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1.
BMC Cancer ; 22(1): 1119, 2022 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-36319973

RESUMO

BACKGROUND: Colorectal cancer remains the second leading cause of cancer death in North America. Fluorouracil and oxaliplatin based adjuvant chemotherapy for resected colon cancer (CC) reduces cancer recurrence, but also causes significant toxicity requiring dose reductions. The effect of dose intensity on survival outcomes is not fully understood and strengthening the evidence supports informed decision making between patients and oncologists. METHODS: Patients treated with adjuvant chemotherapy, between 2006 and 2011, for resected colon cancer at four Canadian academic cancer centers were retrospectively analyzed. All patients must have received oxaliplatin with either capecitabine (CAPOX) or 5-FU (FOLFOX). Dose intensity (DI) was calculated as total delivered dose of an individual chemotherapy agent divided by the cumulative intended dose of that agent. The influence of DI on overall survival was examined. RESULTS: Five hundred thirty-one patients with high-risk stage II or stage III resected CC were eligible and included in the analysis. FOLFOX was the most common regimen (69.6%) with 29.7% of patients receiving CAPOX and 0.7% receiving both therapies. Median follow-up was 36.7 months. The median DI for 5-FU and capecitabine was 100% and 100% with 13.6% and 9.8% of patients receiving ≤ 80% DI, respectively. The median DI of oxaliplatin was 70% with 56.8% of patients receiving ≤ 80% DI. A DI of > 80% for each chemotherapy component was associated with a significant improvement in overall survival compared to those with a DI of ≤ 80% (5-FU HR = 0.23, 95% CI = 0.08-0.65, p = 0.006; capecitabine HR = 0.56, 95% CI = 0.33-0.94, p = 0.026; oxaliplatin HR = 0.52, 95% CI = 0.33-0.82, p = 0.005). Patients with T2 and/or N2 disease with an oxaliplatin DI > 80% had a trend towards improved survival (HR = 0.62, 95% CI = 0.38-1.02, p = 0.06). CONCLUSIONS: In resected CC an adjuvant chemotherapy DI of > 80%, of each chemotherapy agent, is associated with improved overall survival.


Assuntos
Neoplasias do Colo , Neoplasias Testiculares , Masculino , Humanos , Capecitabina , Oxaliplatina , Leucovorina , Estudos Retrospectivos , Compostos Organoplatínicos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Estadiamento de Neoplasias , Recidiva Local de Neoplasia/patologia , Canadá , Quimioterapia Adjuvante/efeitos adversos , Neoplasias do Colo/patologia , Fluoruracila , Neoplasias Testiculares/tratamento farmacológico
2.
Molecules ; 27(21)2022 Oct 26.
Artigo em Inglês | MEDLINE | ID: mdl-36364081

RESUMO

The present study was aimed at examining the anti-tumor effects and molecular mechanisms of 2'-fucosyllactose (2'-FL). At the beginning, the viabilities of four types of colon cancer cells were analyzed after exposure to increasing concentrations of 2'-FL, and HCT116 cells were selected as the sensitive ones, which were applied in the further experiments; then, interestingly, 2'-FL (102.35 µM) was found to induce apoptosis of HCT116 cells, which coincides with significant changes in VEGFA/VEGFR2/p-PI3K/p-Akt/cleaved Caspase3 proteins. Next, in a tumor-bearing nude mouse model, HCT116 was chosen as the sensitive cell line, and 5-fluorouracil (5-Fu) was chosen as the positive medicine. It was noteworthy that both 2'-FL group (2.41 ± 0.57 g) and 2'FL/5-Fu group (1.22 ± 0.35 g) had a significantly lower tumor weight compared with the control (3.87 ± 0.79 g), suggesting 2'-FL could inhibit colon cancer. Since 2'-FL reduced the number of new blood vessels and the malignancy of tumors, we confirmed that 2'-FL effectively inhibited HCT116 tumors, and its mechanism was achieved by regulating the VEGFA/VEGFR2/PI3K/Akt/Caspase3 pathway. Moreover, though HE staining and organ index measurement, 2'-FL was validated to alleviate toxic effects on liver and kidney tissue when combining with 5-Fu. In conclusion, 2'-FL had certain anti-tumor and detoxification effects.


