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1.
Anal Cell Pathol (Amst) ; 2022: 8583382, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36065412

RESUMO

Background: The mortality rate of colorectal cancer (CRC) ranks second. circRNAs are abnormal expression in some diseases, and their dysregulation is associated with cancer progression. Recent studies have shown that the malignant progression of colorectal cancer is inseparable from the abnormal expression of circRNAs. Methods: First, the circ_0052184 expression in clinical tissue and cell samples was analyzed by qRT-PCR. Then, we constructed circ_0052184-silenced CRC cells and detected by qRT-PCR. Furthermore, the proliferation ability of cells was detected by colony formation assay. Cell migration ability was tested by wound healing assay and transwell assay. Cell invasion ability was detected by transwell assay. Results: Expression of circ_0052184 was significantly increased in colorectal cancer cell lines and tissues. Silencing circ_0052184 affected the proliferation, migration, and invasion of colorectal cancer cells. miR-604 was targeted by circ_0052184. The downstream target of miR-604 was HOXA9, and silencing circ_0052184 inhibited HOXA9 expression. The existence of the circ_0052184/miR-604/HOXA9 regulatory network in colorectal cancer was validated. circ_0052184 promoted the occurrence and development of colorectal cancer by targeting the miR-604/HOXA9 axis. Conclusions: Our study revealed that the molecular mechanism of circ_0052184 regulated the miR-604/HOXA9 axis, which might promote the malignant progression of colorectal cancer cells.


Assuntos
Neoplasias Colorretais , Proteínas de Homeodomínio , MicroRNAs , RNA Circular , Proliferação de Células/genética , Neoplasias Colorretais/metabolismo , Regulação Neoplásica da Expressão Gênica , Proteínas de Homeodomínio/genética , Humanos , MicroRNAs/genética , RNA Circular/genética
2.
Genet Res (Camb) ; 2022: 5338956, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36072013

RESUMO

Objectives: Accumulating evidence indicates that the expression and/or variants of several genes play an essential role in the progress of colorectal cancer (CRC). The current study is a meta-analysis undertaken to estimate the prognosis and survival associated with CTNNB1/ß-catenin, APC, Wnt, SMAD3/4, TP53, and Cyclin D1 genes among CRC patients. Methods: The authors searched PubMed, EMBASE, and Science Direct for relevant reports published between 2000 and 2020 and analyzed them to determine any relationship between the (immunohistochemically/sequencing-detected) gene expression and variants of the selected genes and the survival of CRC patients. Results: The analysis included 34,074 patients from 64 studies. To evaluate association, hazard ratios (HRs) were estimated for overall survival (OS) or disease-free survival (DFS), with a 95% confidence interval (CIs). Pooled results showed that ß-catenin overexpression, APC mutation, SMAD-3 or 4 loss of expression, TP53 mutations, and Cyclin D1 expression were associated with shorter OS. ß-Catenin overexpression (HR: 0.137 (95% CI: 0.131-0.406)), loss of expression of SMAD3 or 4 (HR: 0.449 (95% CI: 0.146-0.753)), the mutations of TP53 (HR: 0.179 (95% CI: 0.126-0.485)), and Cyclin D1 expression (HR: 0.485 (95% CI: 0.772-0.198)) also presented risk for shorter DFS. Conclusions: The present meta-analysis indicates that overexpression or underexpression and variants of CTNNB1/ß-catenin, APC, SMAD3/4, TP53, and Cyclin D1 genes potentially acted as unfavorable biomarkers for the prognosis of CRC. The Wnt gene was not associated with prognosis.


Assuntos
Neoplasias Colorretais , beta Catenina , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Ciclina D1/genética , Ciclina D1/metabolismo , Genes bcl-1 , Humanos , Prognóstico , Proteína Smad3/genética , Proteína Smad3/metabolismo , Proteína Supressora de Tumor p53/genética , beta Catenina/genética , beta Catenina/metabolismo
3.
Cell Mol Life Sci ; 79(9): 505, 2022 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-36057892

RESUMO

In multiple cancers, autophagy promotes tumor development by recycling intracellular components into metabolic pathways. Autophagy-induced metabolic reprogramming and plasticity lead to cancer cell survival and resistance to anticancer therapy. We investigated the role of small leucine zipper protein (sLZIP) in autophagy and cell survival under nutrient-deficient conditions in colorectal cancer (CRC). sLZIP was induced by nutrient stress and increased the transcription of microtubule-associated protein 1A/1B-light chain 3 (LC3), by directly binding to its promoter. Under nutrient stress conditions, sLZIP activated autophagy and promoted the survival of CRC cells. sLZIP induced metabolic reprogramming of CRC cells, to activate glutaminolysis and the tricarboxylic acid cycle. sLZIP also enhanced the autophagic degradation of Keap1 and the nuclear accumulation of Nrf2, leading to NQO1 expression, for maintenance of redox homeostasis. sLZIP-knockout CRC cells exhibited impaired autophagy induction in the glycolytic inhibition state. Xenograft mice lacking sLZIP showed decreased tumor growth, by rendering CRC cells sensitive to glycolysis inhibition. The expression of sLZIP and LC3B was highly elevated in tumors of CRC patients compared to that in normal tissues, and correlated with the progression of CRC. These findings suggest that sLZIP drives autophagy and metabolic reprogramming to promote colorectal tumorigenesis.


