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BACKGROUND: Despite the global increase in the adoption of robotic natural orifice specimen extraction surgery (R-NOSES), its advantages over robotic transabdominal specimen extraction surgery (R-TSES) for treating early-stage rectal cancer remain debated. There is scant nationwide, multicenter studies comparing the surgical quality and short-term outcomes between R-NOSES and R-TSES for this condition. OBJECTIVE: This retrospective cohort study was conducted nationally across multiple centers to compare the surgical quality and short-term outcomes between R-NOSES and R-TSES in early-stage rectal cancer. DESIGN: Multicenter retrospective cohort trial. SETTING: Eight experienced surgeons from 8 high-volume Chinese colorectal cancer treatment centers. PATIENTS: The study included 1086 patients who underwent R-NOSES or R-TSES from October 2015 to November 2023 at the 8 centers. Inclusion criteria were: (1) histologically confirmed rectal adenocarcinoma; (2) robotic total mesorectal excision; (3) postoperative pathological staging of TisN0M0 or T1-2N0M0; (4) availability of complete surgical and postoperative follow-up data. Patients were matched 1:1 in the R-NOSES and R-TSES groups using the propensity score matching (PSM) technique. RESULTS: After PSM, 318 matched pairs with well-balanced patient characteristics were identified. The operation time for the R-NOSES group was significantly longer than that for the R-TSES group [140 min (125-170 min) vs. 140 min (120-160 min), P = 0.032]. Conversely, the times to first flatus and initial oral intake in the R-NOSES group were significantly shorter than those in the R-TSES group [48 h (41-56 h) vs. 48 h (44-62 h), P = 0.049 and 77 h (72-94 h) vs. 82 h (72-96 h), P = 0.008], respectively. Additionally, the length of postoperative hospital stay was shorter in the R-NOSES group compared with the R-TSES group [7 day (7-9 day) vs. 8 day (7-9 day), P = 0.005]. The overall postoperative complication rates were similar between the groups (10.7% in the R-NOSES group vs. 11.9% in the R-TSES group, P = 0.617). However, the R-NOSES group had a lower incidence of wound complications compared to the R-TSES group (0.0% vs. 2.2%, P = 0.015). Regarding surgical stress response, the R-NOSES group showed superior outcomes. Additionally, patients in the R-NOSES group required fewer additional analgesics on postoperative days 1, 3, and 5 and reported lower pain scores compared to the R-TSES group. The body image scale (BIS) and cosmetic scale (CS) scores were also significantly higher in the R-NOSES group. Furthermore, the R-NOSES group demonstrated significantly better outcomes in functional dimensions such as physical, role, emotional, social, and cognitive functioning, and in symptoms like fatigue and pain, when compared to the R-TSES group. LIMITATIONS: It is imperative to ensure the safe and standardized implementation of R-NOSES through the establishment of a uniform training protocol. CONCLUSIONS: These results affirm that R-NOSES is a safe and effective treatment for early-stage rectal cancer when meticulously executed by skilled surgeons.