Assuntos
Neoplasias do Colo , Proteínas Proto-Oncogênicas c-akt , Humanos , Camundongos , Animais , Fosfatidilinositol 3-Quinases , Fluoruracila/farmacologia , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/patologia , Células HCT116 , Apoptose , Neovascularização Patológica , Camundongos Nus , Linhagem Celular Tumoral , Proliferação de Células
3.
Sci Rep ; 12(1): 18518, 2022 Nov 02.
Artigo em Inglês | MEDLINE | ID: mdl-36323715

RESUMO

Methyl-CpG-binding protein 2(MeCP2) is an important epigenetic regulatory factor that promotes many tumor developments, such as liver cancer, breast cancer, and colorectal cancer. So far, no pan-cancer analysis has been reported. Therefore, this study aims to explore pan-cancer's prognostic value, immune infiltration pattern, and biological function. We used bioinformatics methods to analyze the expression and prognostic significance of MeCP2, and the relationship between MeCP2 and clinicopathological parameters, genetic variation, methylation, phosphorylation, immune cell infiltration, and biological function in pan-cancer from using a public database. The results showed that expression of MeCP2 was up-regulated in 8 cancers and down-regulated in 2 cancers, which was remarkably correlated with the prognosis, pathological stage, grade and subtype of cancers. The promoter methylation level of MeCP2 DNA was decreased in bladder urothelial carcinoma (BLCA), breast invasive carcinoma (BRCA), liver hepatocellular carcinoma (LIHC), prostate adenocarcinoma (PRAD), uterine corpus endometrial carcinoma (UCEC), testicular germ cell tumors (TGCT), and stomach adenocarcinoma (STAD);decreased phosphorylation of S25, S90, S92, S241, S286, S325 and S435 was found in MeCP2, such as UCEC, lung adenocarcinoma (LUAD), ovarian serous cystadenocarcinoma (OV), colon adenocarcinoma (COAD), and kidney renal clear cell carcinoma (KIRC). Furthermore, MeCP2 expression was significantly associated with multiple immunomodulators and immune cell infiltration levels across most tumors. Therefore, our pan-cancer explored the prognostic markers and immunotherapeutic value of MeCP2 in different cancers.


Assuntos
Adenocarcinoma , Neoplasias da Mama , Carcinoma de Células Renais , Carcinoma de Células de Transição , Neoplasias do Colo , Neoplasias Renais , Neoplasias da Bexiga Urinária , Masculino , Humanos , Prognóstico , Proteína 2 de Ligação a Metil-CpG/genética , Proteína 2 de Ligação a Metil-CpG/análise , Adenocarcinoma/patologia , Biologia Computacional , Neoplasias do Colo/patologia , Neoplasias da Bexiga Urinária/patologia , Carcinoma de Células Renais/patologia , Neoplasias da Mama/patologia , Neoplasias Renais/patologia
4.
Balkan Med J ; 39(6): 436-443, 2022 11 07.
Artigo em Inglês | MEDLINE | ID: mdl-36317726

RESUMO

Background: Extramural venous invasion is an independent predictor of poor outcome in colorectal cancer, whereas the significance of the intramural component of venous and lymphatic and perineural invasion is unclear. Aims: To evaluate the prognostic impact of intramural components for venous, lymphatic, and perineural invasions and the relation of these invasion patterns with clinicopathological features in patients with colon cancer. Study Design: A retrospective cross-sectional study. Methods: The analysis included 626 patients with colon cancer in stages II and III. All patients were divided into four categories (no invasion, intramural invasion only, extramural invasion only, or both intramural and extramural invasions) for vascular invasion, lymphatic invasion and perineural invasion. The primary outcomes were 5-year disease-free and overall survival. Results: Right-sided (for vascular invasion, 24.7% vs. 33.9%, p = 0.007; for perineural invasion, 34.5% vs. 41.5%, p = 0.034) and dMMR tumors (for vascular invasion, 13.5% vs. 33.5, p < 0.001; for perineural invasion, 25% vs. 41.4%, p = 0.004) exhibited less venous and perineural invasion. Compared with no invasion, presence of intramural invasion only, did not exert any effect on disease-free or overall survival for vascular invasion, lymphatic invasion, and perineural invasion. Multivariate analyses revealed that the presence of both intramural and extramural invasion was independently associated with poor disease-free and overall survival for venous (hazard ratios: 2.39, p = 0.001; hazard ratios: 2.46, p = 0.001), lymphatic (hazard ratios: 2.456, p < 0.001; hazard ratios: 2.13, p = 0.02) and perineural invasion (hazard ratios: 2.99, p < 0.001; hazard ratios: 2.68, p < 0.001), respectively. Conclusion: Our data strongly advocates the importance of reporting intramural and extramural components of invasion since the presence of intramural invasion alone may not be considered as a high-risk factor for systemic recurrence.