Assuntos
Neoplasias Colorretais , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico , Animais , Autofagia , Linhagem Celular Tumoral , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Humanos , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Zíper de Leucina , Camundongos , Proteínas Associadas aos Microtúbulos/genética , Proteínas Associadas aos Microtúbulos/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Nutrientes
4.
World J Gastroenterol ; 28(26): 3027-3046, 2022 Jul 14.
Artigo em Inglês | MEDLINE | ID: mdl-36051330

RESUMO

Colorectal cancer (CRC) continues to be one of the main causes of death from cancer because patients progress unfavorably due to resistance to current therapies. Dysregulation of the Wnt/ß-catenin pathway plays a fundamental role in the genesis and progression of several types of cancer, including CRC. In many subtypes of CRC, hyperactivation of the ß-catenin pathway is associated with mutations of the adenomatous polyposis coli gene. However, it can also be associated with other causes. In recent years, studies of the tumor microenvironment (TME) have demonstrated its importance in the development and progression of CRC. In this tumor nest, several cell types, structures, and biomolecules interact with neoplastic cells to pave the way for the spread of the disease. Cross-communications between tumor cells and the TME are then established primarily through paracrine factors, which trigger the activation of numerous signaling pathways. Crucial advances in the field of oncology have been made in the last decade. This Minireview aims to actualize what is known about the central role of the Wnt/ß-catenin pathway in CRC chemoresistance and aggressiveness, focusing on cross-communication between CRC cells and the TME. Through this analysis, our main objective was to increase the understanding of this complex disease considering a more global context. Since many treatments for advanced CRC fail due to mechanisms involving chemoresistance, the data here exposed and analyzed are of great interest for the development of novel and effective therapies.


Assuntos
Neoplasias Colorretais , beta Catenina , Linhagem Celular Tumoral , Proliferação de Células , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Resistencia a Medicamentos Antineoplásicos/genética , Regulação Neoplásica da Expressão Gênica , Humanos , Microambiente Tumoral , Via de Sinalização Wnt/genética , beta Catenina/genética , beta Catenina/metabolismo
5.
Int J Mol Sci ; 23(17)2022 Aug 24.
Artigo em Inglês | MEDLINE | ID: mdl-36076975

RESUMO

Cysteine might scavenge free radicals and is a limiting substrate for the cellular synthesis of glutathione (GSH). We investigated the association of cysteine with oxidative stress and GSH-related antioxidant capacity in colorectal cancer (CRC) patients. Plasma samples were drawn from 66 patients 1 day before (pre-resection) and 4 weeks after resection (post-resection). Tumor and adjacent normal tissues were collected. We measured levels of plasma and tissue cysteine, homocysteine, oxidative stress indicators (malondialdehyde, MDA; advanced oxidation protein products, AOPP), GSH, and antioxidant enzyme activities. After tumor resection, patients had significantly higher levels of plasma cysteine, homocysteine, MDA, AOPP, and GSH-related antioxidant enzyme activities when compared with pre-resection. Levels of cysteine, homocysteine, AOPP and all antioxidant capacity indicators in tumor tissue were significantly higher than those levels in the adjacent normal tissue. Plasma cysteine levels measured at pre-resection were positively associated with MDA levels in the tumor and in the adjacent normal tissues. Cysteine levels in tumor and adjacent normal tissues were significantly associated with tissue levels of homocysteine, almost as indicators of oxidative stress and antioxidant capacities. Cysteine in the circulation was likely utilized to mediate GSH-related antioxidant capacity and further cope with increased oxidative stress in tumor and adjacent normal tissues.


Assuntos
Antioxidantes , Neoplasias Colorretais , Produtos da Oxidação Avançada de Proteínas/metabolismo , Antioxidantes/metabolismo , Neoplasias Colorretais/metabolismo , Cisteína/metabolismo , Glutationa/metabolismo , Homocisteína/metabolismo , Humanos , Malondialdeído/metabolismo , Estresse Oxidativo
6.
Biomed Res Int ; 2022: 7469041, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36119930