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Cirurgia Endoscópica por Orifício Natural , Pontuação de Propensão , Neoplasias Retais , Procedimentos Cirúrgicos Robóticos , Humanos , Neoplasias Retais/cirurgia , Neoplasias Retais/patologia , Procedimentos Cirúrgicos Robóticos/métodos , Feminino , Masculino , Estudos Retrospectivos , Pessoa de Meia-Idade , China/epidemiologia , Cirurgia Endoscópica por Orifício Natural/métodos , Idoso , Estadiamento de Neoplasias , Duração da Cirurgia , Adenocarcinoma/cirurgia , Adenocarcinoma/patologia , Adulto , Tempo de Internação/estatística & dados numéricos , Resultado do TratamentoRESUMO
BACKGROUND AND OBJECTIVES: This study aimed to find the advantages of robotic natural orifice specimen extraction surgery (NOSES) for middle and low rectal cancer, compared with traditional laparoscopic low anterior resection (LAR). METHODS: Patients receiving robotic NOSES or traditional laparoscopic LAR were retrospectively enrolled from 2013-10 to 2019-06, with middle and low rectal cancer, maximum diameter ≤ 5 cm, pT1-3 or ypT1-3 stage, no distant metastases. The baseline of the two groups was balanced using the propensity score matching method. Surgical quality, postoperative recovery, and long-term oncological outcomes were compared. RESULTS: Totally 137 eligible patients with robotic NOSES and 137 matched patients with traditional laparoscopic LAR were enrolled. Robotic NOSES had a significantly lower open conversion rate (0 vs. 4.4%, p = .030), less intraoperative hemorrhage (50 ml vs. 80 ml, p < .001) and longer distance from distal resection margin of low rectal cancer (1.5 cm vs. 1.0 cm, p = .030). Robotic NOSES significantly reduced the 30-day postoperative complication rate of Clavien-Dindo grade II or higher (17.5% vs. 31.4%, p = .008), promoted gastrointestinal and urinary function recovery, reduced postoperative pain and hospital stay (6.0 vs. 7.0 d, p = .022). The two groups were similar in long-term survival. CONCLUSIONS: Compared with traditional laparoscopic LAR, robotic NOSES had significant advantages in improving surgical quality and promoting postoperative recovery.
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Laparoscopia/mortalidade , Protectomia/mortalidade , Neoplasias Retais/cirurgia , Procedimentos Cirúrgicos Robóticos/mortalidade , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Pontuação de Propensão , Neoplasias Retais/patologia , Estudos Retrospectivos , Taxa de SobrevidaRESUMO
During human gastric carcinogenesis, intestinal metaplasia is frequently seen in the atrophic stomach. In mice, a distinct type of metaplasia known as spasmolytic polypeptide-expressing metaplasia (SPEM) is found in several inflammatory and genetically engineered models. Given the diversity of long- and short-term models of mouse SPEM, it remains unclear whether all models have a shared or distinct molecular mechanism. The origin of SPEM in mice is presently under debate. It is postulated that stem or progenitor cells acquire genetic alterations that then supply metaplastic cell clones, whereas the possibility of transdifferentiation or dedifferentiation from mature gastric chief cells has also been suggested. In this study, we report that loss of chief cells was sufficient to induce short-term regenerative SPEM-like lesions that originated from chief cell precursors in the gastric neck region. Furthermore, Lgr5+ mature chief cells failed to contribute to both short- and long-term metaplasia, whereas isthmus stem and progenitor cells efficiently contributed to long-term metaplasia. Interestingly, multiple administrations of high-dose pulsed tamoxifen induced expansion of Lgr5 expression and Lgr5-CreERT recombination within the isthmus progenitors apart from basal chief cells. Thus we conclude that short-term SPEM represents a regenerative process arising from neck progenitors following chief cell loss, whereas true long-term SPEM originates from isthmus progenitors. Mature gastric chief cells may be dispensable for SPEM development. NEW & NOTEWORTHY Recently, dedifferentiation ability in gastric chief cells during metaplasia development has been proposed. Our findings reveal that lesions that were thought to be acute metaplasia in fact represent normal regeneration supplied from neck lineage and that isthmus stem/progenitors are more responsible for sustained metaplastic changes. Cellular plasticity in gastric chief cells may be more limited than recently highlighted.
