CRC. Collectively, this investigation helped us to identify a newly diagnosed pathway in CRC that can be a potential axis for designing effective drugs for treatment of CRC patients.


Assuntos
Neoplasias Colorretais , MicroRNAs , Proteínas Tirosina Quinases/metabolismo , RNA Circular/genética , Proliferação de Células , Neoplasias Colorretais/genética , Regulação Neoplásica da Expressão Gênica , Humanos , MicroRNAs/genética , Prognóstico
7.
World J Surg Oncol ; 19(1): 268, 2021 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-34479589

RESUMO

BACKGROUND: Circular RNA 0029803 (circ_0029803) was found to be upregulated in colorectal cancer (CRC) tissues, but its function and underlying molecular mechanism are not studied in CRC. METHODS: The expression levels of circ_0029803, microRNA-216b-5p (miR-216b-5p), and ski-oncogene-like (SKIL) were measured by quantitative real-time polymerase chain reaction (qRT-PCR). RNase R treatment was used to affirm the existence of circ_0029803. Cell proliferation, apoptosis, migration, and invasion were assessed by colony formation, flow cytometry, and Transwell assays, respectively. A glucose and lactate assay kit was used to detect glucose consumption and lactate production. Western blot was applied to analyze the levels of all proteins. Dual-luciferase reporter assay was performed to assess the relationship between miR-216b-5p and circ_0029803 or SKIL. Tumor xenograft models were established to elucidate the effect of circ_0029803 in vivo. RESULTS: Circ_0029803 expression was enhanced in CRC tissues and cells, and the 5-year overall survival rate of patients with high circ_0029803 expression was substantially reduced. Circ_0029803 depletion retarded proliferation, migration, invasion, EMT and glycolysis of CRC cells in vitro as well as the tumor growth in vivo. Mechanically, circ_0029803 could serve as miR-216b-5p sponge to regulate its expression, and miR-216b-5p knockdown reversed the inhibition of si-circ_0029803 on the malignant behaviors of CRC cells. Additionally, as the target mRNA of miR-216b-5p, SKIL could counteract the inhibitory effect of miR-216b-5p on the development of CRC cells. Importantly, silencing circ_0029803 reduced SKIL expression via sponging miR-216b-5p. CONCLUSION: Circ_0029803 knockdown hindered proliferation, migration, invasion, EMT, and glycolysis and promoted apoptosis in CRC cells by modulating the miR-216b-5p/SKIL axis.


Assuntos
Neoplasias Colorretais , Peptídeos e Proteínas de Sinalização Intracelular/genética , MicroRNAs , RNA Circular , Animais , Neoplasias Colorretais/genética , Regulação Neoplásica da Expressão Gênica , Humanos , MicroRNAs/genética , Prognóstico , Proteínas Proto-Oncogênicas , RNA Circular/genética
8.
World J Gastroenterol ; 27(30): 5076-5087, 2021 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-34497436

RESUMO

BACKGROUND: Leukocytes, such as T cells and macrophages, play an important role in tumorigenesis. CC chemokine ligand (CCL) 4, which is produced by lymphocytes and macrophages, has been found to be expressed in the mucosa of the gastrointestinal tract and is a potent chemoattractant for various leukocytes. AIM: To examine CCL4 expression and its genetic polymorphism rs10491121 in patients with colorectal cancer (CRC) and evaluate their prognostic significance. METHODS: Luminex technology was used to determine CCL4 Levels in CRC tissue (n = 98), compared with paired normal tissue, and in plasma from patients with CRC (n = 103), compared with healthy controls (n = 97). Included patients had undergone surgical resection for primary colorectal adenocarcinomas between 1996 and 2019 at the Department of Surgery, Ryhov County Hospital, Jönköping, Sweden. Reverse transcription quantitative PCR was used to investigate the CCL4 gene expression in CRC tissue (n = 101). Paired normal tissue and TaqMan single nucleotide polymorphism assays were used for the CCL4 rs10491121 polymorphism in 610 CRC patients and 409 healthy controls. RESULTS: The CCL4 protein and messenger RNA expression levels were higher in CRC tissue than in normal paired tissue (90%, P < 0.001 and 45%, P < 0.05, respectively). CRC tissue from patients with localized disease had 2.8-fold higher protein expression levels than that from patients with disseminated disease. Low CCL4 protein expression levels in CRC tissue were associated with a 30% lower cancer-specific survival rate in patients (P < 0.01). The level of plasma CCL4 was 11% higher in CRC patients than in healthy controls (P < 0.05) and was positively correlated (r = 0.56, P < 0.01) with the CCL4 protein level in CRC tissue. The analysis of CCL4 gene polymorphism rs10491121 showed a difference (P < 0.05) between localized disease and disseminated disease in the right colon, with a dominance of allele A in localized disease. Moreover, the rate of the A allele was higher among CRC patients with mucinous cancer than among those with non-mucinous cancer. CONCLUSION: The present study indicates that the CRC tissue levels of CCL4 and CCL4 gene polymorphism rs10491121, particularly in the right colon, are associated with clinical outcome in CRC patients.