RESUMO

Immunohistochemical staining is a common technique to study tissue morphology and in situ protein expression. With the rise of immunotherapy, more and more markers in the tumor microenvironment have been discovered. In this paper, the multiplex immunofluorescence staining method was used to stain paraffin sections of 35 cases of gastric adenocarcinoma tissue and 35 cases of colorectal adenocarcinoma tissue and its adjacent tissue. The infiltration of CD8+ T cells and CD103+CD8+ T cells in the slices was detected by using the slice scanner to form the map and CaseViewer2.0 software analysis. The experimental results in this paper showed that compared with adjacent tissues, the infiltration degree of CD8+ T cells in gastric adenocarcinoma tissue was significantly lower (Z = 2.244, P = 0.025, P < 0.05), and the infiltration degree of cells was significantly lower (Z = 2.785, P = 0.005, P < 0.05). In gastric adenocarcinoma tissue, the infiltration of CD8+ T cells was correlated with the tumor diameter of gastric adenocarcinoma (P = 0.002). There was a statistically significant difference. The degree of CD103+CD8+ T cell infiltration was related to the survival of patients with gastric adenocarcinoma (P = 0.002) and the degree of tumor differentiation (P = 0.004). The infiltration of CD103+CD8+ T cells in gastric cancer tissue and colorectal cancer tissue is related to the survival of patients. CD103+CD8+ T cells are thought to play a role in the prognosis of gastric adenocarcinoma and colorectal adenocarcinoma. Experiments have shown that the more the CD103+CD8+ T cells, the better the prognosis of gastric adenocarcinoma and colorectal adenocarcinoma, so the prognosis of gastric adenocarcinoma and colorectal adenocarcinoma can be improved by increasing CD103+CD8+ T cells.


Assuntos
Adenocarcinoma , Neoplasias Colorretais , Neoplasias Gástricas , Adenocarcinoma/patologia , Linfócitos T CD8-Positivos/metabolismo , Neoplasias Colorretais/metabolismo , Humanos , Linfócitos do Interstício Tumoral/patologia , Parafina , Neoplasias Gástricas/patologia , Microambiente Tumoral
7.
Sci Rep ; 12(1): 14915, 2022 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-36050500

RESUMO

This study aimed to synthesize new thioderivative chalcones and analyze their impact on the NF-κB, STAT3, EGFR and Nrf2 signaling pathways in colorectal cancer cells. Among the studied compounds, derivatives 4 and 5 decreased the activation of NF-κB and the expression of the target gene COX-2. In the case of STAT3, we observed the inhibition of activation of this signaling pathway after influencing derivative 4. Increased activation of the Nrf2 signaling pathway was demonstrated for derivatives 5 and 7 in DLD-1 and HCT116 cells. The results of this study indicated that new chalcone derivatives, especially compounds 4, 5, and-to some degree-7, possess potential applications in the prevention of colorectal cancer.


Assuntos
Chalcona , Chalconas , Neoplasias Colorretais , Chalconas/farmacologia , Neoplasias Colorretais/metabolismo , Fator de Transcrição de Proteínas de Ligação GA/metabolismo , Humanos , Fator 2 Relacionado a NF-E2/metabolismo , NF-kappa B/metabolismo , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais
8.
Biomed Res Int ; 2022: 2268818, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36072467

RESUMO

Inadequate vitamin D status may increase the risk of developing multiple types of cancer. Epidemiological studies suggest an inverse association between 25-hydroxyvitamin D3 (25(OH)D3) and malignancy, including colorectal cancer. Previous studies have suggested that MED28, a Mediator subunit involved in transcriptional regulation, is associated with the growth of colorectal cancer cells; however, its role in the progression of metastasis such as epithelial-mesenchymal transition (EMT) and cell migration of colorectal cancer is unclear at present. The aim of this study was to investigate a potentially suppressive effect of calcitriol, 1,25-dihydroxyvitamin D3 (1,25(OH)2D3), a bioactive form of vitamin D, and the role of MED28 in the progression of EMT in human colorectal cancer cells. Suppression of MED28 increased the expression of E-cadherin and reduced the expression of several mesenchymal and migration biomarkers and Wnt/ß-catenin signaling molecules, whereas overexpression of MED28 enhanced the EMT features. Calcitriol suppressed the expression of MED28, and the effect of calcitriol mirrored that of MED28 silencing. Our data indicate that calcitriol attenuated MED28-mediated cell growth and EMT in human colorectal cancer cells, underlining the significance of MED28 in the progression of colorectal cancer and supporting the potential translational application of calcitriol.


