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1.
Cell Genom ; 4(9): 100641, 2024 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-39216476

RESUMO

Colorectal cancer (CRC) ranks as the second leading cause of cancer deaths globally. In recent years, short-read single-cell RNA sequencing (scRNA-seq) has been instrumental in deciphering tumor heterogeneities. However, these studies only enable gene-level quantification but neglect alterations in transcript structures arising from alternative end processing or splicing. In this study, we integrated short- and long-read scRNA-seq of CRC samples to build an isoform-resolution CRC transcriptomic atlas. We identified 394 dysregulated transcript structures in tumor epithelial cells, including 299 resulting from various combinations of splicing events. Second, we characterized genes and isoforms associated with epithelial lineages and subpopulations exhibiting distinct prognoses. Among 31,935 isoforms with novel junctions, 330 were supported by The Cancer Genome Atlas RNA-seq and mass spectrometry data. Finally, we built an algorithm that integrated novel peptides derived from open reading frames of recurrent tumor-specific transcripts with mass spectrometry data and identified recurring neoepitopes that may aid the development of cancer vaccines.


Assuntos
Neoplasias Colorretais , Análise de Célula Única , Transcriptoma , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Humanos , Análise de Célula Única/métodos , Isoformas de Proteínas/genética , Análise de Sequência de RNA/métodos , Regulação Neoplásica da Expressão Gênica , Processamento Alternativo/genética
2.
NPJ Precis Oncol ; 8(1): 52, 2024 Feb 27.
Artigo em Inglês | MEDLINE | ID: mdl-38413740

RESUMO

Globally, colorectal cancer (CRC) is the third most frequently occurring cancer. Progression on to an advanced metastatic malignancy (metCRC) is often indicative of poor prognosis, as the 5-year survival rates of patients decline rapidly. Despite the availability of many systemic therapies for the management of metCRC, the long-term efficacies of these regimens are often hindered by the emergence of treatment resistance due to intratumoral and intertumoral heterogeneity. Furthermore, not all systemic therapies have associated biomarkers that can accurately predict patient responses. Hence, a functional personalised oncology (FPO) approach can enable the identification of patient-specific combinatorial vulnerabilities and synergistic combinations as effective treatment strategies. To this end, we established a panel of CRC patient-derived organoids (PDOs) as clinically relevant biological systems, of which three pairs of matched metCRC PDOs were derived from the primary sites (ptCRC) and metastatic lesions (mCRC). Histological and genomic characterisation of these PDOs demonstrated the preservation of histopathological and genetic features found in the parental tumours. Subsequent application of the phenotypic-analytical drug combination interrogation platform, Quadratic Phenotypic Optimisation Platform, in these pairs of PDOs identified patient-specific drug sensitivity profiles to epigenetic-based combination therapies. Most notably, matched PDOs from one patient exhibited differential sensitivity patterns to the rationally designed drug combinations despite being genetically similar. These findings collectively highlight the limitations of current genomic-driven precision medicine in guiding treatment strategies for metCRC patients. Instead, it suggests that epigenomic profiling and application of FPO could complement the identification of novel combinatorial vulnerabilities to target synchronous ptCRC and mCRC.

3.
Medicina (Kaunas) ; 59(6)2023 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-37374333

RESUMO

Background and Objectives: It remains unclear which domains of preoperative health-related quality of life (HRQOL) and mental health are predictive of postoperative clinical and patient-reported outcomes in colorectal cancer (CRC) patients. Materials and Methods: A prospective cohort of 78 CRC patients undergoing elective curative surgery was recruited. The EORTC QLQ-C30 and HADS questionnaires were administered preoperatively and one month after surgery. Results: Preoperative cognitive functioning scores (95% CI 0.131-1.158, p = 0.015) and low anterior resection (95% CI 14.861-63.260, p = 0.002) independently predicted poorer 1-month postoperative global QOL. When postoperative complications were represented using the comprehensive complication index (CCI), poorer preoperative physical function scores were associated with higher CCI scores (B = -0.277, p = 0.014). Preoperative social function score (OR = 0.925, 95% CI 0.87 to 0.99; p = 0.019) was an independent predictor for 30-day readmission, while physical functioning score (OR = -0.620, 95% CI -1.073--0.167, p = 0.008) was inversely related to the length of hospitalization. The overall regressions for 1-month postoperative global QOL (R2: 0.546, F: 1.961, p = 0.023) and 30-day readmission (R2: 0.322, χ2: 13.129, p < 0.001) were statistically significant. Conclusions: Various QLQ-C30 domains were found to be predictive of postoperative outcomes, including complications, readmission, and length of hospitalization. Preoperative cognitive dysfunction and low AR were independent predictors of poorer postoperative global QOL. Future research should seek to examine the efficacy of targeting specific baseline QOL domains in improving clinical as well as patient-reported outcomes after CRC surgery.