Assuntos
Neoplasias Colorretais , Polimorfismo de Nucleotídeo Único , Quimiocina CCL4 , Quimiocinas CC , Neoplasias Colorretais/genética , Humanos , Ligantes , Prognóstico
9.
J Coll Physicians Surg Pak ; 31(9): 1051-1056, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34500520

RESUMO

OBJECTIVE: To investigate the expression of chromobox 2 (CBX2) in colorectal adenoma (CRA) and colorectal cancer (CRC), and analyse its correlation with various clinicopathological parameters. STUDY DESIGN: Observational study. PLACE AND DURATION OF STUDY: Pathology Department, Huashan Hospital, Fudan University, from December 2019 to December 2020. METHODOLOGY: The mRNA level of CBX2 in colorectal mucosa, CRA and CRC was evaluated in gene expression profiling interactive analysis (GEPIA) and gene expression omnibus (GEO) dataset, then verified by quantitative real-time PCR (qRT-PCR). CBX2 expression by immunohistochemistry was determined in 122 samples, then its correlation was analysed with various clinicopathological parameters. Diagnostic value of CBX2 was estimated by the receiver operating characteristic curve (ROC). Prognostic value of CBX2 mRNA expression was evaluated via the Kaplan-Meier method in GEPIA. RESULTS: CBX2 expression rate in CRC (89.8%) was greater than adenoma (37.74%) and mucosa (20%). CBX2 protein levels were highest in adenocarcinoma and lowest in mucosa with intermediate level in adenoma. The area under curve (AUC) of CBX2 was 0.810 and 0.734, respectively, in distinguishing CRA from mucosa and CRC from CRA. CBX2 hyperexpression was not significantly correlated with clinicopathological variables, either in CRA or CRC. Kaplan-Meier survival analysis revealed that CBX2 mRNA hyperexpression was not associated with overall survival (OS) of CRC. Although the disease-free survival (DFS) of high CBX2 patients was shorter than those with low expression, but no obvious significance was found in colon adenocarcinoma (COAD, p=0.052) and rectal adenocarcinoma (READ, p=0.097). CONCLUSION: CBX2 expression progressively increased in the sequence of mucosa-adenoma-carcinoma, which may be used as a diagnostic biomarker and therapeutic target for CRA and CRC. Key Words: CBX2, Colorectal adenoma, Colorectal cancer, Biomarker.


Assuntos
Adenocarcinoma , Adenoma , Carcinoma , Neoplasias Colorretais , Complexo Repressor Polycomb 1/genética , Adenocarcinoma/genética , Adenoma/genética , Biomarcadores Tumorais/genética , Neoplasias Colorretais/genética , Humanos , Membrana Mucosa , Prognóstico
10.
Analyst ; 146(18): 5714-5721, 2021 Sep 13.
Artigo em Inglês | MEDLINE | ID: mdl-34515700