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Carcinogênese , Celulas Principais Gástricas , Peptídeos/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Neoplasias Gástricas , Animais , Carcinogênese/metabolismo , Carcinogênese/patologia , Linhagem da Célula , Transdiferenciação Celular/fisiologia , Celulas Principais Gástricas/metabolismo , Celulas Principais Gástricas/patologia , Humanos , Peptídeos e Proteínas de Sinalização Intercelular , Metaplasia , Camundongos , Lesões Pré-Cancerosas/metabolismo , Lesões Pré-Cancerosas/patologia , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patologiaRESUMO
Circulating cell-free DNA (cfDNA) has become a potential diagnostic and prognostic biomarker for colorectal cancer (CRC). In non-cancerous diseases, it has been confirmed that cfDNA can be recognized by Toll-like receptor 9 (TLR9), leading to a significant biological change. Nevertheless, the biological significance of cfDNA and its relationship with TLR9 in tumor malignancy is still unclear. Therefore, the purpose of this study is to explore the biological role of cfDNA in colorectal cancer (CRC). The expression of TLR9 was measured in different CRC cell lines and cancerous samples by RT-PCR or immunohistochemistry, which showed that high expression of TLR9 was significantly correlated with the tumor metastasis, advanced TNM stage and poor prognosis of patients. Then, cfDNA was obtained from fluorouracil (5FU)-induced apoptotic cancer cells in vitro and transfection techniques were used to transfect siRNA and cDNA plasmid for TLR9. Cancer cells were stimulated using isolated cfDNA fragments, and results showed that cfDNA could promote colorectal cancer cell proliferation via TLR9. Meanwhile, we demonstrated that the cfDNA binding to TLR9 could facilitate cell migration and invasion. Finally, we demonstrated that cfDNA initiated downstream TLR9-MyD88 signaling and induced robust release of chemokine interleukin 8 (IL-8), which helped to elucidate the mechanisms underlying these phenomena. Our data suggest that cancer cell-derived cfDNA contributes to cancer progression through activation of TLR9-MyD88 signaling and IL-8 secretion in CRC. These findings provide a novel perspective for understanding of tumor progression and provoke a potential therapeutic target for CRC treatment.
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Ácidos Nucleicos Livres/metabolismo , Neoplasias Colorretais/metabolismo , Interleucina-8/metabolismo , Receptor Toll-Like 9/metabolismo , Idoso , Linhagem Celular Tumoral , Proliferação de Células/genética , Ácidos Nucleicos Livres/genética , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Progressão da Doença , Feminino , Regulação Neoplásica da Expressão Gênica , Células HCT116 , Células HT29 , Humanos , Masculino , Pessoa de Meia-Idade , Interferência de RNA , Transdução de Sinais/genética , Receptor Toll-Like 9/genéticaRESUMO
Microbial dysbiosis plays an important role in the development of intestinal diseases. Recent studies suggest a link between intestinal bacteria and mammary cancer. Here, we report that female ApcMin/+ mice infected with Helicobacter hepaticus exhibited an increased mammary and small/large intestine tumor burden compared with uninfected littermates. H. hepaticus DNA was detected in small/large intestine, mammary tumors, and adjacent lymph nodes, suggesting a migration pathway. CD11b+Gr1+ myeloid-derived suppressor cells (MDSCs) infiltrated and expressed high levels of Wnts, likely enhancing tumorigenesis through activation of Wnt/ß-catenin pathway. Our previous studies indicated that histidine decarboxylase (Hdc) marks a population of myeloid-biased hematopoietic stem cells and granulocytic MDSCs. Cytokines/chemokines secreted by IL-17-expressing mast cells and tumor tissues promoted Hdc+ MDSCs expansion and trafficking toward mammary tumors. Adoptive transfer of MDSCs isolated from H. hepaticus-infected mice increased MDSCs frequencies in peripheral blood, mesenteric lymph nodes, mammary gland, and lymph nodes in recipient ApcMin/+ mice. The adoptive transfer of H. hepaticus primed MDSCs also increased the size and number of mammary tumors. Our results demonstrate that H. hepaticus can translocate from the intestine to mammary tissues to promote mammary tumorigenesis with MDSCs. Targeting bacteria and MDSCs may be useful for the prevention and therapy of extraintestinal cancers. Abbreviations: Helicobacter hepaticus, Hh; myeloid-derived suppressor cell, MDSC; histidine decarboxylase, Hdc; Breast cancer, BC; T regulatory, TR; inflammatory bowel disease, IBD; fluorescence in situ hybridization, FISH; myeloid-biased hematopoietic stem cells, MB-HSCs; granulocytic MDSCs, PMN-MDSCs; Lipopolysaccharide, LPS; Toll-like receptors, TLRs; Mast cells, MCs; Granulocyte-macrophage colony-stimulating factor, GM-CSF; epithelial-mesenchymal transition, EMT; Intestinal epithelial cells, IECs.
