scholarly journals An Integrative Omics Approach Reveals Involvement of BRCA1 in Hepatic Metastatic Progression of Colorectal Cancer

Cancers ◽  
2020 ◽  
Vol 12 (9) ◽  
pp. 2380
Author(s):  
Daniela Gerovska ◽  
Gorka Larrinaga ◽  
Jon Danel Solano-Iturri ◽  
Joana Márquez ◽  
Patricia García Gallastegi ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Endothelial Cells ◽  
Liver Metastasis ◽  
Protein Expression ◽  
Liver Metastases ◽  
Liver Cells ◽  
Differentially Expressed ◽  
Sinusoidal Endothelial Cells ◽  
Ito Cells ◽  
Brca1 Protein

(1) Background & Aims: The roles of different cells in the tumor microenvironment (TME) are critical to the metastatic process. The phenotypic transformation of the liver cells is one of the most important stages of the hepatic metastasis progression of colorectal cancer (CRC). Our aim was to identify the major molecules (i.e., genes, miRNAs and proteins) involved in this process. (2) Methods: We isolated and performed whole-genome analysis of gene, miRNA, and protein expression in three types of liver cells (Ito cells, Kupffer cells, and liver sinusoidal endothelial cells) from the TME of a murine model of CRC liver metastasis. We selected the statistically significant differentially expressed molecules using the Student’s t-test with Benjamini-Hochberg correction and performed functional statistically-significant enrichment analysis of differentially expressed molecules with hypergeometric distribution using the curated collection of molecular signatures, MSigDB. To build a gene-miRNA-protein network centered in Brca1, we developed a software package (miRDiana) that collects miRNA targets from the union of the TargetScan, MicroCosm, mirTarBase, and miRWalk databases. This was used to search for miRNAs targeting Brca1. We validated the most relevant miRNAs with real-time quantitative PCR. To investigate BRCA1 protein expression, we built tissue microarrays (TMAs) from hepatic metastases of 34 CRC patients. (3) Results: Using integrated omics analyses, we observed that the Brca1 gene is among the twenty transcripts simultaneously up-regulated in all three types of TME liver cells during metastasis. Further analysis revealed that Brca1 is the last BRCA1-associated genome surveillance complex (BASC) gene activated in the TME. We confirmed this finding in human reanalyzing transcriptomics datasets from 184 patients from non-tumor colorectal tissue, primary colorectal tumor and colorectal liver metastasis of the GEO database. We found that the most probable sequence of cell activation during metastasis is Endothelial→Ito→Kupffer. Immunohistochemical analysis of human liver metastases showed the BRCA1 protein was co-localized in Ito, Kupffer, and endothelial cells in 81.8% of early or synchronous metastases. However, in the greater part of the metachronous liver metastases, this protein was not expressed in any of these TME cells. (4) Conclusions: These results suggest a possible role of the co-expression of BRCA1 in Ito, Kupffer, and sinusoidal endothelial cells in the early occurrence of CRC liver metastases, and point to BRCA1 as a potential TME biomarker.

scholarly journals Construction and Prognostic Analysis of miRNA-mRNA Regulatory Network in Liver Metastasis from Colorectal Cancer

2020 ◽  
Author(s):  
Ruyun Cai ◽  
Qian Lu ◽  
Da Wang
Keyword(s):  
Colorectal Cancer ◽  
Liver Metastasis ◽  
Liver Metastases ◽  
Immune Cells ◽  
Interaction Analysis ◽  
Enrichment Analysis ◽  
Functional Enrichment ◽  
Differentially Expressed ◽  
Mesenchymal Transition ◽  
Prognostic Analysis

Abstract Background: Colorectal cancer (CRC) is one of the most common cancers in the world, and liver metastasis is the leading cause of colorectal cancer-related deaths. However, the mechanism of liver metastasis in CRC hasn’t been clearly elucidated.Methods: Three datasets from the Gene Expression Omnibus (GEO) database were analyzed to obtain differentially expressed genes (DEGs), which were subjected to functional enrichment analysis and protein-protein interaction analysis. Subsequently, mRNA-miRNA network was constructed and the associated DEGs and DEMs were performed for prognostic analysis. Finally, we did infiltration analysis of GAS1-associated immune cells. Results: We obtained 325 DEGs and 9 differentially expressed miRNAs (DEMs) between primary CRC and liver metastases. Enrichment analysis and protein-protein interactions (PPI) further revealed the involvement of DEGs in the formation of the inflammatory microenvironment and epithelial-mesenchymal transition (EMT) during the liver metastases process in CRC. Survival analysis demonstrated that low-expressed GAS1 as well as low-expressed hsa-miR-33b-5p was a favorable prognostic indicator of overall survival. Further exploration of GAS1 revealed that its expression was interrelated with the infiltration of immune cells in tumor tissues. Conclusions: In summary, DEGs, DEMs and their interactions found in liver metastasis of CRC may provide a basis for further understanding of the mechanism of CRC metastasis.