RESUMO

The molecular diagnosis of KRAS mutations has become crucial for clinical decision-making in colorectal cancer (CRC) treatments. Currently, the common methods for detecting mutations are based on quantitative PCR, DNA sequencing and droplet digital PCR (ddPCR), which require expensive specialized equipment and testing reagents. Herein, we propose a simple and specific strategy by integrating asymmetric PCR with surface-enhanced Raman spectroscopy (Asy-PCR/SERS) for the detection of KRAS G12V mutation, one of the most common driver mutations in CRC. To discriminate mutant targets from non-targets, Asy-PCR was applied to obtain single-stranded DNA (ssDNA) with unequal amounts of forward and reverse primers, subsequently, detection of the target mutant ssDNA amplicons was attempted by hybridization with Raman reporter-coded and allele-specific oligonucleotide-functionalized gold nanoparticles (SERS nanotags). The oligo encoding of the KRAS G12V mutant sequence could be identified by using a portable Raman spectrometer where the characteristic spectra of SERS nanotags indicate the presence of mutant targets. The Asy-PCR/SERS method showed high specificity and sensitivity for identifying as few as 0.1% mutant alleles of KRAS G12V mutation from non-target sequences. Using colorectal polyp biopsies, we demonstrated that Asy-PCR/SERS assay could distinguish KRAS G12V (c.35G > T) and KRAS G12D (c.35G > A) which occur at the same nucleotide location. As KRAS G12V is a driver oncogene in other cancers including lung, pancreatic, ovarian and endometrial cancers, the proposed assay shows great potential for application in additional tumor streams.


Assuntos
Neoplasias Colorretais , Nanopartículas Metálicas , Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/genética , Ouro , Humanos , Mutação , Reação em Cadeia da Polimerase , Polimorfismo de Nucleotídeo Único , Proteínas Proto-Oncogênicas p21(ras)/genética
11.
Orv Hetil ; 162(37): 1502-1507, 2021 09 12.
Artigo em Húngaro | MEDLINE | ID: mdl-34516395

RESUMO

Összefoglaló. Bevezetés: A gyulladásos folyamatok és a tumorok kialakulása, illetve progressziója közötti összetett kapcsolat ismert. Az interleukin-6 (IL6) egy pleiotrop gyulladásos citokin, melynek tumorstimuláló és -gátló tulajdonsága is van. Célkituzés: Kutatásunk célja az IL6-expresszió vizsgálata volt colorectalis adenocarcinoma miatt reszekción átesett betegek szövettani metszetein. Módszer: Az Uzsoki Utcai Kórházban 2004 és 2011 között reszekált 64, colorectalis tumoros beteg demográfiai, sebészeti és patológiai adatait gyujtöttük össze. A betegek szövettani metszeteit IL6-antitesttel festettük. A digitalizált metszeteket kvantitatív színelemzéssel kiértékeltük, majd az eredményeket a betegek klinikai paramétereinek függvényében elemeztük. Eredmények: Elorehaladott stádiumú betegekben a tumorsejtek IL6-expressziója szignifikánsan magasabbnak bizonyult lineáris regresszióval. A tumorsejtek IL6-expressziója azonban nem korrelált a nemmel, az életkorral vagy a tumor differenciáltságával. Megbeszélés: Különbségek mutatkoztak a tumorsejtek és a stromasejtek IL6-kifejezodése között. Következtetés: Az IL6 hasznos marker és potenciális terápiás cél lehet az elorehaladottabb stádiumú colorectalis tumoros betegeknél. Orv Hetil. 2021; 162(37): 1502-1507. INTRODUCTION: It is well known that there is a complex correlation between inflammation and tumor development and tumor progression. Interleukin-6 (IL6) is a pleiotropic inflammatory cytokine with both tumor stimulating and inhibiting effect. OBJECTIVE: The goal of our study was to evaluate the IL6 expression of histological slides from patients after resection of colorectal adenocarcinoma. METHOD: Demographical, surgical, and pathological findings of 64 patients with colorectal cancer operated between 2004 and 2011 in Uzsoki Teaching Hospital were evaluated. Histopathological slides were stained with IL6 antibody. The digitalized slides were assessed with quantitative color analysis, and the results were evaluated according to patients' clinical parameters. RESULTS: Linear regression showed significantly higher IL6 expression in the tumor cells in patients with advanced stages. However, the IL6 expression of the tumor cells did not correlate with sex, age, or tumor grade. DISCUSSION: There were differences between the IL6 expression in tumor cells and stromal cells. CONCLUSION: IL6 may be a useful marker and potential therapeutic target in patients with advanced colorectal cancer. Orv Hetil. 2021; 162(37): 1502-1507.