Assuntos
Neoplasias Colorretais , Transição Epitelial-Mesenquimal , Complexo Mediador , Vitamina D , Calcitriol/farmacologia , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Humanos , Complexo Mediador/genética , Vitamina D/farmacologia , Vitaminas/farmacologia
9.
PLoS One ; 17(9): e0273076, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36095023

RESUMO

The use of humanized mouse models for oncology is rapidly expanding. Autologous patient-derived systems are particularly attractive as they can model the human cancer's heterogeneity and immune microenvironment. In this study, we developed an autologous humanized mouse cancer model by engrafting NSG mice with patient-derived xenografts and infused matched peripheral blood mononuclear cells (PBMCs). We first defined the time course of xenogeneic graft-versus-host-disease (xGVHD) and determined that only minimal xGVHD was observed for up to 8 weeks. Next, colorectal and pancreatic cancer patient-derived xenograft bearing NSG mice were infused with 5x106 human PBMCS for development of the humanized cancer models (iPDX). Early after infusion of human PBMCs, iPDX mice demonstrated engraftment of human CD4+ and CD8+ T cells in the blood of both colorectal and pancreatic cancer patient-derived models that persisted for up to 8 weeks. At the end of the experiment, iPDX xenografts maintained the features of the primary human tumor including tumor grade and cell type. The iPDX tumors demonstrated infiltration of human CD3+ cells with high PD-1 expression although we observed significant intra and inter- model variability. In summary, the iPDX models reproduced key features of the corresponding human tumor. The observed variability and high PD-1 expression are important considerations that need to be addressed in order to develop a reproducible model system.


Assuntos
Neoplasias Colorretais , Doença Enxerto-Hospedeiro , Neoplasias Pancreáticas , Animais , Neoplasias Colorretais/metabolismo , Modelos Animais de Doenças , Humanos , Leucócitos Mononucleares/metabolismo , Camundongos , Neoplasias Pancreáticas/metabolismo , Receptor de Morte Celular Programada 1/metabolismo , Microambiente Tumoral
10.
J Immunol Res ; 2022: 9916228, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36093435

RESUMO

Objective: This study explored the colorectal cancer exosome lncRNA prostate cancer associated transcript 1- (PCAT1) mediated circulating tumors and the mechanism of cell colorectal cancer liver metastasis. Methods: Exosomes were extracted from the primary colorectal cancer (CRC) cell lines HCT116 and SW480 and cultured with T84 and human umbilical vein endothelial (HUVE) cells. The expression of PCAT1 and miR-329-3p was detected by real-time quantitative polymerase chain reaction (RT-qPCR), the expression of Netrin-1, CD146, and epithelial mesenchymal transition (EMT) related proteins was detected by Western blot, the proliferation activity of T84 cells was detected by cell counting kit 8 (CCK-8), and cell migration was detected by Transwell. The expression of the F-actin signal was detected by immunofluorescence after coculture of exosomes with human umbilical vein endothelial cells (HUVECs). Changes in subcutaneous tumor and liver nodule size after PCAT1 deletion were observed in a mouse model of liver metastasis from rectal cancer. Results: PCAT1 expression was upregulated in primary cell lines and their exosomes. After exosomes were cocultured with colorectal cancer tumor circulating T84 cells, the expression of Netrin-1 and CD146 was upregulated, the expression of miR-329-3p was downregulated, the proliferation and migration ability of T84 cells were enhanced, and EMT occurred. After knocking down PCAT1, the above phenomenon was reversed. Similarly, after exosomes were cocultured with HUVECs, the expression of the F-actin signal increased, and after PCAT1 was knocked down, the F-actin signal also decreased. PCAT1 regulates miR-329-3p/Netrin-1 and affects the biological behavior of T84 and F-actin signal expression in HUVECs. In a mouse model of colorectal cancer liver metastasis, knocking down PCAT1 significantly reduced the nodules formed by liver metastasis in mice. Conclusions: LncRNA PCAT1 derived from colorectal cancer exosomes regulates the activity of the Netrin-1-CD146 complex in circulating tumor cells (CTCs) to promote the occurrence of colorectal cancer EMT and liver metastasis and provides new molecular targets for the treatment of colorectal cancer liver metastasis.


Assuntos
Neoplasias Colorretais , Neoplasias Hepáticas , MicroRNAs , RNA Longo não Codificante , Actinas/metabolismo , Animais , Antígeno CD146/genética , Antígeno CD146/metabolismo , Neoplasias Colorretais/metabolismo , Regulação Neoplásica da Expressão Gênica , Células Endoteliais da Veia Umbilical Humana/metabolismo , Células Endoteliais da Veia Umbilical Humana/patologia , Humanos , Neoplasias Hepáticas/metabolismo , Masculino , Camundongos , MicroRNAs/genética , MicroRNAs/metabolismo , Netrina-1/genética , Netrina-1/metabolismo , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo
11.
Cytokine ; 159: 156008, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36063748

RESUMO

IFN-α receptor (IFNAR) is critical for maintaining the crosstalk between cancer cells and lymphocytes. We investigated IFNAR1 expression in peripheral blood CD4+ and CD8+ T cells and explored their relationships with plasma cytokines, chemosensitivity and infiltrated T cells in the tumor microenvironment (TME) of colorectal cancer (CRC). The levels of IFNAR1, IFN-γ, and PD1 in peripheral T cells were tested using flow cytometry. Immunohistochemical staining of IFNAR1 in CRC tissues was performed. A cytometric bead array was used to determine the plasma concentrations of cytokines. In CRC patients, IFNAR1 levels were significantly increased in peripheral blood T cells, and plasma IL-6 levels were also significantly increased. Pearson correlation analysis revealed that IFNAR1 expression in CD8+ T cells was negatively associated with plasma IL-2, IFN-γ, and TNFα. IFNAR1 expression in CD4+ T cells was positively associated with TME infiltrated levels of CD8+ T cells. The levels of CD8+ T cells with IFNAR1 and plasma IFN-γ were associated with chemosensitivity. Collectively, IFNAR1 levels in CD4+ and CD8+ T cells were significantly upregulated in CRC patients and positively associated with T-cell infiltration. IFNAR1 may be a chemotherapy biomarker for predicting response.


