scholarly journals EXPRESSÃO DAS PROTEÍNAS MUTANTES DO KRAS NO ADENOCARCINOMA COLORRETAL – REVISÃO BIBLIOGRAFICA

2019 ◽  
Vol 6 (1) ◽  
pp. 50-53
Author(s):  
Virgílio Ribeiro Guedes ◽  
Natália Ferreira Bueno ◽  
Victor Vargas de Oliveira ◽  
Maria Cristina da Silva Pranchevicius
Keyword(s):  
Colorectal Cancer ◽  
Critical Role ◽  
Google Scholar ◽  
Ras Oncogene ◽  
Kras Gene ◽  
Gastrointestinal Malignancies ◽  
Exon 2 ◽  
First Line Therapy ◽  
Keywords Colorectal Cancer ◽  
The Right

Introdução: Os tumores colorretais foram o terceiro tipo de câncer mais diagnosticado em 2018. Na tentativa de aumentar a sobrevida de pacientes com metástases, o teste KRAS é relevante para a escolha da terapia mais apropriada para o carcinoma colorretal (CCR). O gene KRAS (Kirsten Ras Oncogene) acompanhado dos genes BRAF e NRAS é responsável por codificar as proteínas RAS da importante via de sinalização celular RAS/RAF/MEK/ERK. A presença de KRAS mutante no CCR é o principal biomarcador tecidual que indica a resistência do tumor à terapia de primeira linha com anticorpos monoclonais inibidores do EGFR (Cetuximabe e Panitumumabe). Metodologia: Foi realizado um levantamento bibliográfico na base eletrônica Google Scholar utilizando os descritores: “colorectal cancer” and “KRAS gene”. Resultados: A conversão do aminoácido glicina (G) para ácido aspártico (D) no códon 12, também chamada de KRAS G12D, é a mutação mais frequente do KRAS nas neoplasias malignas gastrointestinais. Cerca de 40% dos CCRs têm a mutação no gene KRAS nos códons 12 e 13 do éxon 2. Houve predomínio (57,4%) das mutações no sexo masculino, e todas as amostras de cólon esquerdo, 66% das de cólon direito e 51,8% das de reto apresentaram mutações no KRAS. A sinalização de células com KRAS mutante determina um papel crítico no rompimento inicial da submucosa e, por isso é essencial para a progressão da invasão e metástase do CCR. A eficácia de anti-EGFR é limitada em pacientes que possuem mutação KRAS, entretanto 20% dos pacientes com KRAS selvagem se beneficiam diante da terapia. Atualmente não há droga ou vacina que consiga focalizar efetivamente a proteína KRAS G12D em humanos. Conclusão: Pode-se inferir que o CCR é um câncer de prognostico ainda reservado. A decisão terapêutica apropriada depende do conhecimento do status mutacional do KRAS e as mutações no éxon 2 são claramente preditivas às terapias com anticorpos monoclonais inibidores do EGFR. Palavras-chave: Carcinoma colorretal; gene KRAS; mutação. ABSTRACT Introduction: Colorectal tumors were the third most diagnosed type of cancer in 2018. Trying to improve the overall survival of patients with metastasis, the KRAS test is relevant for choosing a mora appropriate therapy for the colorectal carcinoma (CRC). The KRAS gene (Kirsten Ras Oncogene) along with BRAF and NRAS genes is responsible for encoding RAS proteins from the important RAS / RAF / MEK / ERK cell signaling pathway. The presence of mutant KRAS in the CCR is the major tissue biomarker indicating the patient's resistance to first-line therapy with the monoclonal vaccine EGFR inhibitors (Cetuximabe and Panitumumabe). Methodology: A bibliographic survey was carried out in the database of Google Scholar using the descriptors: "colorectal cancer" and "KRAS gene". Results: The conversion of the amino acid glycine (G) to aspartic acid (D) at codon 12, also called KRAS G12D, is a more frequent mutation of KRAS in gastrointestinal malignancies. About 40% of the RCCs have a mutation in the KRAS gene at codons 12 and 13 of exon 2. There was a predominance (57.4%) of the mutations in the male sex, and all samples from the left colon, 66% of the right colon and 51.8% of the mutational changes in KRAS. Marking of cells with mutant KRAS determines a non-initial critical role of the submucosa and is therefore essential for progression of CCR invasion and metastasis. Anti-EGFR is limited to patients who have KRAS mutation, in addition, 20% of wild-type KRAS patients benefit from the therapy. There is currently no drug or vaccine that can concentrate on a KRAS G12D protein in humans. Conclusion: It can be inferred that the CRC still has a reserved prognosis. The multitude of KRAS and mutations in exon 2 are clearly prescribed in therapies with EGFR inhibitory monoclonal antibodies. Keywords: Colorectal cancer; KRAS gene; mutation.