Assuntos
Adenocarcinoma , Neoplasias Colorretais , Adenocarcinoma/genética , Neoplasias Colorretais/genética , Humanos , Interleucina-6
12.
World J Surg Oncol ; 19(1): 281, 2021 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-34535152

RESUMO

BACKGROUND: Long noncoding RNAs (lncRNAs) are related to colorectal cancer (CRC) development. However, the role and mechanism of lncRNA LINC01224 in CRC development are largely unknown. METHODS: LINC01224, Yin Yang 1 (YY1), microRNA (miR)-485-5p, and myosins of class VI (MYO6) levels were examined using quantitative reverse transcription polymerase chain reaction and western blotting. Functional analyses were processed through CCK-8, colony formation, flow cytometry, transwell, and xenograft analyses. Dual-luciferase reporter, chromatin immunoprecipitation (ChIP), RNA immunoprecipitation, and pull-down assays were conducted to analyze the binding interaction. RESULTS: LINC01224 abundance was elevated in CRC tissue samples and cell lines. Elevated LINC01224 might indicate the lower 5-year overall survival in 52 CRC patients. LINC01224 was upregulated via the transcription factor YY1. LINC01224 knockdown restrained CRC cell proliferation, migration, and invasion and increased apoptosis. MiR-485-5p was sponged by LINC01224, and miR-485-5p downregulation relieved the influence of LINC01224 interference on CRC progression. MYO6 was targeted via miR-485-5p and regulated via LINC01224/miR-485-5p axis. MiR-485-5p overexpression suppressed CRC cell proliferation, migration, and invasion and facilitated apoptosis. MYO6 upregulation mitigated the role of miR-485-5p. LINC01224 knockdown decreased xenograft tumor growth. CONCLUSION: YY1-induced LINC01224 regulates CRC development via modulating miR-485-5p/MYO6 axis.


Assuntos
Neoplasias Colorretais , MicroRNAs , RNA Longo não Codificante , Proliferação de Células , Neoplasias Colorretais/genética , Humanos , MicroRNAs/genética , Prognóstico , RNA Longo não Codificante/genética
13.
Medicina (Kaunas) ; 57(7)2021 Jul 14.
Artigo em Inglês | MEDLINE | ID: mdl-34356990

RESUMO

Background and objectives: Receptor-interacting serine/threonine-protein kinase-2 (RIPK2) is an important mediator in different pathways in the immune and inflammatory response system. RIPK2 was also shown to play different roles in different cancer types; however, in colorectal cancer (CRC), its role is not well established. This study aims at identifying the role of RIPK2 in CRC progression and survival. Materials and methods: Data of patients and mRNA protein expression level of genes associated with CRC (RIPK2, tumor necrosis factor (TNF), TRAF1, TRAF7, KLF6, interlukin-6 (Il6), interlukin-8 (Il8), vascular-endothelial growth factor A (VEGFA), MKI67, TP53, nuclear factor-kappa B (NFKB), NFKB2, BCL2, XIAP, and RELA) were downloaded from the PrognoScan online public database. Patients were divided between low and high RIPK2 expression and different CRC characteristics were studied between the two groups. Survival curves were evaluated using a Kaplan-Meier estimator. The Pearson correlation was used to study the correlation between RIPK2 and the other factors. Statistical analysis was carried out using SPSS version 25.0. The Human Protein Atlas was also used for the relationship between RIPK2 expression in CRC tissues and survival. Differences were considered statistically significant at p < 0.05. Results: A total of 520 patients were downloaded from the PrognoScan database, and RIPK2 was found to correlate with MKI67, TRAF1, KLF6, TNF, Il6, Il8, VEGFA, NFKB2, BCL2, and RELA. High expression of RIPK2 was associated with high expression of VEGFA (p < 0.01) and increased mortality (p < 0.01). Conclusions: In this study, RIPK2 is shown to be a potential prognostic factor in CRC; however, more studies are needed to assess and verify its potential role as a prognostic marker and in targeted therapy.


Assuntos
Neoplasias Colorretais , Proteína Serina-Treonina Quinase 2 de Interação com Receptor/genética , Neoplasias Colorretais/genética , Humanos , Prognóstico , Fator A de Crescimento do Endotélio Vascular
14.
Medicina (Kaunas) ; 57(8)2021 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-34441055