Assuntos
Neoplasias Colorretais , Linfócitos do Interstício Tumoral , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD8-Positivos/metabolismo , Neoplasias Colorretais/metabolismo , Citocinas/metabolismo , Humanos , Interleucina-2/metabolismo , Interleucina-6/metabolismo , Receptor de Interferon alfa e beta/metabolismo , Microambiente Tumoral , Fator de Necrose Tumoral alfa/metabolismo
12.
BMC Mol Cell Biol ; 23(1): 40, 2022 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-36114463

RESUMO

BACKGROUND: Aquaporins are channel proteins, form pores in the membrane of biological cells to facilitate the transcellular and transepithelial water movement. The role of Aquaporins in carcinogenesis has become an area of interest. In this study, we aimed to investigate the effects of adipose-derived mesenchymal stem cells secreted exosomes on the expression of aquaporin 5 and EGFR genes in the HCT-116 tumor cell line. METHODS AND RESULTS: Surface antigenic profile of Ad-MSCs was evaluated using specific markers. Exosomes were purified from the Ad-MSc supernatant while the quality and the shape of isolated exosomes were assessed by western blot and transmission electron microscopy (TEM) respectively. HCT-116 cells were co-cultured with MSC-conditioned medium (MSC-CM) and/or with 100 µg/ml of MSC-derived exosomes for 48 h and. Real-time PCR was carried out to determine the expression of aquaporin5 and EGFR in HCT-116. Relative expression levels were calculated using the 2-ΔΔct method. Our result showed that AQP5 and EGFR mRNA levels were significantly reduced in CM and/or exosomes treated HCT116 compare to the control group (P-value < 0.05). CONCLUSION: The current study showed that MSC derived exosomes could inhibit expression of two important molecules involved in tumor progression. Hence it seems MSCs-derived exosomes may hold a hopeful future as drug delivery vehicles which need the furtherer investigation.


Assuntos
Neoplasias Colorretais , Exossomos , Células-Tronco Mesenquimais , Aquaporina 5/genética , Aquaporina 5/metabolismo , Linhagem Celular Tumoral , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Meios de Cultivo Condicionados/farmacologia , Receptores ErbB/metabolismo , Exossomos/metabolismo , Humanos , Células-Tronco Mesenquimais/metabolismo , RNA Mensageiro/metabolismo
13.
Clin Transl Med ; 12(9): e1037, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-36116139

RESUMO

BACKGROUND: Colorectal cancer (CRC) has a high mortality rate, and therapeutic approaches to treat these cancers are varied and depend on the metabolic state of the tumour. Profiles of CRC tumours have identified several biomarkers, including microRNAs. microRNA-210 (miR-210) levels are directly correlated with CRC survival. miR-210 expression is higher in metastatic colon cancer cells versus non-metastatic and normal colon epithelium. Therefore, efficient methods to inhibit miR-210 expression in CRC may provide new advances in treatments. METHODS: Expression of miRs was determined in several metastatic and non-metastatic cell lines. miR-210 expression was inhibited using PMIS-miR-210 in transduced cells, which were transplanted into xenograft mice. In separate experiments, CRC tumours were allowed to grow in xenograft mice and treated with therapeutic injections of PMIS-miR-210. Molecular and biochemical experiments identified several new pathways targeted by miR-210 inhibition. RESULTS: miR-210 inhibition can significantly reduce tumour growth of implanted colon cancer cells in xenograft mouse models. The direct administration of PMIS-miR-210 to existing tumours can inhibit tumour growth in both NSG and Foxn1nu/j mouse models and is more efficacious than capecitabine treatments. Tumour cells further transfer the PMIS-miR-210 inhibitor to neighbouring cells by extracellular vesicles to inhibit miR-210 throughout the tumour. miR-210 inhibition activates the cleaved caspase 3 apoptotic pathway to reduce tumour formation. We demonstrate that the long non-coding transcript XIST is regulated by miR-210 correlating with decreased XIST expression in CRC tumours. XIST acts as a competing endogenous RNA for miR-210, which reduces XIST levels and miR-210 inhibition increases XIST transcripts in the nucleus and cytoplasm. The increased expression of NME1 is associated with H3K4me3 and H3K27ac modifications in the NME1 proximal promoter by XIST. CONCLUSION: Direct application of the PMIS-miR-210 inhibitor to growing tumours may be an effective colorectal cancer therapeutic.