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Células Supressoras Mieloides , Animais , Transformação Celular Neoplásica/metabolismo , Feminino , Helicobacter hepaticus , Hibridização in Situ Fluorescente , Camundongos , Camundongos Endogâmicos BALB C , Células Supressoras Mieloides/metabolismoRESUMO
E3 ligase is widely reported to exert fundamental functions in cancers. Through rigorous bioinformatic analysis concentrating E3 ligases based on data from Genotype-Tissue Expression (GTEx) and data from The Cancer Genome Atlas (TCGA), HERC3 was indicated to be downregulated in colorectal cancer (CRC) and HERC3 downregulation showed poor overall survival (OS) and disease-free survival (DFS). Through qRT-PCR, western blotting and Immunohistochemistry (IHC), analytical results were validated based on tissues in Zhongshan hospital. Functionally, HERC3 was indicated to inhibit the migration, invasion and metastasis in vitro and in vivo through transwell assays, wound healing assays and vivo experiments. And HERC3 could regulate epithelial-mesenchymal transition (EMT) in CRC. Furthermore, immunoprecipitation (IP), coimmunoprecipitation (co-IP) and GST-pulldown assays indicated that HERC3 could directly interact with EIF5A2 in vitro and in vivo through the RCC1 domain in HERC3. And HERC3 could function as an E3 to promote the K27 and K48-linked ubiquitination degradation of EIF5A2 via the HECT domain in HERC3, besides, K47, K67, K85, and K121 in EIF5A2 were identified as ubiquitination sites. In addition, HERC3 was indicated to affect the migration, invasion and metastasis and further regulatE EMT via EIF5A2/TGF-/Smad2/3 signal. The present study may provide insight into the mechanism of EMT in CRC.
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Neoplasias Colorretais , Transição Epitelial-Mesenquimal , Fatores de Iniciação de Peptídeos , Proteínas de Ligação a RNA , Ubiquitina-Proteína Ligases , Linhagem Celular Tumoral , Movimento Celular , Neoplasias Colorretais/patologia , Humanos , Metástase Neoplásica , Fatores de Iniciação de Peptídeos/metabolismo , Proteínas de Ligação a RNA/metabolismo , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/metabolismo , Ubiquitinação , Fator de Iniciação de Tradução Eucariótico 5ARESUMO
PURPOSE: This study aimed to evaluate the role of anatomical resection (AR) in lung metastasectomy (LM) of colorectal cancer (CRC) and to investigate clinically relevant prognostic factors. PATIENTS AND METHODS: The medical records of 350 consecutive patients who underwent LM of CRC from 2011 to 2019 were reviewed. The patients were designated into AR group (lobectomy and segmentectomy), and non-anatomical resection (NAR) group (wedge resection), respectively. Kaplan-Meier method was used to analyze disease-free survival (DFS), pulmonary-specific disease-free survival (PDFS) and overall survival (OS). Cox proportional hazards regression model was performed to analyze the factors associated with DFS, PDFS and OS. RESULTS: A total of 92 (31.2%) patients were enrolled in AR group and 203 (68.8%) in non-anatomical resection (NAR) group. AR significantly improved the 3-year DFS (64.1% vs 46.8%, HR 0.587, 95% CI 0.397-0.867, P = 0.007) and PDFS (75.0% vs 60.1%, HR 0.565, 95% CI 0.356-0.899, P = 0.016) compared with NAR. However, the extent of resection did not significantly impact the 3-year OS (AR 92.4% vs NAR 85.7%, HR 0.511, 95% CI 0.224-1.165, P = 0.110). In multivariate analysis, AR was identified as a protective factor for DFS (HR 0.576, 95% CI 0.356-0.934, P = 0.025) and PDFS (HR 0.631, 95% CI 0.409-0.973, P = 0.037). Preoperative abnormal CA19-9 was identified as the only prognostic factor for OS. CONCLUSION: AR was superior to NAR for DFS and PDFS after LM from CRC.