Assuntos
Neoplasias Colorretais , Protectomia , Humanos , Qualidade de Vida/psicologia , Estudos Prospectivos , Saúde Mental , Neoplasias Colorretais/complicações , Inquéritos e Questionários
4.
Nat Cell Biol ; 24(6): 928-939, 2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-35618746

RESUMO

Most mammalian genes generate messenger RNAs with variable untranslated regions (UTRs) that are important post-transcriptional regulators. In cancer, shortening at 3' UTR ends via alternative polyadenylation can activate oncogenes. However, internal 3' UTR splicing remains poorly understood as splicing studies have traditionally focused on protein-coding alterations. Here we systematically map the pan-cancer landscape of 3' UTR splicing and present this in SpUR ( http://www.cbrc.kaust.edu.sa/spur/home/ ). 3' UTR splicing is widespread, upregulated in cancers, correlated with poor prognosis and more prevalent in oncogenes. We show that antisense oligonucleotide-mediated inhibition of 3' UTR splicing efficiently reduces oncogene expression and impedes tumour progression. Notably, CTNNB1 3' UTR splicing is the most consistently dysregulated event across cancers. We validate its upregulation in hepatocellular carcinoma and colon adenocarcinoma, and show that the spliced 3' UTR variant is the predominant contributor to its oncogenic functions. Overall, our study highlights the importance of 3' UTR splicing in cancer and may launch new avenues for RNA-based anti-cancer therapeutics.


Assuntos
Adenocarcinoma , Neoplasias do Colo , Regiões 3' não Traduzidas/genética , Adenocarcinoma/genética , Processamento Alternativo/genética , Animais , Carcinogênese/genética , Neoplasias do Colo/genética , Mamíferos , Regulação para Cima
5.
Cell Mol Life Sci ; 79(3): 147, 2022 Feb 23.
Artigo em Inglês | MEDLINE | ID: mdl-35195778

RESUMO

In addition to genomic alterations, aberrant changes in post-transcriptional regulation can modify gene function and drive cancer development. RNA-binding proteins (RBPs) are a large class of post-transcriptional regulators that have been increasingly implicated in carcinogenesis. By integrating multi-omics data, we identify LARP1 as one of the most upregulated RBPs in colorectal cancer (CRC) and demonstrate its oncogenic properties. We perform LARP1:RNA interactome profiling and unveil a previously unexplored role for LARP1 in targeting the 3'UTR of oncogenes in CRC. Notably, we identify the proto-oncogenic transcription factor MYC as a key LARP1-regulated target. Our data show that LARP1 positively modulates MYC expression by associating with its 3'UTR. In addition, antisense oligonucleotide-mediated blocking of the interaction between LARP1 and the MYC 3'UTR reduces MYC expression and in vitro CRC growth. Furthermore, a systematic analysis of LARP1:protein interactions reveals IGF2BP3 and YBX1 as LARP1-interacting proteins that also regulate MYC expression and CRC development. Finally, we demonstrate that MYC reciprocally modulates LARP1 expression by targeting its enhancer. In summary, our data reveal a critical, previously uncharacterized role of LARP1 in promoting CRC tumorigenesis, validate its direct regulation of the proto-oncogene MYC and delineate a model of the positive feedback loop between MYC and LARP1 that promotes CRC growth and development.


Assuntos
Autoantígenos/metabolismo , Carcinogênese/metabolismo , Neoplasias Colorretais/metabolismo , Retroalimentação Fisiológica , Proteínas Proto-Oncogênicas c-myc/metabolismo , Ribonucleoproteínas/metabolismo , Regiões 3' não Traduzidas , Animais , Autoantígenos/genética , Carcinogênese/genética , Proliferação de Células/genética , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Regulação Neoplásica da Expressão Gênica , Células HCT116 , Humanos , Camundongos , Oncogenes , Ribonucleoproteínas/genética , Transcriptoma/genética , Transfecção , Carga Tumoral/genética , Ensaios Antitumorais Modelo de Xenoenxerto , Antígeno SS-B
6.
Oncogene ; 41(8): 1178-1189, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-34937878