scholarly journals Construction and prognostic analysis of miRNA-mRNA regulatory network in liver metastasis from colorectal cancer

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Ruyun Cai ◽  
Qian Lu ◽  
Da Wang
Keyword(s):  
Colorectal Cancer ◽  
Liver Metastasis ◽  
Liver Metastases ◽  
Immune Cells ◽  
Interaction Analysis ◽  
Enrichment Analysis ◽  
Functional Enrichment ◽  
Differentially Expressed ◽  
Mesenchymal Transition ◽  
Prognostic Analysis

Abstract Background Colorectal cancer (CRC) is one of the most common cancers in the world, and liver metastasis is the leading cause of colorectal cancer-related deaths. However, the mechanism of liver metastasis in CRC has not been clearly elucidated. Methods Three datasets from the Gene Expression Omnibus (GEO) database were analyzed to obtain differentially expressed genes (DEGs), which were subjected to functional enrichment analysis and protein-protein interaction analysis. Subsequently, mRNA-miRNA network was constructed, and the associated DEGs and DEMs were performed for prognostic analysis. Finally, we did infiltration analysis of growth arrest specific 1 (GAS1)-associated immune cells. Results We obtained 325 DEGs and 9 differentially expressed miRNAs (DEMs) between primary CRC and liver metastases. Enrichment analysis and protein-protein interactions (PPI) further revealed the involvement of DEGs in the formation of the inflammatory microenvironment and epithelial-mesenchymal transition (EMT) during the liver metastases process in CRC. Survival analysis demonstrated that low-expressed GAS1 as well as low-expressed hsa-miR-33b-5p was a favorable prognostic indicator of overall survival. Further exploration of GAS1 revealed that its expression was interrelated with the infiltration of immune cells in tumor tissues. Conclusions In summary, DEGs, DEMs, and their interactions found in liver metastasis of CRC may provide a basis for further understanding of the mechanism of CRC metastasis.

Mass Spectrometry-based Label-free Quantitative Proteomic Analysis of CCl4-induced Acute Liver Injury in Mice Intervened by Total Glycosides from Ligustri Lucidi Fructus

2020 ◽  
Vol 17 ◽  
Author(s):  
Qian Lu ◽  
Hai-Zhu Xing ◽  
Nian-Yun Yang
Keyword(s):  
Insulin Resistance ◽  
Liver Injury ◽  
Protein Expression ◽  
Signaling Pathway ◽  
Proteomic Analysis ◽  
Acute Liver Injury ◽  
Liver Cells ◽  
Differentially Expressed ◽  
Liver Protein ◽  
Differentially Expressed Proteins

Background: CCl4 acute liver injury (ALI) is a classical model for experimental research. However, there are few reports involved in the fundamental research of CCl4-induced ALI Ligustri Lucidi Fructus (LLF) are and its prescription have been used to treat hepatitis illness clinically. LLF and its active ingredients displayed anti-hepatitis effects, but the mechanism of function has not been fully clarified Objective: To investigate the proteomic analysis of CCl4-induced ALI, and examine the effects of active total glycosides (TG) from LLF on ALI of mice4, including histopathological survey and proteomic changes of liver tissues, and delineate the possible underlying mechanism. Methods: CCl4 was used to produce ALI mice model. The model mice were intragastrically administrated with TG and the liver his-topathological changes of mice were examined. At the end of test, mice liver samples were collected, after protein denaturation, re-duction, desalination and enzymatic hydrolysis, identification was carried out by nano LC-ESI-OrbiTrap MS/MS technology. The data was processed by Maxquant software. The differentially-expressed proteins were screened and identified, and their biological information was also analyzed based on GO and KEGG analysis. Key protein expression was validated by Western blot analysis Results: A total of 705 differentially-expressed proteins were identified during the normal, model and administration group. 9 signifi-cant differential proteins were focused based on analysis. Liver protein expression changes of CCl4-induced ALI mice were mainly involved in several important signal channels, namely FoxO signaling pathway, autophagy-animal, insulin signaling pathway. TG has anti-liver damnification effect in ALI mice, the mechanism of which is related to FoxO1 and autophagy pathways Conclusion: CCl4 inhibited expression of insulin-Like growth factor 1 (Igf1) and 3-phosphoinositide-dependent protein kinase 1 (Pdpk1) in liver cells and induced insulin resistance, thus interfered with mitochondrial autophagy and regeneration of liver cells and the metabolism of glucose and lipid, and caused hepatic necrosis in mice. TG resisted liver injury in mice. TG adjusted the expression level of key proteins Igf1 and Pdpk1 after liver injury and improved insulin resistance, thus promoted autophagy and resisted the liver damage