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Integrin αvß8 expressed on tumor cells executes crucial regulatory functions during cell adhesion in the tumor microenvironment and supports the activation of TGF-ß1. This study aimed to investigate the expression of integrin αvß8 and its clinical significance in colon cancer, in addition to its influence on the invasion and migration of cancer cells. Our results showed that integrin αvß8 was an indicator of progression and poor prognosis in patients with colon cancer. Moreover, integrin αvß8 significantly promoted the invasion and migration of colon cancer cells by the activation of TGF-ß1 and upregulation of metalloproteinase-9. Furthermore, suppression of integrin αvß8 was found to inhibit the growth of colon cancer in vivo. Our results indicate that integrin αvß8 promotes tumor invasiveness and the migration of colon cancer through TGF-ß1 activation and is a potential prognostic biomarker. This study may provide clues to further understand the manner in which the tumor microenvironment mediates the development of colon cancer and develop strategies for novel therapeutic targets in the prevention and treatment of colon cancer.
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BACKGROUND: The integrin ß6 gene, which is expressed in epithelial cancer, plays a pivotal role in various aspects of cancer progression. The present research for integrin ß6 regulation mainly focuses on the post-transcription and translation related regulation mechanism and its role in tumorigenesis. The mechanisms of how the integrin ß6 gene is regulated transcriptionally, and the promoter and transcription factors responsible for basic transcription of integrin ß6 gene remain unknown. AIM: To clone and characterize the integrin ß6 promoter. METHODS: Software analysis was used to predict the region of integrin ß6 promoter. Luciferase reporter plasmids, which contained the integrin ß6 promoter, were constructed. Element deletion analysis was performed to identify the location of core promoter and binding sites for transcription factors. RESULTS: The regulatory elements for the transcription of the integrin ß6 gene were located between -286 and -85 and contained binding sites for transcription factors such as STAT3 and Ets-1. CONCLUSION: For the first time, we found the region of ß6 core promoter and demonstrated the binding sites for transcription factors such as Ets-1 and STAT3, which are important for integrin ß6 promoter transcription activity. These findings are important for investigating the mechanism of integrin ß6 activation in cancer progression.
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Cancer is believed to arise from stem cells, but mechanisms that limit the acquisition of mutations and tumor development have not been well defined. We show that a +4 stem cell (SC) in the gastric antrum, marked by expression of Cck2r (a GPCR) and Delta-like ligand 1 (DLL1), is a label-retaining cell that undergoes predominant asymmetric cell division. This +4 antral SC is Notch1low/ Numb+ and repressed by signaling from gastrin-expressing endocrine (G) cells. Chemical carcinogenesis of the stomach is associated with loss of G cells, increased symmetric stem cell division, glandular fission, and more rapid stem cell lineage tracing, a process that can be suppressed by exogenous gastrin treatment. This hormonal suppression is associated with a marked reduction in gastric cancer mutational load, as revealed by exomic sequencing. Taken together, our results show that gastric tumorigenesis is associated with increased symmetric cell division that facilitates mutation and is suppressed by GPCR signaling.
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Carcinogênese , Células-Tronco , Divisão Celular , Humanos , Transdução de Sinais , EstômagoRESUMO
Many genes and mutations have been reported for colorectal cancer (CRC); however, very few have been associated with colorectal cancer liver metastasis (CRLM). We performed gene expression profiling experiments to identify genetic markers for CRLM and elucidate the molecular mechanisms. Microarray experiments were performed on CRC primary tumor samples with or without liver metastasis (LM) using the Affymetrix U133 plus 2.0 GeneChip Array. A new identified gene-scinderin (SCIN) was overexpressed with synchronous LM at both the RNA level evaluated with quantitative real-time PCR and protein level evaluated with immunohistochemistry and also with short overall survival analyzed with Kaplan-Meier method. With multivariate analysis indicated that SCIN served as an independent poor prognostic predictor for CRC patients. Disease-free survival was also significantly lower in SCIN overexpressing CRC patients with metachronous LM. In addition, SCIN knockdown significantly reduced cell proliferation, induced cell cycle arrest, and promoted the expression of some cell cycle apoptosis-related protein. Moreover, the DIAPH1, STAT3, CDK2, CDK4, and EGFR levels were downregulated, whereas CDKN2B and COL4A1 were upregulated in DLD-1-shSCIN cells by microarray analysis compared with DLD-1 shCon cells. These findings revealed that SCIN may serve as an important predictor of CRLM and poor outcome for CRC patients. SCIN may be a potential therapeutic target in human CRC. However, translation of its roles into clinical practice will require further investigation and additional experimental validation.