Assuntos
Neoplasias do Colo , Humanos , Neoplasias do Colo/patologia , Estudos Transversais , Invasividade Neoplásica/patologia , Estadiamento de Neoplasias , Estudos Retrospectivos
5.
World J Gastroenterol ; 28(40): 5845-5864, 2022 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-36353202

RESUMO

BACKGROUND: Inflammatory bowel disease (IBD) constitutes a substantial risk factor for colorectal cancer. Connexin 43 (Cx43) is a protein that forms gap junction (GJ) complexes involved in intercellular communication, and its expression is altered under pathological conditions, such as IBD and cancer. Recent studies have implicated epigenetic processes modulating DNA methylation in the pathogenesis of diverse inflammatory and malignant diseases. The ten-eleven translocation-2 (TET-2) enzyme catalyzes the demethylation, hence, regulating the activity of various cancer-promoting and tumor-suppressor genes. AIM: To investigate Cx43 and TET-2 expression levels and presence of 5-hydroxymethylcytosine (5-hmC) marks under inflammatory conditions both in vitro and in vivo. METHODS: TET-2 expression was evaluated in parental HT-29 cells and in HT-29 cells expressing low or high levels of Cx43, a putative tumor-suppressor gene whose expression varies in IBD and colorectal cancer, and which has been implicated in the inflammatory process and in tumor onset. The dextran sulfate sodium-induced colitis model was reproduced in BALB/c mice to evaluate the expression of TET-2 and Cx43 under inflammatory conditions in vivo. In addition, archived colon tissue sections from normal, IBD (ulcerative colitis), and sporadic colon adenocarcinoma patients were obtained and evaluated for the expression of TET-2 and Cx43. Expression levels were reported at the transcriptional level by quantitative real-time polymerase chain reaction, and at the translational level by Western blotting and immunofluorescence. RESULTS: Under inflammatory conditions, Cx43 and TET-2 expression levels increased compared to non-inflammatory conditions. TET-2 upregulation was more pronounced in Cx43-deficient cells. Moreover, colon tissue sections from normal, ulcerative colitis, and sporadic colon adenocarcinoma patients corroborated that Cx43 expression increased in IBD and decreased in adenocarcinoma, compared to tissues from non-IBD subjects. However, TET-2 expression and 5-hmC mark levels decreased in samples from patients with ulcerative colitis or cancer. Cx43 and TET-2 expression levels were also investigated in an experimental colitis mouse model. Interestingly, mice exposed to carbenoxolone (CBX), a GJ inhibitor, had upregulated TET-2 levels. Collectively, these results show that TET-2 levels and activity increased under inflammatory conditions, in cells downregulating gap junctional protein Cx43, and in colon tissues from mice exposed to CBX. CONCLUSION: These results suggest that TET-2 expression levels, as well as Cx43 expression levels, are modulated in models of intestinal inflammation. We hypothesize that TET-2 may demethylate genes involved in inflammation and tumorigenesis, such as Cx43, potentially contributing to intestinal inflammation and associated carcinogenesis.


Assuntos
Adenocarcinoma , Colite Ulcerativa , Colite , Neoplasias do Colo , Dioxigenases , Doenças Inflamatórias Intestinais , Animais , Camundongos , Adenocarcinoma/patologia , Carcinogênese/patologia , Colite/induzido quimicamente , Colite Ulcerativa/patologia , Colo/patologia , Neoplasias do Colo/patologia , Conexina 43/genética , Conexina 43/metabolismo , Sulfato de Dextrana/toxicidade , Dioxigenases/metabolismo , Modelos Animais de Doenças , Inflamação/patologia , Doenças Inflamatórias Intestinais/patologia
6.
Clin Transl Med ; 12(11): e973, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36377223

RESUMO

BACKGROUND: Colon cancer is the second leading cause of death worldwide. Exploring key regulators in colon cancer metastatic progression could lead to better outcomes for patients. METHODS: Initially, the transcriptional profiles of 681 colonrectal cancer (CRC) cases were used to discover signature genes that were significantly correlated with colon cancer metastasis. These signature genes were then validated using another independent 210 CRC cases' transcriptomics and proteomics profiles, and Kaplan-Meier regression analyses were used to screen the key regulators with patients' survival. Immunohistochemical staining was used to confirm the biomarkers, and transit knockdown was used to explore their implications on colon cancer cells migration and invasion abilities. The impact on the key signalling molecules in epithelial-mesenchymal transition (EMT) process that drive tumour metastasis was tested using Western blot. The response to clinical standard therapeutic drugs was compared to clinical prognosis of key regulators using an ROC plotter. RESULTS: Five genes (BGN, THBS2, SPARC, CDH11 and SPP1) were initially identified as potential biomarkers and therapeutic targets of colon cancer metastasis. The most significant signatures associated with colon cancer metastasis were determined to be BGN and THBS2. Furthermore, highly expression of BGN and THBS2 in tumours was linked to a worse survival rate. BGN and THBS2 knockdown significantly reduced colon cancer cells migration and invasion, as well as down-regulating three EMT-related proteins (Snail, Vimentin and N-cadherin), and increasing the proliferation inhibitory effect of 5-fluorouracil, irinotecan and oxaliplatin treatment. CONCLUSIONS: CRC metastatic progression, EMT phenotypic transition and poor survival time have been linked to BGN and THBS2. They could be utilized as potential diagnostic and therapeutic targets for colon cancer metastatic patients with a better prognosis.