scholarly journals KRAS gene mutation in patients with primary colorectal cancer

Acta Medica ◽  
2019 ◽  
Vol 50 (1) ◽  
pp. 20-25
Author(s):  
Minh Thuc Vu Thi ◽  
Van Thieu Le ◽  
Quang Huy Huynh ◽  
Minh Duc Nguyen
Keyword(s):  
Colorectal Cancer ◽  
Gene Mutation ◽  
Kras Mutation ◽  
Pcr Amplification ◽  
Colorectal Cancers ◽  
Kras Gene ◽  
Kras Mutations ◽  
Exon 2 ◽  
Mutational Status ◽  
Keywords Colorectal Cancer

Objective: KRAS mutation occurs in 30% to 50% of colorectal cancers. The aim of our study was to determine the frequency of KRAS mutations among patients with colorectal cancer; and the relationship with clinicopathologic features. Materials and Methods: 79 colorectal cancer cases at a hospital in Hai Phong of Vietnam were collected, including 45 colon cancer and 34 rectal cancer during January 2010 and July 2012. PCR amplification and DNA sequencing were used to detect mutations in exon 2 of KRAS gene. The study was based on informed consent and approval by the Ethics Committee of Viet Tiep Hospital. Results: KRAS mutation was found in 40.4% (225/557) colorectal cancer. All mutation locations were in codon 12. There was significant association (p < 0.05) between KRAS mutations, tumor size and tumor stage. No significant association was observed between KRAS mutations and gender, tumor location, tumor grade or histologic presence of mucin (p>0.05). Conclusion: Determining the KRAS mutational status of tumor samples has become an essential tool for managing patients with colorectal cancers Keywords: colorectal cancer, KRAS gene mutation, clinicopathology.

Oncogenic alterations detected by droplet digital PCR in patients with metastatic colorectal cancer resistant to cetuximab.

2019 ◽  
Vol 37 (4_suppl) ◽  
pp. 575-575
Author(s):  
Rujiao Liu ◽  
Zhi-Yu Chen ◽  
Weijian Guo ◽  
Xiaodong Zhu ◽  
Mingzhu Huang ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Acquired Resistance ◽  
Standard Of Care ◽  
Digital Pcr ◽  
Droplet Digital Pcr ◽  
Egfr Mutations ◽  
Exon 2 ◽  
First Line Therapy ◽  
Line Setting

575 Background: Anti-EGFR therapy is the standard of care for metastatic colorectal cancer (mCRC) patients with RAS and BRAF genes wild type (wt). Secondary alterations of several genes have been identified as possibly resistant mechanisms to EGFR blockade, these including mutations of KRAS, NRAS, BRAF, MEK and EGFR ectodomain, as well as amplifications of HER2 and c-MET. In this study, we investigated alterations of these targeted genes for mCRC patients with acquired resistance to cetuximab treatment by using non-invasive droplet digital PCR (ddPCR) method within circulating DNA. Methods: We enrolled 38 RAS and BRAF wt patients, who progressed after failure of cetuximab contained regimens between Jul 2015 and Jan 2018. Plasma samples from all 38 patients were collected and detected for seven candidates (mutation of KRAS, NRAS, EGFR, BRAF, MEK, amplification of HER2, c-MET) by using ddPCR at the time of baseline, each evaluation by interval of 2 months and documented progression. All clinical parameters were collected simultaneously. Results: A total of 23 secondary alterations were found in 17 (17/38,44.7%) cetuximab resistant patients. The targeted gene alterations were detected as follows: 9 (9/23,39%) RAS mutations, 5 (22%) HER2 amplifications, 5 (22%) EGFR mutations, 2 (9%) c-MET amplifications, 1 (4%) BRAF and 1 MEK mutation. Among 17 patients, 6 patients had multiple alterations, including 2 patients with KRAS+EGFR mutations, 2 patients with HER2+c-MET co-amplifications and 2 patients with KRAS gene exon 2 and 3 multiple mutations. Primary sites were 15 left sides and 2 right sides, descending colon (12 cases) was the most common origins. Eleven patients were synchronous disease. Twelve patients received cetuximab as first line therapy, whereas 5 patients in the ≥ 2nd line setting. All of these 17 patients, plasma levels of oncogenic alterations detected by ddPCR were showed dynamic changing and good agreement with tumor responding status. Conclusions: Oncogenic alterations detected by ddPCR were found in almost half mCRC patients resistant to cetuximab. Dynamic changes of specific alteration may facilitate making decisions for selection of anti-EGFR mAb during the treatment course.