RESUMO

Background and Objectives: Colorectal cancer (CRC) can be classified as mismatch-repair-deficient (dMMR) with high levels of microsatellite instability (MSI-H), or mismatch-repair-proficient (pMMR) and microsatellite stable (MSS). Approximately 15% of patients have microsatellite instability (MSI). MSI-H tumors are associated with a high mutation burden. Monoclonal antibodies that block immune checkpoints can induce long-term durable responses in some patients. Pembrolizumab is the first checkpoint inhibitor approved in the EU to treat dMMR-MSI-H metastatic CRC. Materials and Methods: Our study assesses the regional variability of MSI-H colorectal cancer tumors in Romania. Formalin-fixed, paraffin-embedded (FFPE) tissue blocks containing tumor samples from 90 patients diagnosed with colorectal cancer were collected from two tertiary referral Oncology Centers from Romania. Tissues were examined for the expression loss of MMR proteins (MLH1, PMS2, MSH2, MSH6) using immunohistochemistry or MSI status using polymerase chain reaction (PCR), respectively. Results: MSI-H was detected in 19 (21.1%) patients. MSI-H was located more in ascending colon (36.8% vs. 9.9%, p-value = 0.0039) and less in sigmoid (5.3% vs. 33.8%, p-value = 0.0136) than MSS patients. Most patients were stage II for MSI-H (42.1%) as well as for MSS (56.3%), with significant more G1 (40.9% vs. 15.8%, p-value = 0.0427) for MSS patients. Gender, N stage, and M stage were identified as significant prognostic factors in multivariate analysis. MSI status was not a statistically significant predictor neither in univariate analysis nor multivariate analysis. Conclusion: Considering the efficacy of PD-1 inhibitor in metastatic CRC with MSI-H or dMMR, and its recent approval in EU, it is increasingly important to understand the prevalence across tumor stage, histology, and demographics, since our study displayed higher regional MSI-H prevalence (21%) compared to the literature.


Assuntos
Neoplasias Colorretais , Reparo de Erro de Pareamento de DNA , Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Reparo de Erro de Pareamento de DNA/genética , Detecção Precoce de Câncer , Humanos , Projetos Piloto , Romênia
15.
In Vivo ; 35(5): 2809-2814, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34410972

RESUMO

BACKGROUND/AIM: The monoclonal antibody bevacizumab is a standard drug used in combination with oxaliplatin (FOLFOX) or irinotecan (FOLFIRI) based chemotherapy in the first or second-line treatment of metastatic colorectal cancer (mCRC). Our previous study identified and subsequently validated 4 microRNAs in a small group of patients as predictors of the therapeutic response to bevacizumab combined with chemotherapy. The aim of this follow-up study is to confirm the predictive ability of these tissue miRNAs in a larger independent cohort of mCRC patients. PATIENTS AND METHODS: The retrospective study included 92 patients with generalized-radically inoperable tumors treated with the combined therapy of bevacizumab/FOLFOX in a standard regimen. RESULTS: Expression levels of candidate miRNA biomarkers (miR-92b-3p, miR-3156-5p, miR-10a-5p and miR-125a-5p) were determined in tumor tissue specimens and statistically evaluated. MiR-92b-3p and miR-125a-5p were confirmed to be associated with radiological response according to RECIST criteria (p=0.005 and 0.05, respectively) and to be up-regulated in responders to bevacizumab/FOLFOX therapy. Higher levels of miR-92b-3p were also significantly associated with extended progression-free survival (p=0.024). CONCLUSION: We have successfully confirmed miR-92b-3p to be up-regulated in tumor tissue of mCRC patients with good response to bevacizumab/FOLFOX therapy.


Assuntos
Neoplasias Colorretais , MicroRNAs , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Bevacizumab/uso terapêutico , Biomarcadores , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Fluoruracila , Seguimentos , Humanos , MicroRNAs/genética , Estudos Retrospectivos
16.
In Vivo ; 35(5): 2841-2844, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34410976

RESUMO

AIM: To determinate molecular changes in the downstream epidermal growth factor receptor signaling pathway using serial liquid biopsies in patients with metastatic colorectal tumors (mCRC) under anti-angiogenic treatment. PATIENTS AND METHODS: Determination of RAS mutation in primary tissue samples from colorectal tumors was performed in the 23 patients included in the study at diagnosis using quantitative-polymerase chain reaction. Sequential mutations were studied in circulating tumor (ct) DNA obtained from plasma samples. RESULTS: Twenty-three patients with RAS-mutated primary tumors were included. In the first ctDNA determination, 17 of these patients were found to have wild-type RAS status. Remarkably, three out of these 17 wild-type cases changed to RAS-mutated in subsequent ctDNA assays. CONCLUSION: Serial liquid biopsies in patients with mCRC might be a useful tool for identifying changes in the RAS mutation status in patients who had undergone previous anti-angiogenic therapy. The understanding of these changes might help to better define the landscape of mCRC and be the path to future randomized studies.