Evaluation of Histopathological Heterogeneity After Preoperative Chemotherapy in Patients With Liver Metastases from Colorectal Cancer

2021 ◽  
Author(s):  
Nobuhisa matsuhashi ◽  
Hiroyuki Tomita ◽  
Takazumi Kato ◽  
Yoshinori Iwata ◽  
Satoshi Matsui ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Liver Metastasis ◽  
Liver Metastases ◽  
Surgical Oncology ◽  
Resected Specimen ◽  
Histopathological Changes ◽  
School Of Medicine ◽  
Response To Chemotherapy ◽  
Grade 3 ◽  
The Right

Abstract Background: Patients with liver metastases from colorectal cancer (CRLMs) frequently receive chemotherapy prior to liver resection. Histopathological assessment of the resected specimen can evaluate the response to chemotherapy. This study analyzed the correlation between histopathological changes in the primary site and liver metastases. Patients and Methods: This study comprised 45 patients with resectable CRLMs at the Surgical Oncology Department of Gifu University School of Medicine from January 2006 to August 2015. Results: The study included 24 men and 21 women. The primary colonic tumor was located in the right side in 13 (28.9%) patients and the left side in 32 (71.9%) patients. We evaluated patients with metastatic colorectal cancer (31/45) after excluding those in whom histopathological heterogeneity between the primary and liver metastasis changed to grade 3 after chemotherapy. We compared the group which underwent hepatectomy after chemotherapy (n=25) with that underwent hepatectomy alone (n=6). In 16 (53.3%) out of 25 patients, histopathological heterogeneity of the liver metastasis was lost (p=0.04). Conclusion: Chemotherapy appears to change histopathological heterogeneity.Our study suggests that the change of intratumoral heterogeneity reflect by the response of chemotherapy.

scholarly journals Genome-Wide Scan for Copy Number Alteration Association with Relapse-Free Survival in Colorectal Cancer with Liver Metastasis Patients

2018 ◽  
Vol 7 (11) ◽  
pp. 446 ◽  
Author(s):  
Po-Sheng Yang ◽  
Hsi-Hsien Hsu ◽  
Tzu-Chi Hsu ◽  
Ming-Jen Chen ◽  
Cin-Di Wang ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Liver Metastasis ◽  
Liver Metastases ◽  
Copy Number ◽  
Copy Number Alteration ◽  
Gene Signature ◽  
Comparative Genomic ◽  
Relapse Free Survival ◽  
Cgh Array ◽  
Free Survival

Predicting a patient’s risk of recurrence after the resection of liver metastases from colorectal cancer is critical for evaluating and selecting therapeutic approaches. Clinical and pathologic parameters have shown limited accuracy thus far. Therefore, we combined the clinical status with a genomic approach to stratify relapse-free survival in colorectal cancer liver metastases patients. To identify new molecular and genetic signatures specific to colorectal cancer with liver metastasis (CRCLM) patients, we conducted DNA copy number profiling on a cohort of 21 Taiwanese CRCLM patients using a comparative genomic hybridization (CGH) array. We identified a three-gene signature based on differential copy number alteration between patients with different statuses of (1) recurrence and (2) synchronous metastasis. In relapse hotspot regions, only three genes (S100PBP, CSMD2, and TGFBI) were significantly associated with the synchronous liver metastasis factor. A final set of three genes—S100PBP, CSMD2, TGFBI—significantly predicted relapse-free survival in our cohort (p = 0.04) and another CRCLM cohort (p = 0.02). This three-gene signature is the first genomic signature validated for relapse-free survival in post-hepatectomy CRCLM patients. Our three-gene signature was developed using a whole-genome CGH array and has a good prognostic position for the relapse-free survival of CRCLM patients after hepatectomy.