Assuntos
Neoplasias do Colo , Humanos , Biglicano/metabolismo , Biglicano/farmacologia , Biomarcadores , Movimento Celular/genética , Neoplasias do Colo/diagnóstico , Neoplasias do Colo/genética , Neoplasias do Colo/patologia , Transição Epitelial-Mesenquimal/genética , Prognóstico
7.
ACS Appl Mater Interfaces ; 14(45): 50475-50484, 2022 Nov 16.
Artigo em Inglês | MEDLINE | ID: mdl-36327132

RESUMO

Tumor-associated macrophages (TAMs) widely exist in the solid tumors, which participate in the entire course of tumor development and execute momentous impacts. Therefore, manipulating TAMs has been identified as an expecting strategy with immense potential for cancer therapy. Herein, a nanodrug delivery system was leveraged for simultaneously targeting tumor cells and M2-type TAMs for efficient colon cancer therapy. The broad-spectrum anticancer chemotherapeutic drug doxorubicin (DOX) was hitchhiked in a mannose-modified bovine serum albumin (MAN-BSA) carrier. The DOX@MAN-BSA nanodrug delivery system was verified to possess feasible physical performances for unhindered systemic circulation and active targeting on colon tumors. DOX@MAN-BSA nanoparticles could be preferentially swallowed by colon tumor cells and M2 TAMs through mannose receptor-mediated endocytosis. Further in vivo antitumor therapy in CT26 colon tumor-bearing mice has achieved remarkable suppression efficacy with satisfactory biosafety. Leveraging the nanodrug delivery system for simultaneously targeting tumor cells and M2 TAMs has contributed a feasible strategy to collaboratively repress the malignant tumor cells and the collusive M2 TAMs for efficient cancer therapy.


Assuntos
Antineoplásicos , Neoplasias do Colo , Nanopartículas , Camundongos , Animais , Macrófagos Associados a Tumor , Macrófagos/patologia , Sistemas de Liberação de Medicamentos , Doxorrubicina/farmacologia , Doxorrubicina/uso terapêutico , Nanopartículas/uso terapêutico , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/patologia , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Manose , Soroalbumina Bovina , Linhagem Celular Tumoral , Microambiente Tumoral
8.
Dis Markers ; 2022: 2823042, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36393968

RESUMO

Chemokines have been reported to be involved in tumorigenesis and progression and can also modulate the tumor microenvironment. However, it is still unclear whether chemokine-related long noncoding RNAs (lncRNAs) can affect the prognosis of colon adenocarcinoma (COAD). We summarized chemokine-related genes and downloaded RNA-seq and clinical data from The Cancer Genome Atlas (TCGA) database. A total of 52 prognostic chemokine-related lncRNAs were screened by univariate Cox regression analysis; patients were grouped according to cluster analysis results. Lasso regression analysis was applied to determine chemokine-related lncRNAs to construct a risk model for further research. This study first investigated the differences between the prognosis and immune status of two chemokine-related lncRNAs clusters by consensus clustering. Then, using various algorithms, we obtained ten chemokine-related lncRNAs to construct a new prognostic chemokine-related lncRNAs risk model. The risk model's predictive efficiency, validity, and accuracy were further validated and determined in the test and training cohorts. Furthermore, this risk model played a vital role in predicting immune cell infiltration, immune checkpoint gene expression, tumor mutational burden (TMB), immunotherapy score, and drug sensitivity in COAD patients. These findings elucidated the critical role of novel prognostic chemokine-related lncRNAs in prognosis, immune landscape, and drug therapy, thereby providing valuable insights for prognosis assessment and personalized treatment strategies for COAD patients.


Assuntos
Adenocarcinoma , Neoplasias do Colo , RNA Longo não Codificante , Humanos , RNA Longo não Codificante/genética , Prognóstico , Neoplasias do Colo/genética , Neoplasias do Colo/patologia , Adenocarcinoma/genética , Adenocarcinoma/patologia , Quimiocinas/genética , Microambiente Tumoral/genética
9.
BMC Mol Cell Biol ; 23(1): 48, 2022 Nov 16.
Artigo em Inglês | MEDLINE | ID: mdl-36384455