Assuntos
Adenocarcinoma , DNA Tumoral Circulante , Neoplasias Colorretais , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/genética , DNA Tumoral Circulante/genética , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Humanos , Biópsia Líquida , Mutação
17.
World J Surg Oncol ; 19(1): 248, 2021 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-34419055

RESUMO

BACKGROUND: Colorectal cancer (CRC) is one of the most common cancers of the gastrointestinal tract and ranks third in cancer-related deaths worldwide. This study was conducted to identify novel biomarkers related to the pathogenesis of CRC based upon a bioinformatics analysis, and further verify the biomarkers in clinical tumor samples and CRC cell lines. METHODS: A series of bioinformatics analyses were performed using datasets from NCBI-GEO and constructed a protein-protein interaction (PPI) network. This analysis enabled the identification of Hub genes, for which the mRNA expression and overall survival of CRC patients data distribution was explored in The Cancer Genome Atlas (TCGA) colon cancer and rectal cancer (COADREAD) database. Furthermore, the differential expression of HCAR3 and INLS5 was validated in clinical tumor samples by Real-time quantitative PCR analysis, western blotting analysis, and immunohistochemistry analysis. Finally, CRC cells over-expressing INSL5 were constructed and used for CCK8, cell cycle, and cell apoptosis validation assays in vitro. RESULTS: A total of 286 differentially expressed genes (DEGs) were screened, including 64 genes with increased expression and 143 genes with decreased expression in 2 CRC database, from which 10 key genes were identified: CXCL1, HCAR3, CXCL6, CXCL8, CXCL2, CXCL5, PPY, SST, INSL5, and NPY1R. Among these genes, HCAR3 and INSL5 had not previously been explored and were further verified in vitro. CONCLUSIONS: HCAR3 expression was higher in CRC tissues and associated with better overall survival of CRC patients. INSL5 expression in normal tissue was higher than that in tumor tissue and its high expression was associated with a better prognosis for CRC. The overexpression of INSL5 significantly inhibited the proliferation and promoted the shearing of PARP of CRC cells. This integrated bioinformatics study presented 10 key hub genes associated with CRC. HCAR3 and INSL5 were expressed in tumor tissue and these were associated with poor survival and warrant further studies as potential therapeutic targets.


Assuntos
Neoplasias Colorretais , Insulina , Proteínas , Receptores Nicotínicos , Biomarcadores Tumorais/genética , Neoplasias Colorretais/genética , Bases de Dados Genéticas , Regulação Neoplásica da Expressão Gênica , Humanos , Prognóstico , Receptores Acoplados a Proteínas G
18.
Artigo em Inglês | MEDLINE | ID: mdl-34444383

RESUMO

Colorectal cancer (CRC) is one of the most frequently diagnosed cancers and, as such, is important for public health. The increased incidence of this neoplasm is attributed to non-modifiable controls such as family history and modifiable variable behavioral risk factors involved in lifestyle like diets in Mexico. The presence of these factors is unknown. Therefore, the aim of this study was to evaluate family history and lifestyle factors associated with developing colorectal cancer in a Mexican population. Descriptive statistics and multivariate logistic regression were used to estimate the adjusted odds ratios (OR), as well as the 95% confidence intervals (CI). In this paper, significant differences were demonstrated between cases and controls. A family history of cancer (FHC) increased the probability of CRC [OR = 3.19 (95% CI: 1.81-5.60)]. The area of urban residence was found to be a protective factor compared to the rural area. This was also the case for frequent consumption of fruits [OR = 0.49 (95% CI: 0.28-0.88)], the frequent consumption of beef [OR = 2.95 (95% CI: 1.05-8.26)], pork [OR = 3.26 (95% CI: 1.34-7.90)], and region-typical fried food [OR = 2.79 (95% CI (1.32-5.89)]. These results provide additional evidence supporting the association of some CRC risk factors with family history of cancer, low fruit consumption, high consumption of red meat, and fried foods typical of the region of México. It is important to establish intervention methods, as well as genetic counseling to relatives of patients with CRC.