A grading system for predicting the prognosis of gastric cancer with liver metastasis

2021 ◽  
Author(s):  
Soshi Hori ◽  
Michitaka Honda ◽  
Hiroshi Kobayashi ◽  
Hidetaka Kawamura ◽  
Koichi Takiguchi ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Gastric Cancer ◽  
Overall Survival ◽  
Liver Metastasis ◽  
Confidence Interval ◽  
Liver Metastases ◽  
Hazard Ratio ◽  
Maximum Diameter ◽  
Grading System ◽  
Computed Tomography Images

Abstract Objective The prognosis of patients with liver metastases from gastric cancer is determined using tumor size and number of metastases; this is similar to the factors used for the prediction of liver metastases from colorectal cancer. The relationship between the degree of liver metastasis from gastric cancer and prognosis with reference to the classification of liver metastasis from colorectal cancer was investigated. Methods This was a multi-institutional historical cohort study. Among patients with stage IV gastric cancer, who visited the cancer hospitals in Fukushima Prefecture, Japan, between 2008 and 2015, those with simultaneous liver metastasis were included. Abdominal pretreatment computed tomography images were reviewed and classified into H1 (four or less liver metastases with a maximum diameter of ≤5 cm); H2 (other than H1 and H3) or H3 (five or more liver metastases with a maximum diameter of ≥5 cm). The hazard ratio for overall survival according to the H grade (H1, H2 and H3) was calculated using the Cox proportional hazards model. Results A total of 412 patients were analyzed. Patients with H1, H2 and H3 grades were 118, 162 and 141, respectively, and their median survival time was 10.2, 5.7 and 3.1 months, respectively (log-rank P < 0.001). The adjusted hazard ratio for overall survival was H1: H2: H3 = reference: 1.39 (95% confidence interval: 1.04–1.85): 1.69 (95% confidence interval: 1.27–2.27). Conclusions The grading system proposed in this study was a simple and easy-to-use prognosis prediction index for patients with liver metastasis from gastric cancer.

scholarly journals Assessment of colorectal liver metastasis: results of the Dutch Colorectal Cancer Group (DCCG) liver metastases expert panel of the CAIRO5 study

HPB ◽  
2019 ◽  
Vol 21 ◽  
pp. S802-S803
Author(s):  
J. Huiskens ◽  
P.B. Olthof ◽  
A. Keijser ◽  
K.P. van Lienden ◽  
M.R. Engelbrecht ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Liver Metastasis ◽  
Liver Metastases ◽  
Colorectal Liver Metastasis ◽  
Expert Panel ◽  
Cancer Group

scholarly journals The Impact of miRNA in Colorectal Cancer Progression and Its Liver Metastases

2018 ◽  
Vol 19 (12) ◽  
pp. 3711 ◽  
Author(s):  
Ovidiu Balacescu ◽  
Daniel Sur ◽  
Calin Cainap ◽  
Simona Visan ◽  
Daniel Cruceriu ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Liver Metastasis ◽  
Liver Metastases ◽  
Cancer Progression ◽  
Dependent Manner ◽  
Mesenchymal Transition ◽  
Cancer Management ◽  
Incidence And Mortality ◽  
The Impact

Colorectal cancer (CRC) is one of the most commonly diagnosed malignancies with a high incidence and mortality rate. An essential challenge in colorectal cancer management is to identify new prognostic factors that could better estimate the evolution and treatment responses of this disease. Considering their role in cancer development, progression and metastasis, miRNAs have become an important class of molecules suitable for cancer biomarkers discovery. We performed a systematic search of studies investigating the role of miRNAs in colorectal progression and liver metastasis published until October 2018. In this review, we present up-to-date information regarding the specific microRNAs involved in CRC development, considering their roles in alteration of Wnt/βcatenin, EGFR, TGFβ and TP53 signaling pathways. We also emphasize the role of miRNAs in controlling the epithelial–mesenchymal transition of CRC cells, a process responsible for liver metastasis in a circulating tumor cell-dependent manner. Furthermore, we discuss the role of miRNAs transported by CRC-derived exosomes in mediating liver metastases, by preparing the secondary pre-metastatic niche and in inducing liver carcinogenesis in a Dicer-dependent manner.