RESUMO

BACKGROUND: Abnormal expression of ribosomal proteins has an important regulatory effect on the progression of cancer. RPL5 is involved in the progression of various malignancies, however, the role of RPL5 in colon cancer remains is still unclear. METHODS: Data from TCGA and GTEx databases were used to analyze the RPL5 expression in pan-cancer. The expression level of RPL5 in clinical colon cancer tissue samples and human colon cancer cell lines was detected by western blotting; siRNA targeting RPL5 was designed, and its interference efficiency was verified by western blotting and RT-qPCR; CCK8 assay, clone formation assay, cell cycle assay, and cell scratch assay were used to observe the effect of RPL5 on colon cancer cell proliferation and migration; the changes of proteins related to MAPK/ERK signaling pathway were also detected using western blotting. RESULTS: The expression level of RPL5 in colon cancer tissues and cell lines was significantly higher than that in adjacent tissues and NCM460 cells, respectively, and its expression level was higher in HCT116 cells and RKO cells. Knockdown of RPL5 significantly inhibited the proliferation and migration of HCT16 and RKO cells, and arrested the cell cycle in G0/G1 phase. Mechanistic studies revealed that the expression of p-MEK1/2, p-ERK, c-Myc were down-regulated, and the expression of FOXO3 was up-regulated after down-regulation of RPL5, ERK activator (TBHQ) could partially reverse the above-mentioned effects caused by siRPL5. Moreover, TBHQ could partially reverse the inhibitory effect of siRPL5 on the proliferation and migration of colon cancer cells. Collectively, RPL5 promoted colon cell proliferation and migration, at least in part, by activating the MAPK/ERK signaling pathway. CONCLUSION: RPL5 promoted colon cell proliferation and migration, at least in part, by activating the MAPK/ERK signaling pathway, which may serve as a novel therapeutic target for cancers in which MAPK/ERK signaling is a dominant feature.


Assuntos
Neoplasias do Colo , Proteínas Ribossômicas , Humanos , Movimento Celular/genética , Proliferação de Células , Neoplasias do Colo/patologia , Proteínas Ribossômicas/genética , Proteínas Ribossômicas/metabolismo , Transdução de Sinais
10.
JCO Precis Oncol ; 6: e2200244, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36356286

RESUMO

PURPOSE: Prognostic tools to estimate the risk of relapse for patients with liver-limited metastatic colorectal cancer (LL-mCRC) undergoing resection with curative intent are needed. Circulating tumor DNA (ctDNA) as a surrogate of postsurgical minimal residual disease is a promising marker in localized CRC. We explored the role of postoperative ctDNA as a marker of minimal residual disease in patients with radically resected LL-mCRC. MATERIALS AND METHODS: Seventy-six patients with LL-mCRC were retrospectively included. DNA from tumor tissue was sequenced, and one somatic mutation was then assessed by digital droplet polymerase chain reaction in plasma samples collected after surgery to identify the persistence of ctDNA. Relapse-free survival and postresection overall survival were compared between patients with positive vs negative postoperative ctDNA. RESULTS: ctDNA was found in 39 (51%) of 76 patients with LL-mCRC. At a median follow-up of 77 months, 33 of 39 ctDNA-positive patients and 20 of 37 ctDNA-negative patients experienced disease relapse (P = .008). ctDNA-positive patients reported significantly shorter RFS than ctDNA-negative ones (median RFS 12.7 v 27.4 months hazard ratio, 2.09, P = .008). In the multivariable model including other prognostic covariates, this association was still significant (P = .046) and a trend toward shorter overall survival among ctDNA-positive patients was reported (hazard ratio, 1.65, P = .183). CONCLUSION: The detection of postsurgical ctDNA is an independent negative prognostic marker and identifies patients at high risk of relapse after liver metastases resection.


Assuntos
DNA Tumoral Circulante , Neoplasias do Colo , Neoplasias Hepáticas , Humanos , DNA Tumoral Circulante/genética , Neoplasia Residual , Estudos Retrospectivos , Biomarcadores Tumorais/genética , Recidiva Local de Neoplasia/diagnóstico , Estudos Prospectivos , Neoplasias Hepáticas/diagnóstico , Neoplasias do Colo/patologia
12.
Gan To Kagaku Ryoho ; 49(11): 1255-1257, 2022 Nov.
Artigo em Japonês | MEDLINE | ID: mdl-36412031

RESUMO

We report a rare case of postoperative ascending colon cancer metastasis to the right external iliac lymph nodes. A 57- year-old woman underwent a laparoscopic right colectomy and D3 lymph node dissection. Pathological findings indicated a Stage Ⅲb, pT4aN1bM0 cancer. Because side effects were observed on adjuvant chemotherapy with FOLFOX, she was switched to S-1 administration every other week. Sixteen months postoperatively, right inguinal pain and elevated CEA values were noted. CT revealed two swollen right external iliac nodes with high FDG uptake on PET-CT. With the diagnosis of lymph node metastasis, an open celiotomy was performed to remove the lymph nodes. Pathological findings confirmed lymph node recurrence of ascending colon cancer. Postoperatively, her CEA values were normal and no recurrence was noted. This rare occurrence highlights the importance of examining adjacent lymph nodes for possible tumor recurrence. We report this case with the necessary literature review.