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BACKGROUND: Growing evidence suggests that miR-150 plays an inhibitory role in various types of cancer. However, the function and underlying mechanisms of miR-150 in triple-negative breast cancer (TNBC) remain unknown. PATIENTS AND METHODS: miR-150 expression was detected by qRT-PCR and ISH in TNBC tumor and adjacent normal breast tissues. miR-150 function was analyzed by wound healing and transwell assay in vitro and mouse lung metastasis model in vivo. mRNA microarray, qRT-PCR, western blotting and luciferase assay were used to identify the target gene of miR-150. HMGA2 over-expression plasmid was co-transfected with miR-150 to study the role of miR-150 through regulating HMGA2. RESULTS: We found that miR-150 was down-regulated in TNBC tumor tissues compared to corresponding adjacent, normal breast tissues, and was correlated with decreased lymph-node metastasis. Ectopic expression of miR-150 suppressed TNBC cell migration in vitro and metastasis in vivo. Mechanistic study revealed that miR-150 down-regulates HMGA2 by directly targeting its mRNA. Moreover, the suppression of cell migration caused by miR-150 is relieved by over-expression of HMGA2, suggesting that miR-150 inhibits migration of TNBC cells by down-regulating HMGA2. CONCLUSION: This work indicates that the miR-150/HMGA2 axis may serve as a treatment marker in TNBC.
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This study aimed to explore the prognostic impact of KRAS and BRAF mutations in patients who underwent simultaneous resection for synchronous colorectal liver metastases (SCRLMs) that were initially resectable. Clinicopathological and outcome data of 139 consecutive patients with SCRLMs who underwent resection between July 2003 and July 2013 was collected from our prospectively established SCRLM database. The KRAS and BRAF genotypes were evaluated in the primary cancer tissues by pyrosequencing. The prognostic value of KRAS and BRAF status was assessed by Kaplan-Meier and Cox regression analyses. KRAS and BRAF mutated in 28.8% and 7.2% of the patients with SCRLMs, respectively, but the genotypes did not significantly associate with any clinicopathologic characteristics. By Kaplan-Meier survival analysis, we found KRAS mutation was not significantly associated with short overall survival (OS) (P = 0.213), but was significantly correlated with short disease-free survival (DFS) (P = 0.041); BRAF mutation was significantly associated with both short OS and DFS (P = 0.001, P<0.001, respectively). Multivariate survival analysis showed KRAS mutation was an independent negative prognostic factor for DFS (P = 0.005) and BRAF mutation was an independent negative prognostic factor for OS and DFS (P = 0.001, P<0.001, respectively). KRAS and BRAF mutation similarly contributed to an adverse prognostic effect in patients who underwent simultaneous resection for SCRLMs that were initially resectable. These findings should suggest the use of KRAS and BRAF status in current practice as an important determinant for precision surgery for initially resectable SCRLMs.
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Oxaliplatin is a core chemotherapeutic agent used for the treatment of colorectal liver metastasis; however, liver injury caused by oxaliplatin increases the risk of perioperative morbidity and mortality. Magnesium isoglycyrrhizinate (MgiG) is a magnesium salt of 18α glycyrrhizic acid stereoisomer that has demonstrated liverprotective effects against toxins and hepatitis. In the present study, the liverprotective effect of MgiG against oxaliplatininduced hepatic injury was examined in vitro and in vivo. The results demonstrated that MgiG had a protective effect against oxaliplatininduced liver injury, as evidenced by the alleviation of hepatic pathological damage and transaminase levels. The protective effect of MgiG was demonstrated to be correlated with inhibition of oxidative stress, the interleukin6 pathway and the coagulation system. Altogether, the present findings suggested that MgiG may have potential value in the clinical prevention and treatment of oxaliplatininduced liver injury.