scholarly journals miR-5000-3p confers oxaliplatin resistance by targeting ubiquitin-specific peptidase 49 in colorectal cancer

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Yan-yan Zhuang ◽  
Wa Zhong ◽  
Zhong-sheng Xia ◽  
Shu-zhen Lin ◽  
Man chung Chan ◽  
...  
Keyword(s):  
Gene Expression ◽  
Colorectal Cancer ◽  
Drug Resistance ◽  
Critical Role ◽  
Treatment Strategies ◽  
Luciferase Reporter ◽  
Multi Drug Resistance ◽  
Gastrointestinal Malignancies

AbstractColorectal cancer (CRC) is the most common form of gastrointestinal malignancies. A growing number of reports focusing on oxaliplatin (OXA) resistance in CRC treatment have revealed that drug resistance is an urgent issue in clinical applications, especially for finding effective therapeutic targets. Recently, microRNAs (miRNAs) are reported to play a critical role in tumor progressions and multi-drug resistance. The main aim of this study is to establish whether miR-5000-3p is an oncogene that is resistant to OXA and further confirm its underlying regulatory role in CRC. The OXA-associated gene expression dataset in CRC cells was downloaded from Gene Expression Omnibus (GEO) database. Statistical software R was used for significance analysis of differentially expressed genes (DEGs) between OXA-resistant (OR)-CRC cells and CRC cells, and results indicated ubiquitin-specific peptidase 49 (USP49) was upregulated in OR-CRC cells. Luciferase reporter assay showed that USP49 was verified to act as a downstream target gene of miR-5000-3p. From the results of TCGA database, miR-5000-3p expression was upregulated and USP49 was downregulated in patients with CRC. The function of miR-5000-3p was detected using MTT assay, wound healing, Transwell, and flow cytometry assays. Moreover, through in vitro and in vivo experiments, miR-5000-3p expression was confirmed to be upregulated in CRC cells or OR-CRC cells comparing to normal cell lines. Molecular mechanism assays revealed that USP49 binds to the miR-5000-3p promoter to increase the expression of miR-5000-3p, resulting in cancer cells sensitized to OXA. To sum up, these results suggest that miR-5000-3p may be a novel biomarker involved in drug-resistance progression of CRC. Moreover, the drug-resistance mechanism of miR-5000-3p/USP49 axis provides new treatment strategies for CRC in clinical trials.

scholarly journals Discordance in RAS Mutations between Primary Colon Tumor and Metastases: A Real Event or a Matter of Methodology?

2017 ◽  
Vol 32 (4) ◽  
pp. 474-477 ◽  
Author(s):  
Alfonso De Stefano ◽  
Mario Rosanova ◽  
Umberto Malapelle ◽  
Maurizio Martini ◽  
Stefano De Falco ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Liver Metastases ◽  
Primary Tumor ◽  
Mutational Analysis ◽  
Direct Sequencing ◽  
Kras Gene ◽  
Exon 2 ◽  
Ras Mutations ◽  
Primary Colon ◽  
Colorectal Cancer Patients

Background Analysis of K- and N-RAS mutations is mandatory before planning treatment of metastatic colorectal cancer, because only RAS wild-type (WT) patients can benefit from treatment with anti-EGFR monoclonal antibodies (cetuximab and panitumumab). Case report Here we report the case of a 69-year-old male patient affected by metastatic sigmoid cancer. He underwent left hemicolectomy, and histology diagnosed a well-differentiated, pT4, node-positive adenocarcinoma; KRAS analysis performed with direct sequencing identified a mutation in exon 2 of the KRAS gene (GGT->GTT). After first-line chemotherapy with FOLFOX6 plus bevacizumab, the patient underwent surgical resection of residual liver metastases. Histology showed metastatic deposits from colic adenocarcinoma with extensive coagulative necrosis. Mutational analysis of the KRAS gene was also performed on liver metastases by pyrosequencing assay, and no mutation was identified. Due to the discordant results (GGT->GTT exon 2 KRAS mutation in the primary tumor, and KRAS-WT in the liver metastases), mutational analysis on liver metastasis was repeated using next-generation sequencing and enriching the sample in tumor cells by manual microdissection; the same type of mutation of the primary tumor (GGT->GTT exon 2 KRAS gene) was confirmed. Conclusions Accurate tissue sampling and adequately sensitive assays are essential to correctly identify colorectal cancer patients who can be treated with an anti-EGFR monoclonal antibody.

