scholarly journals NE/β2-AR Promotes Directional Migration of Colorectal Cancer Cells to the Liver by Inducing M2 Polarization of Kupffer Cells and Upregulating CXCL12 Expression

2021 ◽  
Author(s):  
Xiaoyan Li ◽  
Na Yuan ◽  
Ce Zhou ◽  
Jie Zhi ◽  
Yang Li ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Colon Cancer ◽  
Liver Metastasis ◽  
Mouse Models ◽  
Akt Pathway ◽  
Control Group ◽  
Directional Migration ◽  
Cxcl12 Expression ◽  
M2 Polarization

Abstract Background and Aim The exact mechanism of colorectal cancer (CRC) liver metastasis remains unclear. This study aimed to explore the role and mechanism of the norepinephrine (NE) in the directional migration of CRC cells to the liver.Methods In mouse models of CRC liver metastasis, the effects of NE on the number of liver metastases and the density of intrahepatic Kupffer cells (KCs) were observed. In vitro experiments were performed to detect KC polarization markers by flow cytometry, cytokines by enzyme-linked immunosorbent assay (ELISA), migration of colon cancer cells by Transwell migration assay, AR expression and PI3K/Akt signaling pathway-related protein expressions by Western blotting, and chemokine mRNA expressions by reverse transcription-polymerase chain reaction (RT-PCR).Results Two weeks after intraperitoneal injection of different doses of NE in CRC liver metastasis mouse models, the number of liver metastases were (111.00±51.43) and (102.40±54.85) in the low-dose (0.28 nmol) NE group and high-dose groups (2.8 nmol), respectively, which were significantly higher than those in the control group (both P＜0.05); in addition, the density of intrahepatic KCs in the NE group was significantly reduced compared with the control group (P<0.05). In vitro experiments showed that low-concentration NE induced M2 polarization of KCs; NE upregulated the expression level of NE receptor β2-AR on KCs and activated the PI3K/Akt pathway, while blocking β2-AR or using a PI3K inhibitor inhibited this process (P< 0.05). M2 KCs promoted the migration of colon cancer cell line CT26. Eight macrophage-associated chemokines were screened from the TISIDB website. CXCL12 expression in KCs was significantly higher in low-concentration (10-9 M) NE group than in controls, and a β2-AR blocker down-regulated CXCL12 expression in KCs (both P < 0.05).Conclusions NE/β2-AR may induce intrahepatic KC M2 polarization through the PI3K/Akt pathway and promote its secretion of CXCL12 to induce the directional migration of CRC to the liver. Our findings provide important evidence in the search for new strategies to prevent liver metastasis from CRC.

scholarly journals Cell-Free Supernatant Odoribacter splanchnicus Isolated From Human Feces Exhibits Anti-colorectal Cancer Activity

2021 ◽  
Vol 12 ◽  
Author(s):  
Byeong Seob Oh ◽  
Won Jung Choi ◽  
Ji-Sun Kim ◽  
Seoung Woo Ryu ◽  
Seung Yeob Yu ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Colon Cancer ◽  
Mouse Model ◽  
Proliferative Activity ◽  
Control Group ◽  
Healthy Individuals ◽  
Gut Microbes ◽  
Cancer Activity

The gut microbiota (GM) has been shown to be closely associated with the development of colorectal cancer (CRC). However, the involvement of GM is CRC has mainly been demonstrated by metagenomic profiling studies showing the compositional difference between the GM of healthy individuals and that of CRC patients and not by directly studying isolated gut microbes. Thus, to discover novel gut microbes involved in CRC, we isolated the GM from the feces of healthy individuals and evaluated its anti-CRC activity in vitro and in vivo. After GM isolation, cell-free supernatants (CFSs) were prepared from the isolated gut microorganisms to efficiently screen a large amount of the GM for anti-proliferative ability in vitro. Our results showed that the CFSs of 21 GM isolates had anti-proliferative activity against human colon cancer HCT 116 cells. Of these 21 GM isolates, GM07 was chosen for additional study because it had the highest anti-cancer activity against mouse colon cancer CT 26 cells in vitro and was further evaluated in a CT 26 allograft mouse model in vivo. GM07 was identified as Odoribacter splanchnicus through phylogenetic analysis based on 16S rRNA gene sequencing. Further investigation determined that the CFS of O. splanchnicus (OsCFS) induced anti-proliferative activity via apoptosis, but not cell cycle arrest. Moreover, GC/MS analysis suggested that the putative active molecule in OsCFS is malic acid. Finally, in the CRC mouse model, peri-tumoral injection of OsCFS significantly decreased CRC formation, compared to the control group. Altogether, these findings will provide valuable information for the discovery of potential probiotic candidates that inhibit CRC.