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Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Fígado/lesões , Fígado/metabolismo , Compostos Organoplatínicos/efeitos adversos , Estresse Oxidativo/efeitos dos fármacos , Saponinas/farmacologia , Triterpenos/farmacologia , Animais , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/patologia , Interleucina-6/metabolismo , Fígado/patologia , Masculino , Camundongos , Compostos Organoplatínicos/farmacologia , OxaliplatinaRESUMO
PURPOSE: In recent years, aberrant mRNA translational control has gained much attention as a critical player in the malignant process of tumors. Eukaryotic initiation factor 4E (eIF4E), by binding to the mRNA cap, can regulate specific protein synthesis, contributing to malignancy in human tumors. However, integrin ß1 mediated chemoresistance under translational control remains unknown in colorectal cancer. PATIENTS AND METHODS: The expression relationship between eIF4E and Integrin ß1, along with their clinical significance was investigated in colorectal cancerous tissues of 118 cases using immunohistochemistry. Cell transfection techniques of small interfering RNA (siRNA) and cDNA expression plasmid were applied to investigate the molecular relationship of integrin ß1 and eIF4E and their biological effects on 5FU resistance in SW480 and LoVo cell lines. RESULTS: The expression of eIF4E and integrin ß1 was positively correlated in colorectal cancer, and patients with high expressions of both markers tended to have a worse prognosis according to a Kaplan-Meier survival analysis. Integrin ß1 could contribute to 5-fluorouracil (5FU) resistance in colorectal cancer cell lines. Moreover, the protein expression of ß1 could be regulated by eIF4E, interestingly, without any change of mRNA expression level. Significantly, Hoechst/PI double staining and an MTT assay proved integrin ß1 could contribute to cellular survival and 5FU resistance under translational control of eIF4E in these cells. CONCLUSION: We conclude that integrin ß1 mediated 5FU chemo resistance in colorectal cancer could be translationally regulated by eIF4E. Promisingly, targeting key molecules of this translational apparatus may provide an innovative therapeutic strategy for colorectal cancer.
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PURPOSE: We aimed to identify new predictive biomarkers for cetuximab in first-line treatment for patients with RAS wild-type metastatic colorectal cancer (mCRC). METHODS: The study included patients with KRAS wild-type unresectable liver-limited mCRC treated with chemotherapy with or without cetuximab. Next-generation sequencing was done for single nucleotide polymorphism according to custom panel. Potential predictive biomarkers were identified and integrated into a predictive model within a training cohort. The model was validated in a validation cohort. RESULTS: Thirty-one of 247(12.6%) patients harbored RAS mutations. In training cohort (N=93), six potential predictive genes, namely, ATP6V1B1, CUL9, ERBB2, LY6G6D, PTCH1, and RBMXL3, were identified. According to predictive model, patients were divided into responsive group (n=66) or refractory group (n=27). In responsive group, efficacy outcomes were significantly improved by addition of cetuximab to chemotherapy. In refractory group, no benefit was observed. Interaction test was significant across all endpoints. In validation cohort (N=123), similar results were also observed. CONCLUSIONS: In the first-line treatment of mCRC, the predictive model integrating six new predictive mutations divided patients well, indicating a promising approach to further refine patient selection for cetuximab on the basis of RAS mutations.
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An increasing number of studies have demonstrated that circular RNAs (circRNAs) can regulate gene expression through interacting with microRNAs. In this study, we analyzed the expression of antisense to CDR1as in colorectal cancer (CRC). CDR1as had a higher expression in CRC tissues compared to adjacent, normal mucosa and was positively associated with tumor size, T stage, lymph node metastasis, and poor overall survival (OS). Downregulation of CDR1as suppressed CRC cell proliferation and invasion and increased microRNA-7 (miR-7) expression. Intriguingly, ectopic expression of miR-7 in CRC cells consistently inhibited proliferation and invasion, and the miR-7 inhibitor was able to rescue the function of CDR1as knockdown. Mechanistic studies demonstrated that CDR1as silencing suppressed EGFR and IGF-1R expression, which could be partially blocked by the miR-7 inhibitor. Finally, positive correlations between CDR1as expression and EGFR and IGF-1R expression were observed in CRC samples. Thus, given the importance of CDR1as in blocking miR-7 and positively regulating EGFR and IGF-1R, dysregulated CDR1as expression may play an important role in CRC progression.