The Critical Role of the miR-21-MEG2 Axis in Colorectal Cancer

2020 ◽  
Vol 30 (6) ◽  
pp. 509-518
Author(s):  
Zengtao Bao ◽  
Shanting Gao ◽  
Baoming Zhang ◽  
Wenchao Shi ◽  
Aimin Li ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Critical Role

INVESTIGATION KRAS MUTATION IN CIRCULATION TUMOR DNA IN DIFFERENT STAGES OF COLORECTAL CANCER

2019 ◽  
Vol 65 (5) ◽  
pp. 701-707
Author(s):  
Vitaliy Shubin ◽  
Yuriy Shelygin ◽  
Sergey Achkasov ◽  
Yevgeniy Rybakov ◽  
Aleksey Ponomarenko ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Plasma Volume ◽  
Kras Mutation ◽  
Stage Iv ◽  
Circulating Tumor Dna ◽  
Stage Ii ◽  
Kras Gene ◽  
Kras Mutations ◽  
Droplet Pcr ◽  
Tumor Dna

To determine mutations in the plasma KRAS gene in patients with colorectal cancer was the aim of this study. The material was obtained from 44 patients with colorectal cancer of different stages (T1-4N0-2bM0-1c). Plasma for the presence of KRAS gene mutation in circulating tumor DNA was investigated using digital droplet polymerase chain reaction (PCR). KRAS mutations in circulating tumor DNA isolated from 1 ml of plasma were detected in 13 (30%) patients with cancer of different stages. Of these, with stage II, there were 3 patients, with III - 5 and with IV - 5. Patients who did not have mutations in 1 ml of plasma were analyzed for mutations of KRAS in circulating tumor DNA isolated from 3 ml of plasma. Five more patients with KRAS mutations were found with II and III stages. The highest concentrations of circulating tumor DNA with KRAS mutation were found in patients with stage IV. The increase in plasma volume to 3 ml did not lead to the identification of mutations in I stage. This study showed that digital droplet PCR allows identification of circulating tumor DNA with the KRAS mutations in patients with stage II-IV of colon cancer. The results can be used to determine the degree of aggressiveness of the tumor at different stages of the disease, but not the 1st, and it is recommended to use a plasma volume of at least 3 ml.

Jurisprudence Study of the Importance of the Role of a Woman’s Right to Have a Child: A Review

2020 ◽  
Vol 16 (3) ◽  
pp. 188-193
Author(s):  
Fatemeh Ghodrati
Keyword(s):  
Pregnant Women ◽  
Civil Law ◽  
Google Scholar ◽  
Review Of The Literature ◽  
Maternal Role ◽  
The Right ◽  
Time Limitations ◽  
Natural Barrier ◽  
Taking Care

Background: Every woman has the right to have children. Objective: This study aimed to investigate the Jurisprudence study of the importance of the role of a woman right to have a child. Methods: A review of the literature with keywords of motherhood. The viewpoints of the jurists, jurisprudent law, right contraception and breastfeeding, spiritual rewards, pregnant women, instinct of having a child and the Quran. The Information Centers such as Scopus and Iranmedex, Magi ran SID, Google Scholar, Science Direct, Pub med, and in the returns without any time limitations up to 2018. Therefore, Qur'anic verses based on the topic and authentic Hadith texts as well as authoritative, authentic scientific articles. Results: Narrations and Quran verses on greatness and respect of a mother show the importance of the maternal role. The maternal role is a fabulous facet of perfection of a woman and Islam has considered spiritual rewards for it. In the Quran, many biological changes such as pregnancy, childbirth, breastfeeding and taking care of a child and spiritual characteristics of mothers as the instinct seeking a child or generosity towards child have been mentioned. Islamic rules have a duty to extend this culture and aid mothers to achieve this right. Nobody can deprive a woman of it. Conclusion: In view of jurisprudent rules in Islam, if there is no limitation or natural barrier for a woman to have a child but her husband’s illogical unwillingness for having a child; this is, according to article 1130 of civil law, a kind of distress and embarrassment and the woman has the right to divorce.