Assuntos
Neoplasias do Colo , Neoplasias Colorretais , Vesículas Extracelulares , MicroRNAs , Animais , Apoptose/genética , Capecitabina , Caspase 3 , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Vesículas Extracelulares/genética , Vesículas Extracelulares/metabolismo , Vesículas Extracelulares/patologia , Humanos , Camundongos , MicroRNAs/genética , MicroRNAs/metabolismo , Nucleosídeo NM23 Difosfato Quinases
14.
J Transl Med ; 20(1): 402, 2022 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-36064706

RESUMO

BACKGROUND: Colorectal cancer (CRC) is the third most common cancer and leading cause of cancer-related deaths worldwide. Aberrant cellular metabolism is a hallmark of cancer cells, and disturbed metabolism showed clinical significance in CRC. The membrane-associated RING-CH 8 (MARCH8) protein, the first MARCH E3 ligase, plays an oncogenic role and serves as a prognostic marker in multiple cancers, however, the role of MARCH8 in CRC is unclear. In the present study, we aimed to investigate the biomarkers and their underlying mechanism for CRC. METHOD: In this study, we first examined the function of MARCH8 in CRC by analysing public database. Besides, we performing gene silencing studies and generating cellular overexpression and xenograft models. Then its protein substrate was identified and validated. In addition, the expression of MARCH8 was investigated in tissue samples from CRC patients, and the molecular basis for decreased expression was analysed. RESULTS: Systematic analysis reveals that MARCH8 is a beneficial prognostic marker in CRC. In CRC, MARCH8 exhibited tumor-suppressive activity both in vivo and in vitro. Furthermore, we found that MARCH8 is negatively correlated with hexokinase 2 (HK2) protein in CRC patients. MARCH8 regulates glycolysis and promotes ubiquitination-mediated proteasome degradation to reduces HK2 protein levels. Then HK2 inhibitor partially rescues the effect of MARCH8 knockdown in CRC. Poised chromatin and elevated miR-32 repressed MARCH8 expression. CONCLUSION: In summary, we propose that in CRC, poised chromatin and miR-32 decrease the expression of MARCH8, further bind and add ubiquitin, induce HK2 degradation, and finally repress glycolysis to promote tumor suppressors in CRC.


Assuntos
Neoplasias Colorretais , MicroRNAs , Ubiquitina-Proteína Ligases , Linhagem Celular Tumoral , Proliferação de Células , Cromatina , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Glicólise , Humanos , Proteínas de Membrana/genética , MicroRNAs/genética , MicroRNAs/metabolismo , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/metabolismo
15.
Chem Res Toxicol ; 35(9): 1533-1540, 2022 Sep 19.
Artigo em Inglês | MEDLINE | ID: mdl-36074022

RESUMO

Nonylphenol (NP) is a widely used chemical, which has been considered a kind of endocrine-disrupting chemical and is involved in the occurrence and development of many types of cancers. Our recent studies demonstrated that NP exposure is related to colorectal cancer (CRC) progression. In this study, we also found epithelial-mesenchymal transition (EMT) promoted by NP treatment in CRC cells. However, the mechanism of NP on tumor metastasis is still unclear. In this study, we focused on the effect of the regulator of cell cycle (RGCC) induced by NP treatment. The cancer genome atlas (TCGA) analysis suggested that the expression of RGCC increased in CRC tissues, and our clinical samples showed that the expression of RGCC in tumor tissues is positively correlated with the serum level of NP in CRC patients. Further studies revealed that overexpression of RGCC could enhance the NP-induced EMT process in CRC cells and activate ERK signaling pathways. Inhibiting ERK signaling by ERK inhibitors or the knockdown of RGCC could attenuate the NP-induced EMT process. In addition, both RGCC overexpression and NP treatment could activate ERK pathways and attenuate the effect of ERK inhibitors on the EMT process in CRC cells. Altogether, this study demonstrated that NP could induce cell invasion and migration by increasing the expression of RGCC to enhance the EMT process, which might be through the activation of ERK signaling pathways. This finding supported a potential target for studying NP exposure-related colorectal cancers.


