RESUMEN
Incomplete knowledge of the molecular basis of colorectal cancer, with subsequent limitations in early diagnosis and effective treatment, has contributed to this form of malignancy becoming the second most common cause of cancer-related death worldwide. With the advances in high-throughput profiling techniques and the availability of public data sets such as The Cancer Genome Atlas Program (TCGA), a broad range of coding transcripts have been profiled and their underlying modes of action have been mapped. However, there is still a huge gap in our understanding of noncoding RNA dysregulation. To this end, we used a bioinformatics approach to shortlist and evaluate yet-to be-profiled long noncoding RNAs (lncRNAs) in colorectal cancer. We analysed the TCGA RNA-seq data and followed this by validating the expression patterns using a qPCR technique. Analysing in-house clinical samples, the real-time PCR method revealed that the shortlisted lncRNAs, that is MER1 Repeat Containing Imprinted Transcript 1 (MIMT1) and Non-Protein Coding RNA 1550 (LINC01550), were down-regulated in colorectal cancer tumours compared with the paired adjacent normal tissues. Mechanistically, the in silico results suggest that LINC01550 could form a complex competitive endogenous RNA (ceRNA) network leading to the subsequent regulation of colorectal cancer-related genes, such as CUGBP Elav-Like Family Member (CELF2), Polypyrimidine Tract Binding Protein 1 (PTBP1) and ELAV Like RNA Binding Protein 1 (ELAV1). The findings of this work indicate that MIMT1 and LINC01550 could be novel tumour suppressor genes that can be studied further to assess their roles in regulating the cancer signalling pathway(s).
Asunto(s)
Neoplasias Colorrectales , MicroARNs , ARN Largo no Codificante , Humanos , Biomarcadores de Tumor/genética , Proteínas CELF/genética , Proteínas CELF/metabolismo , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , Biología Computacional , Regulación Neoplásica de la Expresión Génica , Redes Reguladoras de Genes , Ribonucleoproteínas Nucleares Heterogéneas/genética , Ribonucleoproteínas Nucleares Heterogéneas/metabolismo , MicroARNs/genética , Proteínas del Tejido Nervioso/genética , Proteínas del Tejido Nervioso/metabolismo , Proteína de Unión al Tracto de Polipirimidina/genética , Proteína de Unión al Tracto de Polipirimidina/metabolismo , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismoRESUMEN
Cell surface proteins (CSPs) are an important type of protein in different essential cell functions. This study aimed to distinguish overexpressed CSPs in colorectal cancer to investigate their biomarker, prognosis, and drug resistance potential. Raw data of three datasets including 1187 samples was downloaded then normalization and differential expression were performed. By the combination of the cancer genome atlas (TCGA) clinical data, survival analysis was carried out. Information of all CSPs was collected from cell surface protein atlas. The role of each candidate gene expression was investigated in drug resistance by CCEL and GDSC data from PharmacoGX. CRC samples including 30 tumor samples and adjacent normal were used to confirm data by RT-qPCR. Outcomes showed that 66 CSPs overexpressed in three datasets, and 146 CSPs expression associated with poor prognosis features in TCGA data that TIMP1 and QSOX2 can associate with poor patient survival independently. High-risk patients illustrated more fatality than low-risk patients based on the risk score calculated by the expression level of these genes. Receiver operating characteristic curve analysis showed that 39 CSPs as perfect biomarkers for diagnosis in CRC. Furthermore, QSOX2 and TIMP1 expression levels increased in tumor samples compared to adjacent normal samples. The Drug resistance analysis demonstrated ADAM12 and COL1A2 up-regulation among 66 overexpressed CSPs caused resistance to Venetoclax and Cyclophosphamide with a high estimate, respectively. Many CSPs are deregulated in CRC, and can be valuable candidates as biomarkers for diagnosis, prognosis, and drug resistance.