scholarly journals LncRNA MIR17HG promotes colorectal cancer liver metastasis by mediating a glycolysis-associated positive feedback circuit

Oncogene ◽  
2021 ◽  
Author(s):  
Senlin Zhao ◽  
Bingjie Guan ◽  
Yushuai Mi ◽  
Debing Shi ◽  
Ping Wei ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Liver Metastasis ◽  
Positive Feedback ◽  
Feedback Loop ◽  
Metastatic Tumor ◽  
Feedback Circuit ◽  
Colorectal Cancer Liver Metastasis ◽  
Positive Feedback Circuit

AbstractGlycolysis plays a crucial role in reprogramming the metastatic tumor microenvironment. A series of lncRNAs have been identified to function as oncogenic molecules by regulating glycolysis. However, the roles of glycolysis-related lncRNAs in regulating colorectal cancer liver metastasis (CRLM) remain poorly understood. In the present study, the expression of the glycolysis-related lncRNA MIR17HG gradually increased from adjacent normal to CRC to the paired liver metastatic tissues, and high MIR17HG expression predicted poor survival, especially in patients with liver metastasis. Functionally, MIR17HG promoted glycolysis in CRC cells and enhanced their invasion and liver metastasis in vitro and in vivo. Mechanistically, MIR17HG functioned as a ceRNA to regulate HK1 expression by sponging miR-138-5p, resulting in glycolysis in CRC cells and leading to their invasion and liver metastasis. More interestingly, lactate accumulated via glycolysis activated the p38/Elk-1 signaling pathway to promote the transcriptional expression of MIR17HG in CRC cells, forming a positive feedback loop, which eventually resulted in persistent glycolysis and the invasion and liver metastasis of CRC cells. In conclusion, the present study indicates that the lactate-responsive lncRNA MIR17HG, acting as a ceRNA, promotes CRLM through a glycolysis-mediated positive feedback circuit and might be a novel biomarker and therapeutic target for CRLM.

scholarly journals Farnesyl dimethyl chromanol targets colon cancer stem cells and prevents colorectal cancer metastasis

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Kazim Husain ◽  
Domenico Coppola ◽  
Chung S. Yang ◽  
Mokenge P. Malafa
Keyword(s):  
Colorectal Cancer ◽  
Colon Cancer ◽  
Cancer Metastasis ◽  
Annexin V ◽  
Cancer Cell Growth ◽  
Ki 67 ◽  
Sox2 Expression ◽  
Tumour Metastasis

AbstractThe activation and growth of tumour-initiating cells with stem-like properties in distant organs characterize colorectal cancer (CRC) growth and metastasis. Thus, inhibition of colon cancer stem cell (CCSC) growth holds promise for CRC growth and metastasis prevention. We and others have shown that farnesyl dimethyl chromanol (FDMC) inhibits cancer cell growth and induces apoptosis in vitro and in vivo. We provide the first demonstration that FDMC inhibits CCSC viability, survival, self-renewal (spheroid formation), pluripotent transcription factors (Nanog, Oct4, and Sox2) expression, organoids formation, and Wnt/β-catenin signalling, as evidenced by comparisons with vehicle-treated controls. In addition, FDMC inhibits CCSC migration, invasion, inflammation (NF-kB), angiogenesis (vascular endothelial growth factor, VEGF), and metastasis (MMP9), which are critical tumour metastasis processes. Moreover, FDMC induced apoptosis (TUNEL, Annexin V, cleaved caspase 3, and cleaved PARP) in CCSCs and CCSC-derived spheroids and organoids. Finally, in an orthotopic (cecum-injected CCSCs) xenograft metastasis model, we show that FDMC significantly retards CCSC-derived tumour growth (Ki-67); inhibits inflammation (NF-kB), angiogenesis (VEGF and CD31), and β-catenin signalling; and induces apoptosis (cleaved PARP) in tumour tissues and inhibits liver metastasis. In summary, our results demonstrate that FDMC inhibits the CCSC metastatic phenotype and thereby supports investigating its ability to prevent CRC metastases.