Assuntos
Neoplasias Colorretais , Transição Epitelial-Mesenquimal , Ciclo Celular , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células/genética , Neoplasias Colorretais/metabolismo , Regulação Neoplásica da Expressão Gênica , Humanos , Fenóis/farmacologia
16.
Mar Drugs ; 20(8)2022 Jul 27.
Artigo em Inglês | MEDLINE | ID: mdl-36005485

RESUMO

Overexpressed EGFR and mutant K-Ras play vital roles in therapeutic resistance in colorectal cancer patients. To search for an effective therapeutic protocol is an urgent task. A secondary metabolite in the sponge Hippospongia sp., Heteronemin, has been shown to induce anti-proliferation in several types of cancers. A thyroxine-deaminated analogue, tetrac, binds to integrin αvß3 to induce anti-proliferation in different cancers. Heteronemin- and in combination with tetrac-induced antiproliferative effects were evaluated. Tetrac enhanced heteronemin-induced anti-proliferation in HT-29 cells (KRAS WT CRC) and HCT-116 cells (KRAS MT CRC). Heteronemin and tetrac arrested cell cycle in different phases. Combined treatment increased the cell accumulation in sub-G1 and S phases. The combined treatment also induced the inactivation of EGFR signaling and downregulated the phosphorylated ERK1/2 protein in both cell lines. Heteronemin and the combination showed the downregulation of the phosphorylated and total PI3K protein in HT-29 cells (KRAS WT CRC). Results by NanoString technology and RT-qPCR revealed that heteronemin and combined treatment suppressed the expression of EGFR and downstream genes in HCT-116 cells (KRAS MT CRC). Heteronemin or combined treatment downregulated genes associated with cancer progression and decreased cell motility. Heteronemin or the combined treatment suppressed PD-L1 expression in both cancer cell lines. However, only tetrac and the combined treatment inhibited PD-L1 protein accumulation in HT-29 cells (KRAS WT CRC) and HCT-116 cells (KRAS MT CRC), respectively. In summary, heteronemin induced anti-proliferation in colorectal cancer cells by blocking the EGFR-dependent signal transduction pathway. The combined treatment further enhanced the anti-proliferative effect via PD-L1 suppression. It can be an alternative strategy to suppress mutant KRAS resistance for anti-EGFR therapy.


Assuntos
Neoplasias Colorretais , Tiroxina , Antígeno B7-H1/metabolismo , Linhagem Celular Tumoral , Proliferação de Células , Neoplasias Colorretais/metabolismo , Receptores ErbB/metabolismo , Humanos , Mutação , Proteínas Proto-Oncogênicas p21(ras)/genética , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Proteínas Proto-Oncogênicas p21(ras)/farmacologia , Transdução de Sinais , Terpenos , Tiroxina/análogos & derivados
17.
Cells ; 11(16)2022 Aug 09.
Artigo em Inglês | MEDLINE | ID: mdl-36010550

RESUMO

Although artesunate has been reported to be a promising candidate for colorectal cancer (CRC) treatment, the underlying mechanisms and molecular targets of artesunate are yet to be explored. Here, we report that artesunate acts as a senescence and autophagy inducer to exert its inhibitory effect on CRC in a reactive oxygen species (ROS)-dependent manner. In SW480 and HCT116 cells, artesunate treatment led to mitochondrial dysfunction, drastically promoted mitochondrial ROS generation, and consequently inhibited cell proliferation by causing cell cycle arrest at G0/G1 phase as well as subsequent p16- and p21-mediated cell senescence. Senescent cells underwent endoplasmic reticulum stress (ERS), and the unfolded protein response (UPR) was activated via IRE1α signaling, with upregulated BIP, IRE1α, phosphorylated IRE1α (p-IRE1α), CHOP, and DR5. Further experiments revealed that autophagy was induced by artesunate treatment due to oxidative stress and ER stress. In contrast, N-Acetylcysteine (NAC, an ROS scavenger) and 3-Methyladenine (3-MA, an autophagy inhibitor) restored cell viability and attenuated autophagy in artesunate-treated cells. Furthermore, cellular free Ca2+ levels were increased and could be repressed by NAC, 3-MA, and GSK2350168 (an IRE1α inhibitor). In vivo, artesunate administration reduced the growth of CT26 cell-derived tumors in BALB/c mice. Ki67 and cyclin D1 expression was downregulated in tumor tissue, while p16, p21, p-IRE1α, and LC3B expression was upregulated. Taken together, artesunate induces senescence and autophagy to inhibit cell proliferation in colorectal cancer by promoting excessive ROS generation.


Assuntos
Neoplasias Colorretais , Endorribonucleases , Animais , Apoptose , Artesunato/farmacologia , Autofagia , Linhagem Celular Tumoral , Proliferação de Células , Senescência Celular , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/metabolismo , Camundongos , Proteínas Serina-Treonina Quinases , Espécies Reativas de Oxigênio/metabolismo
18.
Technol Cancer Res Treat ; 21: 15330338221118717, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35929169