Asunto(s)
Proteína ADAM12/genética , Colágeno Tipo I/genética , Neoplasias Colorrectales/genética , Oxidorreductasas actuantes sobre Donantes de Grupos Sulfuro/genética , Inhibidor Tisular de Metaloproteinasa-1/genética , Biomarcadores de Tumor/genética , Compuestos Bicíclicos Heterocíclicos con Puentes/efectos adversos , Compuestos Bicíclicos Heterocíclicos con Puentes/uso terapéutico , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/epidemiología , Neoplasias Colorrectales/patología , Simulación por Computador , Ciclofosfamida/efectos adversos , Ciclofosfamida/uso terapéutico , Supervivencia sin Enfermedad , Resistencia a Antineoplásicos/genética , Femenino , Regulación Neoplásica de la Expresión Génica/genética , Humanos , Masculino , Proteínas de la Membrana/genética , Persona de Mediana Edad , Sulfonamidas/efectos adversos , Sulfonamidas/uso terapéuticoRESUMEN
Acute lymphoblastic leukemia (ALL) is one of the most frequent hematological malignancies in children, representing approximately 25 % of all pediatric cancers. Despite striking advances in ALL treatments, a small population of patients does not still respond to chemotherapy, raising the number of deaths in children. ABC transporters are one of the major causes of multidrug resistance (MDR) in cancers and overexpression of ABCA3 is directly associated with increased chemo-resistance in pediatric ALL. Here, we aimed to identify the microRNAs (miRNAs) which may regulate the expression of ABCA3 in childhood ALL. Bone marrow samples from a total of 50 ALLs and 59 controls were collected and after in silico and literature search, miR-324-3p and miR-508-5p were nominated from a list of putative miRNAs targeting ABCA3. Our qPCR analysis showed a low expression profile of selected miRNAs in pediatric ALL patients compared with non-cancer controls. Furthermore, we found that both miR-324-3p and miR-508-5p were significantly differentially expressed between patients with positive and negative minimal residual disease (MRD + vs MRD-) after one year of chemotherapy while only miR-508-5p was underexpressed in relapsed ALL patients. Additionally, a negative correlation was identified between the expression of these two miRNAs and ABCA3, supporting the regulatory effect of them on drug resistance through interacting with ABCA3. Overall, we suggested miR-324-3p and miR-508-5p as potential diagnostic and drug-resistant biomarkers in pediatric ALL. Moreover, our findings presented miR-508-5p to behave as a promising relapsed indicator in childhood ALL which can be applied in the development of novel therapeutic strategies.
Asunto(s)
Transportadoras de Casetes de Unión a ATP/metabolismo , Biomarcadores de Tumor/metabolismo , Resistencia a Múltiples Medicamentos , Resistencia a Antineoplásicos , MicroARNs/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/patología , Transportadoras de Casetes de Unión a ATP/genética , Biomarcadores de Tumor/genética , Estudios de Casos y Controles , Niño , Femenino , Estudios de Seguimiento , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Humanos , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , PronósticoRESUMEN
A higher expression of MALAT1 has been reported in breast cancer. However, more studies are needed to decipher the mechanisms by which this lncRNA imposes its oncogenic effects. In this study, blood and tissue samples were taken from healthy normal and breast cancer subjects. qPCR was used to analyze the gene expression. HRM-PCR method was carried out to genotype the selected samples. Computational analysis was recruited to find novel targets of MALAT1 and miR-143-3p. The data analyses revealed that MALAT1 was up-regulated in breast cancer and could be a distinctive factor to diagnose cancer. The expression of MALAT1 was inversely correlated with miR-143-3p expression in the studied clinical samples. The down-regulation of miR-143-3p was proven in the clinical tumor samples as compared to the healthy controls. A negative correlation of miR-143-3p with its putative target, RALGAPA2 was observed. A functional SNP rs3827693 located within the 3'UTR region of RALGAPA2 mRNA was validated in this study to associate with breast cancer risk. The rs3827693 allele G significantly decreased the breast cancer incidence and augmented the negative correlation between RALGAPA2 and miR-143-3p, presumably through strengthening the interaction between these two transcripts. This study proposed MALAT1 miR-143-3p and miR-143-3p RALGAPA2 axis in breast cancer, whereby the latter can be altered by the clinically functional SNP rs3827693.