PGM1 Suppresses Colorectal Cancer Cell Migration And Invasion by Regulating PI3K/ AKT Pathway

2021 ◽  
Author(s):  
Zhewen Zheng ◽  
Xue Zhang ◽  
Jian Bai ◽  
Long Long ◽  
Di Liu ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cell Cycle ◽  
Colony Formation ◽  
Tumor Formation ◽  
Akt Pathway ◽  
Migration And Invasion ◽  
Cycle Arrest ◽  
Cancer Pathogenesis

Abstract BackgroundPhosphoglucomutase 1(PGM1) is known for its involvement in cancer pathogenesis. However, its biological role in colorectal cancer (CRC) is unknown. Here, we studied the functions and mechanisms of PGM1 in CRC.Methods We verified PGM-1 as a DEG by a comprehensive strategy of the TCGA-COAD dataset mining and computational biology. Relative levels of PGM-1 in CRC tumors and adjoining peritumoral tissue were identified by qRT-PCR, WB, and IHC staining in a tissue microarray. PGM1 functions were analyzed using CCK8, EdU, colony formation, cell cycle, apoptosis, and Transwell migration and invasion assays. The influence of PGM1 was further investigated using tumor formation in vivo.ResultsPGM1 mRNA and protein were both reduced in CRC and the reduction was related to CRC pathology and overall survival. PGM1 knockdown stimulated both proliferation and colony formation, promoting cell cycle arrest and apoptosis while overexpression has opposite effects in CRC cells both in vivo and in vitro. Furthermore, we lined the actions of PGM1 to the PI3K/ AKT pathway. ConclusionWe verified that PGM1 suppresses CRC through the PI3K/ AKT pathway. These results suggest the potential for targeting PGM1 in CRC therapies.

scholarly journals Analysis of Co-Expression Module of Liver Metastasis Genes in Colorectal Cancer and Mining of Potential High-Expression Biomarkers

2021 ◽  
Author(s):  
Xuehu Wang ◽  
Nie Li ◽  
Yun Wang ◽  
Xiaoping Yin ◽  
Yongchang Zheng
Keyword(s):  
Colorectal Cancer ◽  
Colon Cancer ◽  
Liver Metastasis ◽  
High Expression ◽  
Data Set ◽  
Colorectal Cancer Liver Metastasis ◽  
Functional Annotations ◽  
Public Data ◽  
Highly Correlated ◽  
Expression Module

Abstract AimsThe Hub genes highly related to the disease were found from the gene co-expression module, and the potential high expression genes were analyzed to predict the liver metastasis of colorectal cancer, so as to provide reference for subsequent targeted therapy.MethodsIn this study, we used the public data set of GEO database (GSE50760) to analyze the gene co-expression of liver metastasis of colon cancer, primary colon cancer and normal colon tissue (54 cases) and 50 cases of clinical cases. The functional annotations based on GO database are enriched, and the functional annotations of five gene modules are obtained through the enrichment of biological processes. Then the data mining is carried out to find the sub-networks with high adjacency in the gene co-expression network. At the same time, these sub-networks are annotated to find oncogenes related to liver metastasis of colorectal cancer.ResultsThis experiment found that KRAS, APC, FBXW7, PIK3CA, TP53 were highly correlated with liver metastasis of colorectal cancer. Finally, two protein genes STAT1 and MAPK1 were found by MCODE, which may be highly correlated with liver metastasis of colorectal cancer. Two new genes with high expression proteins found in this experiment have potential cancer, which has not been reflected in previous studies.ConclusionAccording to clinical data, KRAS, APC, FBXW7, PIK3CA, TP53 are related to colorectal cancer liver metastasis, and the analysis of the data set shows that STAT1 and MAPK1 are not only related to colorectal cancer liver metastasis oncogene but also related to clinically obtained genes.

Schisandrin B Attenuates Colitis-Associated Colorectal Cancer through SIRT1 Linked SMURF2 Signaling

2021 ◽  
pp. 1-17
Author(s):  
Zhichen Pu ◽  
Weiwei Zhang ◽  
Minhui Wang ◽  
Maodi Xu ◽  
Haitang Xie ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Colon Cancer ◽  
Cell Growth ◽  
Protein Expression ◽  
Hct116 Cell ◽  
Enzyme Linked Immunosorbent Assay ◽  
Schisandrin B ◽  
In Vivo Models

Colon cancer, a common type of malignant tumor, seriously endangers human health. However, due to the relatively slow progress in diagnosis and treatment, the clinical therapeutic technology of colon cancer has not been substantially improved in the past three decades. The present study was designed to investigate the effects and involved mechanisms of schisandrin B in cell growth and metastasis of colon cancer. C57BL/6 mice received AOM and dextran sulfate sodium. Mice in treatment groups were gavaged with 3.75–30 mg/kg/day of schisandrin B. Transwell chamber migration, enzyme-linked immunosorbent assay (ELISA), Western blot analysis, immunoprecipitation (IP) and immunofluorescence were conducted, and HCT116 cell line was employed in this study. Data showed that schisandrin B inhibited tumor number and tumor size in the AOD+DSS-induced colon cancer mouse model. Schisandrin B also inhibited cell proliferation and metastasis of colon cancer cells. We observed that schisandrin B induced SMURF2 protein expression and affected SIRT1 in vitro and in vivo. SMURF2 interacted with SIRT1 protein, and there was a negative correlation between SIRT1 and SMURF2 expressions in human colorectal cancer. The regulation of SMURF2 was involved in the anticancer effects of schisandrin B in both in vitro and in vivo models. In conclusion, the present study revealed that schisandrin B suppressed SIRT1 protein expression, and SIRT1 is negatively correlated with the induction of SMURF2, which inhibited cell growth and metastasis of colon cancer. Schisandrin B could be a leading compound, which will contribute to finding novel potential agents and therapeutic targets for colon cancer.