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Mist1 was recently shown to identify a discrete population of stem cells within the isthmus of the oxyntic gland within the gastric corpus. Chief cells at the base of the gastric corpus also express Mist1. The relevance of Mist1 expression as a marker of specific cell populations within the antral glands of the distal stomach, however, is unknown. Using Mist1-CreERT mice, we revealed that Mist1+ antral cells, distinct from the Mist1+ population in the corpus, comprise long-lived progenitors that reside within the antral isthmus above Lgr5+ or CCK2R+ cells. Mist1+ antral progenitors can serve as an origin of antral tumors induced by loss of Apc or MNU treatment. Mist1+ antral progenitors, as well as other antral stem/progenitor population, express Cxcr4, and are located in close proximity to Cxcl12 (the Cxcr4 ligand)-expressing endothelium. During antral carcinogenesis, there is an expansion of Cxcr4+ epithelial cells as well as the Cxcl12+ perivascular niche. Deletion of Cxcl12 in endothelial cells or pharmacological blockade of Cxcr4 inhibits antral tumor growth. Cxcl12/Cxcr4 signaling may be a potential therapeutic target.
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Myeloid-biased hematopoietic stem cells (MB-HSCs) play critical roles in recovery from injury, but little is known about how they are regulated within the bone marrow niche. Here we describe an auto-/paracrine physiologic circuit that controls quiescence of MB-HSCs and hematopoietic progenitors marked by histidine decarboxylase (Hdc). Committed Hdc+ myeloid cells lie in close anatomical proximity to MB-HSCs and produce histamine, which activates the H2 receptor on MB-HSCs to promote their quiescence and self-renewal. Depleting histamine-producing cells enforces cell cycle entry, induces loss of serial transplant capacity, and sensitizes animals to chemotherapeutic injury. Increasing demand for myeloid cells via lipopolysaccharide (LPS) treatment specifically recruits MB-HSCs and progenitors into the cell cycle; cycling MB-HSCs fail to revert into quiescence in the absence of histamine feedback, leading to their depletion, while an H2 agonist protects MB-HSCs from depletion after sepsis. Thus, histamine couples lineage-specific physiological demands to intrinsically primed MB-HSCs to enforce homeostasis.
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Medula Óssea/metabolismo , Células-Tronco Hematopoéticas/metabolismo , Histamina/metabolismo , Células Mieloides/metabolismo , Animais , Medula Óssea/efeitos dos fármacos , Transplante de Medula Óssea , Citometria de Fluxo , Células-Tronco Hematopoéticas/efeitos dos fármacos , Lipopolissacarídeos/farmacologia , Camundongos , Células Mieloides/efeitos dos fármacosRESUMO
Norcantharidin (NCTD) is an efficacious anti-cancer drug that has been used in China for many years, but its underlying mechanism of action is still not fully understood. In the present study, we found that NCTD could induce morphological changes in colon cancer cells, causing a transition from a spindle-shaped morphology to a typical round or oval shape, which was indicative of a mesenchymal-epithelial transition (MET) process. Next, we investigated the mechanism by which NCTD induced the MET process. Using a transwell assay, we found that NCTD could suppress the migratory and invasive ability of colon cancer cells in a dose-dependent manner. Moreover, NCTD suppressed the expression of integrin αvß6, MMP-3, and MMP-9 as well as the polymerization of F-actin, further supporting its suppressive effect on migratory and invasive ability. Furthermore, the expression of αvß6, N-cadherin, vimentin and phosphorylated ERK was decreased, while the expression of E-cadherin was up-regulated. We verified that phosphorylated Ets1 was down-regulated substantially after treatment with NCTD. Taken together, our data demonstrated that NCTD could inhibit the EMT process of colon cancer cells by inhibiting the αvß6-ERK-Ets1 signaling pathway. This study revealed part of the mechanism through which NCTD could reverse the EMT process in colon cancer.