Assuntos
Colo Ascendente , Neoplasias do Colo , Humanos , Feminino , Pessoa de Meia-Idade , Colo Ascendente/cirurgia , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Linfonodos/cirurgia , Linfonodos/patologia , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/cirurgia , Neoplasias do Colo/patologia , Excisão de Linfonodo
13.
Med Sci (Basel) ; 10(4)2022 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-36412903

RESUMO

BACKGROUND: 5-Fluorouracil (5-FU) represents one of the major constituents of chemotherapy combination regimens in colon cancer (CRC) treatments; however, this regimen is linked with severe adverse effects and chemoresistance. Thus, developing more efficient approaches for CRC is urgently needed to overcome these problems and improve the patient survival rate. Currently, 17ß-estradiol (E2) has gained greater attention in colon carcinogenesis, significantly lowering the incidence of CRC in females at reproductive age compared with age-matched males. AIMS: This study measured the effects of E2 and/or 5-FU single/dual therapies on cell cycle progression and apoptosis against human HT-29 female and SW480 male primary CRC cells versus their impact on SW620 male metastatic CRC cells. METHODS: The HT-29, SW480, and SW620 cells were treated with IC50 of E2 (10 nM) and 5-FU (50 µM), alone or combined (E+F), for 48 h before cell cycle and apoptosis analyses using flow cytometry. RESULTS: The data here showed that E2 monotherapy has great potential to arrest the cell cycle and induce apoptosis in all the investigated colon cancer cells, with the most remarkable effects on metastatic cells (SW620). Most importantly, the dual therapy (E+F) has exerted anti-cancer activities in female (HT-29) and male (SW480) primary CRC cells by inducing apoptosis, which was preferentially provoked in the sub-G1 phase. However, the dual treatment showed the smallest effect in SW620 metastatic cells. CONCLUSION: this is the first study that demonstrated that the anti-cancer actions of 17ß-estradiol and 5-Fluorouracil dual therapy were superior to the monotherapies in female and male primary CRC cells; it is proposed that this treatment strategy could be promising for the early stages of CRC. At the same time, 17ß-estradiol monotherapy could be a better approach for treating the metastatic forms of the disease. Nevertheless, additional investigations are still required to determine their precise therapeutic values in CRC.


Assuntos
Neoplasias do Colo , Fluoruracila , Masculino , Feminino , Humanos , Fluoruracila/efeitos adversos , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/metabolismo , Neoplasias do Colo/patologia , Células HT29 , Apoptose , Estradiol/farmacologia , Estradiol/uso terapêutico
14.
Sci Rep ; 12(1): 17787, 2022 Oct 22.
Artigo em Inglês | MEDLINE | ID: mdl-36272991

RESUMO

Colorectal cancer (CRC) is one of the most common and malignant carcinomas. Many long noncoding RNAs (lncRNAs) have been reported to play important roles in the tumorigenesis of CRC by influencing the expression of some mRNAs via competing endogenous RNA (ceRNA) networks and interacting with miRNAs. Pseudogene is one kind of lncRNA and can act as RNA sponges for miRNAs and regulate gene expression via ceRNA networks. However, there are few studies about pseudogenes in CRC. In this study, 31 differentially expressed (DE) pseudogenes, 17 DE miRNAs and 152 DE mRNAs were identified by analyzing the expression profiles of colon adenocarcinoma obtained from The Cancer Genome Atlas. A ceRNA network was constructed based on these RNAs. Kaplan-Meier analysis showed that 7 pseudogenes, 4 miRNAs and 30 mRNAs were significantly associated with overall survival. Then multivariate Cox regression analysis of the ceRNA-related DE pseudogenes was performed and a 5-pseudogene signature with the greatest prognostic value for CRC was identified. Moreover, the results were validated by the Gene Expression Omnibus database, and quantitative real-time PCR in 113 pairs of CRC tissues and colon cancer cell lines. This study provides a pseudogene-associated ceRNA network, 7 prognostic pseudogene biomarkers, and a 5-pseudogene prognostic risk signature that may be useful for predicting the survival of CRC patients.


Assuntos
Adenocarcinoma , Neoplasias do Colo , MicroRNAs , RNA Longo não Codificante , Humanos , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Prognóstico , Pseudogenes/genética , Redes Reguladoras de Genes , Regulação Neoplásica da Expressão Gênica , Adenocarcinoma/patologia , Neoplasias do Colo/patologia , MicroRNAs/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Biomarcadores
15.
Molecules ; 27(20)2022 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-36296703

RESUMO

Seven styrylquinolines were synthesized in this study. Two of these styrylquinolines are new and were elucidated by spectroscopic analysis. The chemopreventive potential of these compounds was evaluated against SW480 human colon adenocarcinoma cells, its metastatic derivative SW620, and normal cells (HaCaT). According to the results, compounds 3a and 3d showed antiproliferative activity in SW480 and SW620 cells, but their effect seemed to be caused by different mechanisms of action. Compound 3a induced apoptosis independent of ROS production, as evidenced by increased levels of caspase 3, and had an immunomodulatory effect, positively regulating the production of different immunological markers in malignant cell lines. In contrast, compound 3d generated a pro-oxidant response and inhibited the growth of cancer cells, probably by another type of cell death other than apoptosis. Molecular docking studies indicated that the most active compound, 3a, could efficiently bind to the proapoptotic human caspases-3 protein, a result that could provide valuable information on the biochemical mechanism for the in vitro cytotoxic response of this compound in SW620 colon carcinoma cell lines. The obtained results suggest that these compounds have chemopreventive potential against CRC, but more studies should be carried out to elucidate the molecular mechanisms of action of each of them in depth.