RESUMO

3'UTR shortening in cancer has been shown to activate oncogenes, partly through the loss of microRNA-mediated repression. This suggests that many reported microRNA-oncogene target interactions may not be present in cancer cells. One of the most well-studied oncogenes is the transcription factor MYC, which is overexpressed in more than half of all cancers. MYC overexpression is not always accompanied by underlying genetic aberrations. In this study, we demonstrate that the MYC 3'UTR is shortened in colorectal cancer (CRC). Using unbiased computational and experimental approaches, we identify and validate microRNAs that target the MYC coding region. In particular, we show that miR-138 inhibits MYC expression and suppresses tumor growth of CRC and hepatocellular carcinoma (HCC) cell lines. Critically, the intravenous administration of miR-138 significantly impedes MYC-driven tumor growth in vivo. Taken together, our results highlight the previously uncharacterized shortening of the MYC 3'UTR in cancer, and identify miR-138 as a potent regulator of the heterogenous MYC transcript population.


Assuntos
Carcinoma Hepatocelular
7.
Ann Acad Med Singap ; 50(10): 773-781, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34755171

RESUMO

INTRODUCTION: Surgical resection of the primary and metastatic tumour is increasingly recommended in suitable patients with metastatic colorectal cancer (CRC). While the role of metastasectomy is well studied and established in colorectal liver metastasis, evidence remains limited in pulmonary metastases. This systematic review was conducted to examine the current evidence on the role of lung metastasectomy (LUM) in CRC. METHODS: Three databases were systematically searched, to identify studies that compared survival outcomes of LUM, and factors that affected decision for LUM. RESULTS: From a total of 5,477 records, 6 studies were eventually identified. Two papers reported findings from one randomised controlled trial and 4 were retrospective reviews. There was no clear survival benefit in patients who underwent LUM compared to those who did not. When compared against patients who underwent liver metastasectomy, there was also no clear survival benefit. Patients who underwent LUM were also more likely to have a single pulmonary tumour, and metachronous disease. CONCLUSION: The evidence suggests a role for LUM, but is limited by inherent selection bias in retrospective reviews, and the single randomised clinical trial performed was not completed. More prospective studies are required to understand the true effect of LUM on outcomes in metastatic CRC.


Assuntos
Neoplasias Colorretais , Neoplasias Hepáticas , Neoplasias Pulmonares , Metastasectomia , Neoplasias Colorretais/cirurgia , Humanos , Neoplasias Hepáticas/cirurgia , Neoplasias Pulmonares/cirurgia , Pneumonectomia , Prognóstico , Ensaios Clínicos Controlados Aleatórios como Assunto , Estudos Retrospectivos , Taxa de Sobrevida
8.
Food Funct ; 5(9): 2043-51, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-25080220

RESUMO

It is unclear how the nutritional supplement chicken extract (CE) enhances cognition. Human apolipoprotein E (ApoE) can regulate cognition and this isoform-dependent effect is associated with the N-methyl-d-aspartate receptor (NMDAR). To understand if CE utilizes this pathway, we compared the NMDAR signaling in neuronal cells expressing ApoE3 and ApoE4. We observed that CE increased S896 phosphorylation on NR1 in ApoE3 cells and this was linked to higher protein kinase C (PKC) activation. However, ApoE4 cells treated with CE have lowered S897 phosphorylation on NR1 and this was associated with reduced protein kinase A (PKA) phosphorylation. In ApoE3 cells, CE increased calmodulin kinase II (CaMKII) activation and AMPA GluR1 phosphorylation on S831. In contrast, CE reduced CaMKII phosphorylation and led to higher de-phosphorylation of S831 and S845 on GluR1 in ApoE4 cells. While CE enhanced ERK/CREB phosphorylation in ApoE3 cells, this pathway was down-regulated in both ApoE4 and mock cells after CE treatment. These results show that CE triggers ApoE isoform-specific changes on ERK/CREB signaling.


Assuntos
Apolipoproteína E3/metabolismo , Apolipoproteína E4/metabolismo , Cognição , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Produtos Avícolas/análise , Transdução de Sinais , Animais , Apolipoproteína E3/genética , Apolipoproteína E4/genética , Galinhas , Humanos , Camundongos , Camundongos Knockout , Neurônios/enzimologia , Neurônios/metabolismo , Fosforilação , Receptores de N-Metil-D-Aspartato/metabolismo
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