scholarly journals RNF141 interacts with KRAS to promote colorectal cancer progression

Oncogene ◽  
2021 ◽  
Author(s):  
Jiuna Zhang ◽  
Xiaoyu Jiang ◽  
Jie Yin ◽  
Shiying Dou ◽  
Xiaoli Xie ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Plasma Membrane ◽  
Tumor Growth ◽  
Cancer Progression ◽  
Critical Role ◽  
Ring Finger ◽  
Immunohistochemical Analysis ◽  
Bimolecular Fluorescence Complementation

AbstractRING finger proteins (RNFs) play a critical role in cancer initiation and progression. RNF141 is a member of RNFs family; however, its clinical significance, roles, and mechanism in colorectal cancer (CRC) remain poorly understood. Here, we examined the expression of RNF141 in 64 pairs of CRC and adjacent normal tissues by real-time PCR, Western blot, and immunohistochemical analysis. We found that there was more expression of RNF141 in CRC tissue compared with its adjacent normal tissue and high RNF141 expression associated with T stage. In vivo and in vitro functional experiments were conducted and revealed the oncogenic role of RNF141 in CRC. RNF141 knockdown suppressed proliferation, arrested the cell cycle in the G1 phase, inhibited migration, invasion and HUVEC tube formation but promoted apoptosis, whereas RNF141 overexpression exerted the opposite effects in CRC cells. The subcutaneous xenograft models showed that RNF141 knockdown reduced tumor growth, but its overexpression promoted tumor growth. Mechanistically, liquid chromatography-tandem mass spectrometry indicated RNF141 interacted with KRAS, which was confirmed by Co-immunoprecipitation, Immunofluorescence assay. Further analysis with bimolecular fluorescence complementation (BiFC) and Glutathione-S-transferase (GST) pull-down assays showed that RNF141 could directly bind to KRAS. Importantly, the upregulation of RNF141 increased GTP-bound KRAS, but its knockdown resulted in a reduction accordingly. Next, we demonstrated that RNF141 induced KRAS activation via increasing its enrichment on the plasma membrane not altering total KRAS expression, which was facilitated by the interaction with LYPLA1. Moreover, KRAS silencing partially abolished the effect of RNF141 on cell proliferation and apoptosis. In addition, our findings presented that RNF141 functioned as an oncogene by upregulating KRAS activity in a manner of promoting KRAS enrichment on the plasma membrane in CRC.

scholarly journals Colorectal Cancer Apoptosis Induced by Dietary δ-Valerobetaine Involves PINK1/Parkin Dependent-Mitophagy and SIRT3

2021 ◽  
Vol 22 (15) ◽  
pp. 8117
Author(s):  
Nunzia D’Onofrio ◽  
Elisa Martino ◽  
Luigi Mele ◽  
Antonino Colloca ◽  
Martina Maione ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Colon Cancer ◽  
Mitochondrial Dysfunction ◽  
Cancer Cells ◽  
Current Knowledge ◽  
Apoptotic Cell ◽  
Critical Role ◽  
Dependent Manner ◽  
Colon Cancer Cells ◽  
Protein Levels

Understanding the mechanisms of colorectal cancer progression is crucial in the setting of strategies for its prevention. δ-Valerobetaine (δVB) is an emerging dietary metabolite showing cytotoxic activity in colon cancer cells via autophagy and apoptosis. Here, we aimed to deepen current knowledge on the mechanism of δVB-induced colon cancer cell death by investigating the apoptotic cascade in colorectal adenocarcinoma SW480 and SW620 cells and evaluating the molecular players of mitochondrial dysfunction. Results indicated that δVB reduced cell viability in a time-dependent manner, reaching IC50 after 72 h of incubation with δVB 1.5 mM, and caused a G2/M cell cycle arrest with upregulation of cyclin A and cyclin B protein levels. The increased apoptotic cell rate occurred via caspase-3 activation with a concomitant loss in mitochondrial membrane potential and SIRT3 downregulation. Functional studies indicated that δVB activated mitochondrial apoptosis through PINK1/Parkin pathways, as upregulation of PINK1, Parkin, and LC3B protein levels was observed (p < 0.0001). Together, these findings support a critical role of PINK1/Parkin-mediated mitophagy in mitochondrial dysfunction and apoptosis induced by δVB in SW480 and SW620 colon cancer cells.

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