Assuntos
Adenocarcinoma , Anticarcinógenos , Antineoplásicos , Neoplasias do Colo , Humanos , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/patologia , Caspase 3/metabolismo , Simulação de Acoplamento Molecular , Espécies Reativas de Oxigênio/metabolismo , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/patologia , Linhagem Celular Tumoral , Anticarcinógenos/farmacologia , Apoptose , Antineoplásicos/farmacologia , Antineoplásicos/química , Proteínas Reguladoras de Apoptose , Proliferação de Células
16.
Front Immunol ; 13: 1043512, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36304472

RESUMO

CUL7, a gene composed of 26 exons associated with cullin 7 protein, is also an E3 ligase that is closely related to cell senescence, apoptosis, and cell transformation and also plays an important role in human cancer. However, there is no systematic pan-cancer analysis has been performed to explore its role in prognosis and immune prediction. In this study, the expression of CUL7 in colon adenocarcinoma (COAD) was investigated to determine its prognosis value. First, based on the Cancer Genome Atlas (TCGA), Genotypic-Tissue Expression Project(GTEx), Cancer Cell Line Encyclopedias(CCLE), and TISIDB database, the potential role of CUL7 in different tumors was explored. Subsequently, the expression of CUL7 in COAD was explored and verified by Immunohistochemistry (IHC). Furthermore, the mutation frequency of CUL7 in COAD was analyzed, and the prognostic value of CUL7 in COAD was discussed. In addition, the nomogram was constructed, and its prognostic value was verified by follow-up data from Jiangmen Central Hospital. Finally, PPI network analysis explored the potential biological function of CUL7 in COAD. The results show that CUL7 is upregulated in most tumors, which is significantly associated with poor survival. At the same time, CUL7 is correlated with the clinical stage and immune landscape of various tumors. In colorectal cancer, CUL7 was overexpressed in tumor tissues by IHC with a mutation frequency of about 4%. CUL7 is an independent prognostic factor for colorectal cancer. The nomogram constructed has effective predictive performance, and external databases proved the prognostic value of CUL7. In addition, PPI network analysis showed that CUL7 was closely related to FBXW8, and further pathway enrichment analysis showed that CUL7 was mainly involved in ubiquitin-mediated proteolysis. Therefore, our study provides a comprehensive understanding of the potential role of CUL7 in different tumors, and CUL7 might be a prognostic marker for COAD.


Assuntos
Adenocarcinoma , Neoplasias do Colo , Humanos , Prognóstico , Neoplasias do Colo/genética , Neoplasias do Colo/patologia , Adenocarcinoma/genética , Adenocarcinoma/patologia , Proteínas Culina/genética , Proteínas Culina/metabolismo , Nomogramas
17.
Eur Rev Med Pharmacol Sci ; 26(20): 7649-7655, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-36314336

RESUMO

OBJECTIVE: Recent literature suggests that tumor budding (TB) may have a significant clinical impact on colorectal cancers. Our study aims to reveal the effect of TB on the long-term outcomes of patients and to reveal whether there is a difference in tumor location and TB in colonic cancer. PATIENTS AND METHODS: A cohort of 100 patients with non-metastatic colon cancer was included in the study. The clinicopathological information of the patients was reviewed. Patients' preparations were re-evaluated to identify TB as: low, medium, and high and represent 0-4 buds, 5-9 buds, and 10 or more buds per 0.785 mm2, respectively. Long-term oncological outcomes of patients were analyzed. The recurrence, metastasis, and final status of the patients were determined during the follow-up period. RESULTS: Low TN was associated with <65 year (p = 0.048), absence of lymphatic metastasis (p = 0.003), and absence of perineural invasion (p = 0.023). High TB was associated with higher pT stage (p = 0.017) and tumor stage (p = 0.005). Additionally, right-sided tumors had a high TB score than left side (82.3% vs. 23.6%, p = 0.011). Patients with high TB had lower overall survival, but these were not statically significant. According to multiple regression analysis, mortality risk was associated with age (p = 0.046), pN status (p = 0.003) and TB (p = 0.040). CONCLUSIONS: High TB is associated with mortality in colon cancer and is more common in right colonic carcinoma.