Assuntos
Neoplasias Colorretais , Animais , Estudos de Casos e Controles , Bovinos , Neoplasias Colorretais/epidemiologia , Neoplasias Colorretais/genética , Dieta , Hábitos , Humanos , México/epidemiologia , Razão de Chances , Fatores de Risco
19.
Artigo em Inglês | MEDLINE | ID: mdl-34444091

RESUMO

Colorectal cancer (CRC) remains the second leading cause of cancer-related deaths worldwide. Approximately 3-5% of CRCs are associated with hereditary cancer syndromes. Individuals who harbor germline mutations are at an increased risk of developing early onset CRC, as well as extracolonic tumors. Genetic testing can identify genes that cause these syndromes. Early detection could facilitate the initiation of targeted prevention strategies and surveillance for CRC patients and their families. The aim of this study was to determine the cost-effectiveness of CRC genetic testing. We utilized a cross-sectional design to determine the cost-effectiveness of CRC genetic testing as compared to the usual screening method (iFOBT) from the provider's perspective. Data on costs and health-related quality of life (HRQoL) of 200 CRC patients from three specialist general hospitals were collected. A mixed-methods approach of activity-based costing, top-down costing, and extracted information from a clinical pathway was used to estimate provider costs. Patients and family members' HRQoL were measured using the EQ-5D-5L questionnaire. Data from the Malaysian Study on Cancer Survival (MySCan) were used to calculate patient survival. Cost-effectiveness was measured as cost per life-year (LY) and cost per quality-adjusted life-year (QALY). The provider cost for CRC genetic testing was high as compared to that for the current screening method. The current practice for screening is cost-saving as compared to genetic testing. Using a 10-year survival analysis, the estimated number of LYs gained for CRC patients through genetic testing was 0.92 years, and the number of QALYs gained was 1.53 years. The cost per LY gained and cost per QALY gained were calculated. The incremental cost-effectiveness ratio (ICER) showed that genetic testing dominates iFOBT testing. CRC genetic testing is cost-effective and could be considered as routine CRC screening for clinical practice.


Assuntos
Neoplasias Colorretais , Qualidade de Vida , Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/genética , Análise Custo-Benefício , Estudos Transversais , Testes Genéticos , Humanos , Anos de Vida Ajustados por Qualidade de Vida
20.
BMC Gastroenterol ; 21(1): 326, 2021 Aug 23.
Artigo em Inglês | MEDLINE | ID: mdl-34425783

RESUMO

BACKGROUND: Constitutional mismatch repair deficiency (CMMRD) is an extremely rare autosomal recessive hereditary disease characterized by the absence of mismatch repair gene activity from birth, which results in brain tumors, colonic polyposis, gastrointestinal cancers, and lymphomas later in life. An aggressive approach, including colectomy or proctocolectomy, is recommended for the treatment of colorectal cancer. Additionally, partial colectomy with subsequent endoscopic surveillance may be an alternative strategy due to poor patient's condition, although there is no evidence of surveillance endoscopy after partial colectomy for CMMRD. CASE PRESENTATION: A 13-year-old male patient with a history of T-lymphoblastic lymphoma underwent total gastrointestinal endoscopy, which revealed rectal cancer, colorectal polyposis, and duodenal adenoma. Differential diagnosis included constitutional mismatch repair deficiency according to its scoring system and microsatellite instability, and subsequent germline mutation testing for mismatch repair genes confirmed the diagnosis of constitutional mismatch repair deficiency based on a homozygous mutation in mutS homolog 6 (MSH6). The patient and his family refused colectomy due to the high risk of malignancies other than colorectal cancer, which could require radical surgery. Therefore, the patient underwent low anterior resection of the rectosigmoid colon for rectal cancer and intensive surveillance endoscopy for the remaining colon polyposis. During the 3-year period after initial surgery, 130 polyps were removed and the number of polyps gradually decreased during 6-months interval surveillance endoscopies, although only one polyp was diagnosed as invasive adenocarcinoma (pT1). CONCLUSIONS: Our experience of short surveillance endoscopy illustrates that this strategy might be one of options according to patient's condition.


Assuntos
Neoplasias Encefálicas , Neoplasias Colorretais , Neoplasias Gastrointestinais , Síndromes Neoplásicas Hereditárias , Adolescente , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/cirurgia , Neoplasias Colorretais/genética , Neoplasias Colorretais/cirurgia , Endoscopia , Humanos , Masculino
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