scholarly journals Lemongrass Extract Possesses Potent Anticancer Activity Against Human Colon Cancers, Inhibits Tumorigenesis, Enhances Efficacy of FOLFOX, and Reduces Its Adverse Effects

2019 ◽  
Vol 18 ◽  
pp. 153473541988915 ◽  
Author(s):  
Ivan Ruvinov ◽  
Christopher Nguyen ◽  
Benjamin Scaria ◽  
Caleb Vegh ◽  
Ola Zaitoon ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Colon Cancer ◽  
Anticancer Activity ◽  
Cancer Cells ◽  
Human Colon ◽  
Dependent Manner ◽  
Anticancer Efficacy ◽  
Colon Cancers ◽  
Induced Apoptosis

Current chemotherapeutics for metastatic colorectal cancers have limited success and are extremely toxic due to nonselective targeting. Some natural extracts have been traditionally taken and have shown anticancer activity. These extracts have multiple phytochemicals that can target different pathways selectively in cancer cells. We have shown previously that lemongrass ( Cymbopogon citratus) extract is effective at inducing cell death in human lymphomas. However, the efficacy of lemongrass extract on human colorectal cancer has not been investigated. Furthermore, its interactions with current chemotherapies for colon cancer is unknown. In this article, we report the anticancer effects of ethanolic lemongrass extract in colorectal cancer models, and importantly, its interactions with FOLFOX and Taxol. Lemongrass extract induced apoptosis in colon cancer cells in a time and dose-dependent manner without harming healthy cells in vitro. Oral administration of lemongrass extract was well tolerated and effective at inhibiting colon cancer xenograft growth in mice. It enhanced the anticancer efficacy of FOLFOX and, interestingly, inhibited FOLFOX-related weight loss in animals given the combination treatment. Furthermore, feeding lemongrass extract to APCmin/+ transgenic mice led to the reduction of intestinal tumors, indicating its preventative potential. Therefore, this natural extract has potential to be developed as a supplemental treatment for colorectal cancer.

scholarly journals Taurine Attenuates Carcinogenicity in Ulcerative Colitis-Colorectal Cancer Mouse Model

2020 ◽  
Vol 2020 ◽  
pp. 1-7 ◽  
Author(s):  
Guifeng Wang ◽  
Ning Ma ◽  
Feng He ◽  
Shosuke Kawanishi ◽  
Hatasu Kobayashi ◽  
...  
Keyword(s):  
Colon Cancer ◽  
Drinking Water ◽  
Mouse Model ◽  
Histopathological Examination ◽  
Tumor Formation ◽  
Water Model ◽  
Control Group ◽  
Ki 67

Taurine (2-aminoethane-sulfonic acid) is a type of amino acids and has numerous physiological and therapeutic functions, including anti-inflammation. However, there are few studies on the anticancer action of taurine. Our previous studies have demonstrated that taurine exhibits an apoptosis-inducing effect on human nasopharyngeal carcinoma cells in vitro. In this study, we have investigated whether taurine has an anticancer effect, using azoxymethane (AOM)/sulfate sodium (DSS)- induced mouse model for colon carcinogenesis. All mice, except those in control group, received a single intraperitoneal injection of AOM and DSS in the drinking water for 7 days twice, with 1-week interval. After the first DSS treatment, mice were given distilled water (model group) or taurine in the drinking water (taurine group) ad libitum. No tumor was observed in the control group. Taurine significantly suppressed AOM+DSS-induced tumor formation. Histopathological examination revealed AOM/DSS treatment induced colon cancer in all mice (8/8, 100%), and taurine significantly inhibited the progression of colon cancer (4/9, 44.4%). Taurine significantly attenuated cell proliferation in cancer tissues detected by Ki-67 staining. Taurine significantly increased the levels of an apoptosis marker cleaved caspase-9 and tumor suppressor protein PTEN. This is the first study that demonstrated that taurine significantly reduced carcinogenicity in vivo using AOM/DSS-induced colon cancer mouse model.

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