Assuntos
Neoplasias do Colo , Humanos , Prognóstico , Estadiamento de Neoplasias , Estudos Retrospectivos , Neoplasias do Colo/patologia , Metástase Linfática
18.
World J Gastroenterol ; 28(37): 5420-5443, 2022 Oct 07.
Artigo em Inglês | MEDLINE | ID: mdl-36312839

RESUMO

BACKGROUND: Colorectal cancer (CRC) is one of the most common malignant tumors worldwide. The identification of novel diagnostic and prognostic biomarkers for CRC is a key research imperative. Immunohistochemical analysis has revealed high expression of centromere protein K (CENPK) in CRC. However, the role of CENPK in the progression of CRC is not well characterized. AIM: To evaluate the effects of knockdown of CENPK and overexpression of Cullin 4A (CUL4A) in RKO and HCT116 cells. METHODS: Human colon cancer samples were collected and tested using a human gene expression chip. We identified CENPK as a potential oncogene for CRC based on bioinformatics analysis. In vitro experiments verified the function of this gene. We investigated the expression of CENPK in RKO and HCT116 cells using quantitative polymerase chain reaction (qPCR), western blot, and flow cytometry. The effect of short hairpin RNA (shRNA) virus-infected RKO cells on tumor growth was evaluated in vivo using quantitative analysis of fluorescence imaging. To evaluate the effects of knockdown of CENPK and overexpression of CUL4A in RKO and HCT116 cells, we performed a series of in vitro experiments, using qPCR, western blot, MTT assay, and flow cytometry. RESULTS: We demonstrated overexpression of CENPK in human colon cancer samples. CENPK was an independent risk factor in patients with CRC. The downstream genes FBX32, CUL4A, and Yes-associated protein isoform 1 were examined to evaluate the regulatory action of CENPK in RKO cells. Significantly delayed xenograft tumor emergence, slower growth rate, and lower final tumor weight and volume were observed in the CENPK short hairpin RNA virus infected group compared with the CENPK negative control group. The CENPK gene interference inhibited the proliferation of RKO cells in vitro and in vivo. The lentivirus-mediated shRNA interference of CENPK inhibited the proliferation of RKO and HCT116 colon cancer cells, with overexpression of the CUL4A. CONCLUSION: We indicated a potential role of CENPK in promoting tumor proliferation, and it may be a novel diagnostic and prognostic biomarker for CRC.


Assuntos
Neoplasias do Colo , Neoplasias Colorretais , Humanos , Lentivirus/genética , RNA Interferente Pequeno/genética , Proteínas Culina/genética , Proteínas Culina/metabolismo , Proliferação de Células/genética , Neoplasias Colorretais/patologia , Linhagem Celular Tumoral , Neoplasias do Colo/patologia , Regulação Neoplásica da Expressão Gênica , Interferência de RNA , Movimento Celular , Proteínas de Ligação a DNA/genética , Proteínas Nucleares/metabolismo
20.
Molecules ; 27(19)2022 Oct 06.
Artigo em Inglês | MEDLINE | ID: mdl-36235161

RESUMO

Inflammation prompts cancer development and promotes all stages of tumorigenesis. Calcitriol is a nutraceutical essential regulator for host health benefits. However, the influence of calcitriol on inflammatory mediators involved in cancer cells is not clear. This study aimed to assess the sensitivity of calcitriol alone and combined with capric acid, and identify the possible influence of calcitriol on inflammatory mediators. The colorectal cancer cell line (HCT116) was induced by LPS/TNF-α and the inflammation and metastatic mediators (IL-1ß, IL-6, IL-17) were quantified in calcitriol and capric acid supplemented colon cancer cells. The mRNA and protein expression of MMP-2, NF-κB and COX-2 were quantified. The significant reduction in MMP-2 expression was confirmed at combination treatment by zymogram analysis. Our findings demonstrated the anti-inflammatory and anti-metastatic potentials of capric acid and calcitriol in individual exposure in a combination of human colon cancer cell lines (HCT116). These abilities may be due to the inhibition of COX-2 mediators and NF-κB transcription factor and reciprocally regulated MMP-2 and MMP-9 signaling pathways. These findings elucidate the activation of COX-2 and NF-κB via disruption of the cellular outer matrix could be considered a novel molecular target suitable for colorectal cancer therapy. This study confirmed that capric acid activates calcitriol sensitization in colon cancer cells and could be used as a successful supplement for intestinal diseases and colon aberrations.


Assuntos
Neoplasias do Colo , Mediadores da Inflamação , Anti-Inflamatórios/uso terapêutico , Calcitriol/farmacologia , Neoplasias do Colo/patologia , Ciclo-Oxigenase 2/genética , Ciclo-Oxigenase 2/metabolismo , Ácidos Decanoicos , Humanos , Inflamação/tratamento farmacológico , Mediadores da Inflamação/metabolismo , Interleucina-17 , Interleucina-6/metabolismo , Lipopolissacarídeos/farmacologia , Metaloproteinase 2 da Matriz/genética , Metaloproteinase 9 da Matriz/genética , NF-kappa B/metabolismo , RNA Mensageiro , Fator de Necrose Tumoral alfa/metabolismo
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