Cellular Uptake of rFVIIIFc in Liver Is Primarily Contributed by Sinusoidal Endothelial Cells.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2219-2219
Author(s):  
Siyuan Tan ◽  
Kai Chen ◽  
Arjan van der Flier ◽  
Zhan Liu ◽  
David R. Light ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Factor Viii ◽  
Cellular Uptake ◽  
Kupffer Cells ◽  
Half Life ◽  
Hemophilia A ◽  
Liver Cells ◽  
Whole Body ◽  
Sinusoidal Endothelial Cells ◽  
The Impact

Abstract Abstract 2219 rFVIIIFc is a recombinant fusion protein consisting of human B-domain deleted factor VIII covalently linked to the Fc domain of IgG1. In hemophilia A patients, rFVIIIFc has been shown to display a ∼1.6-fold longer half-life than recombinant full length FVIII (Advate®) (Powell et al., 2012. Blood). This half-life extension can be attributed to a natural pathway mediated by the neonatal Fc receptor (FcRn) that re-circulates IgG molecules into the vascular system, as the long-lasting activity of rFVIIIFc is not observed in FcRn knockout mice. To identify the cell type that takes up and subsequently protects and recycles rFVIIIFc, we have recombinantly replaced the missing B-domain with a Halo tag in rFVIIIFc (rFVIIIFc-Halo) to allow visualization of the protein in the presence of fluorescently labeled Halo-ligand using confocal microscopy. Purified rFVIIIFc-Halo protein displayed similar specific activity and pharmacokinetic properties as rFVIIIFc in hemophilia A (HemA) mice, indicating that the addition of the Halo tag does not alter the functionality and the clearance mechanisms of rFVIIIFc. In quantitative whole body autoradiography studies (QWBA) in HemA mice with radiolabeled rFVIIIFc, we observed that 125I-rFVIIIFc is predominately distributed to the liver. Therefore, we selected primary liver cells isolated from HemA mice to study cellular uptake of rFVIIIFc. A co-culture of hepatocytes and non-parenchymal cells was isolated from HemA mice and prepared at a 1:1 ratio. Liver sinusoidal endothelial cells (LSECs) and Kupffer cells (KCs) in this culture were identified by fluorescently labeled antibodies to CD31 and F4/80 respectively. Both cell types effectively took up the fluorescently labeled AcLDL, confirming that the isolated LSECs and KCs retained the capacity for functional endocytosis in vitro. It was found that LSECs, as opposed to Kupffer cells or hepatocytes, are predominantly responsible for the cellular uptake of rFVIIIFc, as the localization of rFVIIIFc-Halo is apparent only in LSECs within 5 minutes after exposing 10 nM of rFVIIIFc-Halo to primary co-culture freshly isolated from HemA mice. In contrast, even with longer exposure time (up to 1 hour) and higher protein concentration (up to 40 nM), the localization of rFVIIIFc-Halo in Kupffer cells and hepatocytes still remains undetectable. Analysis of recombinant Halo-tagged factor VIII (rFVIII-Halo) yielded similar results, suggesting that the Fc-fusion does not alter the cellular uptake pathway of FVIII, which is consistent with the notion that the interaction of Fc with FcRn occurs at the intracellular level. Therefore, interestingly, both rFVIII-Halo and rFVIIIFc-Halo are internalized by LSEC that are the same cells reported to express FVIII by in situ hybridization studies (Hollestelle et al. 2001 Thromb Haemost). This study, together with recent findings that somatic cells in the liver are primarily responsible for rFVIIIFc recycling (Abstract by van der Flier et al), highlights the critical role of LSECs in the clearance of rFVIIIFc and suggests that rFVIIIFc is primarily recycled by FcRn in LSECs. The impact of VWF on the cellular uptake and recycling of the rFVIIIFc-VWF complex in liver cells may also be assessed utilizing this system. Disclosures: Tan: BiogenIdec: Employment. Chen:BiogenIdec: Employment. van der Flier:BiogenIdec: Employment. Liu:BiogenIdec: Employment. Light:biogenidec: Employment. Jiang:biogenidec: Employment.

Sign in / Sign up

Export Citation Format

Share Document