RESUMO

Background: Forkhead box F2, a member of the Forkhead box transcription factor superfamily, plays an important role in several types of cancer. However, the mechanisms of Forkhead box F2 in the progression of colorectal cancer remain unclear. PRUNE2 is closely associated with prostate cancer, neuroblastoma, glioblastoma, and melanoma. The relationship between Forkhead box F2 and PRUNE2 in colorectal cancer remains unknown. Method: We investigated the effects of Forkhead box F2 upregulation on colorectal cancer cell behavior in vitro using Cell Counting Kit-8, colony formation, flow cytometry, Transwell, reverse transcription quantitative polymerase chain reaction and Western blot analyses. Nude mouse xenografts were established to investigate the effect of Forkhead box F2 upregulation on the growth of colorectal cancer cells. Dual-luciferase reporter assays were performed to confirm the Forkhead box F2 regulation of PRUNE2 transcription. A series of in vitro assays was performed in cells with Forkhead box F2 upregulation and PRUNE2 knockdown to elucidate the function and regulatory effects of Forkhead box F2 on PRUNE2 transcription in colorectal cancer. Results: Forkhead box F2 was downregulated in colorectal cancer tissues compared with adjacent tissues. Forkhead box F2 overexpression significantly suppressed the proliferation and invasion of colorectal cancer cells in vitro and in vivo. Moreover, Forkhead box F2 directly targeted PRUNE2 to promote its transcription in colorectal cancer cells. Furthermore, PRUNE2 mediated the Forkhead box F2-regulated proliferation and invasion of colorectal cancer cells. Additionally, we demonstrated a significant positive correlation between Forkhead box F2 and PRUNE2 mRNA levels in colorectal cancer tissues. Conclusion: These results indicated that Forkhead box F2 and PRUNE2 in combination may serve as a prognostic biomarker for colorectal cancer and that Forkhead box F2 upregulation inhibits the proliferation and invasion of colorectal cancer cells by upregulating PRUNE2.


Assuntos
Neoplasias Colorretais , Fatores de Transcrição Forkhead , Regulação Neoplásica da Expressão Gênica , MicroRNAs , Proteínas de Neoplasias , Animais , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Fatores de Transcrição Forkhead/genética , Fatores de Transcrição Forkhead/metabolismo , Regulação Neoplásica da Expressão Gênica/genética , Regulação Neoplásica da Expressão Gênica/fisiologia , Humanos , Camundongos , MicroRNAs/genética , MicroRNAs/metabolismo , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Regulação para Cima/genética , Ensaios Antitumorais Modelo de Xenoenxerto
19.
Sci Adv ; 8(32): eabo2389, 2022 08 12.
Artigo em Inglês | MEDLINE | ID: mdl-35947664

RESUMO

An alarming rise in young onset colorectal cancer (CRC) has been reported; however, the underlying molecular mechanism remains undefined. Suspected risk factors of young onset CRC include environmental aspects, such as lifestyle and dietary factors, which are known to affect the circadian clock. We find that both genetic disruption and environmental disruption of the circadian clock accelerate Apc-driven CRC pathogenesis in vivo. Using an intestinal organoid model, we demonstrate that clock disruption promotes transformation by driving Apc loss of heterozygosity, which hyperactivates Wnt signaling. This up-regulates c-Myc, a known Wnt target, which drives heightened glycolytic metabolism. Using patient-derived organoids, we show that circadian rhythms are lost in human tumors. Last, we identify that variance between core clock and Wnt pathway genes significantly predicts the survival of patients with CRC. Overall, our findings demonstrate a previously unidentified mechanistic link between clock disruption and CRC, which has important implications for young onset cancer prevention.


Assuntos
Relógios Circadianos , Neoplasias Colorretais , Relógios Circadianos/genética , Ritmo Circadiano/genética , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Humanos , Perda de Heterozigosidade , Organoides/metabolismo , Via de Sinalização Wnt
20.
Sci Rep ; 12(1): 13409, 2022 Aug 04.
Artigo em Inglês | MEDLINE | ID: mdl-35927308

RESUMO

Diapeutics gene markers in colorectal cancer (CRC) can help manage mortality caused by the disease. We applied a game-theoretic link relevance Index (LRI) scoring on the high-throughput whole-genome transcriptome dataset to identify salient genes in CRC and obtained 126 salient genes with LRI score greater than zero. The biomarkers database lacks preliminary information on the salient genes as biomarkers for all the available cancer cell types. The salient genes revealed eleven, one and six overrepresentations for major Biological Processes, Molecular Function, and Cellular components. However, no enrichment with respect to chromosome location was found for the salient genes. Significantly high enrichments were observed for several KEGG, Reactome and PPI terms. The survival analysis of top protein-coding salient genes exhibited superior prognostic characteristics for CRC. MIR143HG, AMOTL1, ACTG2 and other salient genes lack sufficient information regarding their etiological role in CRC. Further investigation in LRI methodology and salient genes to augment the existing knowledge base may create new milestones in CRC diapeutics.


Assuntos
Neoplasias Colorretais , Regulação Neoplásica da Expressão Gênica , Angiomotinas , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Neoplasias Colorretais/metabolismo , Perfilação da Expressão Gênica , Humanos , Proteínas de Membrana/metabolismo , Prognóstico , Análise de Sobrevida , Transcriptoma
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